Author: Ajay Bhoyar, Senior Global Technical Manager, EW Nutrition

The global use of feed enzymes has become a central feature of efficient monogastric animal production systems. Rising feed ingredient costs, tighter margins, and increasing regulatory pressure to reduce environmental impact have all accelerated enzyme innovation. At the same time, feed mills have shifted toward higher conditioning temperatures and time in pursuit of improved pellet durability, pathogen control, and throughput. However, this creates a hostile environment for most exogenous feed enzymes, which can lose significant activity under the harsh conditions of feed processing.

Historically, enzyme manufacturers have attempted to overcome heat degradation of by coating, encapsulating, or post-pelleting liquid application (PPLA) of enzymes. While these approaches provide partial solutions, they can also have limitations, including delayed enzyme activity, uneven distribution, reduced mixing uniformity, and reliance on specialized liquid enzyme applicators.

These limitations prompted a novel direction: enzymes designed or selected to be intrinsically heat-stable, capable of surviving pelleting without protective matrices.

This article highlights recent advancements in intrinsically heat-stable xylanase technology, explains its advantages over coated and post-pelleting enzyme solutions, and outlines its practical benefits for feed manufacturers, integrators, and nutritionists operating under modern high-temperature feed pelleting conditions.

Intrinsically Thermostable Enzymes

An enzyme is considered intrinsically heat-stable when its native protein structure resists unfolding and retains catalytic activity under high temperatures associated with feed processing—typically 80–95°C for 30–90 seconds. Unlike coated enzymes that rely on external protection, intrinsically thermostable enzymes depend on their internal protein architecture for heat tolerance. Enzymes from organisms living in compost, thermal springs, and geothermal soils naturally withstand temperatures of 80–100 °C or higher. Intrinsically thermostable enzymes are often sourced from thermophiles (organisms living in hot springs and deep-sea vents) or engineered for stability. They resist denaturation (loss of shape and function) at high-temperature processing.

Storage and transport stability

Reduces the need for over-formulation or overdosing of the enzyme

Better mixing uniformity in the feed, as coating is not required

Superior and consistent post-pelleting recovery across different feed mills

Lower cost-in-use due to reliable, repeatable enzyme performance

Consistently better animal performance

Limitations of Current Thermostability Solutions

Coating / Encapsulation

A method of protecting enzymes from heat is to encapsulate or coat them with a protective coating. An ideal enzyme coating for animal feed needs to:

1. Protect the enzyme through steam conditioning (typically 85–90°C or higher) and through subsequent pelleting.

2. Release the enzyme from the coating quickly in the gastrointestinal tract of the target animal, to ensure optimum efficacy. (Gilbert and Cooney, 2007)

There is some evidence, however, suggesting that the coating of enzymes may reduce the efficacy of the product, compared to an uncoated version of the same product (Kwakkel et al., 2000).

Post-Pelleting Liquid Application (PPLA)

Post-pelleting liquid enzyme application requires sophisticated applicators to minimize the risk of uneven spraying or calibration errors, which is often not feasible in small or mid-size mills. Accurate application of the liquid enzyme, as with some other critical liquid micro-ingredients, requires specialized spraying equipment and, even then, consistency of accurate enzyme application can be an issue (Bedford and Cowieson, 2009). Research has shown that as much as 30% of the enzyme activity can be found in the pellet fines, and therefore, adding the enzyme before screening would result in a lower than expected dosage in the final feed and wastage of the enzyme product (Engelen, 1998). In some cases, adjusting the pelleting machines to the output of the PPLA’s spray nozzles to ensure a homogenous and even application of the enzyme on the pellets may reduce the overall pellet production rate, especially in big feed mills with very high throughput.

These limitations of the coated or PPLA technologies strengthen the value proposition of intrinsically heat-stable enzymes.

Nutritional and Commercial Benefits of Intrinsically Heat-Stable Xylanase

The use of intrinsically heat-stable xylanase delivers consistent nutritional benefits in poultry and swine feeds, including predictable non-starch polysaccharide (NSP) degradation, a significant increase in the metabolizable energy (ME) value of the feed, and enhanced gut health resilience supporting reduced antibiotic use.

From a commercial and operational perspective, this technology simplifies enzyme application, improves mixing uniformity, reduces formulation risk, and lowers feed cost per unit of meat or egg produced.

In-Vitro Thermal Stability Profile of Axxess XY

Axxess XY is a novel, intrinsically thermostable GH10 xylanase originating from Thermotoga maritima, a hyperthermophilic bacterium found in hydrothermal vents near volcanic grounds, and commercially it is produced by proprietary strain of Bacillus subtilis.

The superior heat stability of Axxess XY has been proven under various commercial pelleting conditions across different geographies. Axxess XY showed excellent post-pelleting recovery under commercial feed-milling conditions across varying temperatures and conditioning times (Fig. 2).

In one study, in addition to excellent post-pelleting recovery, Axxess XY also demonstrated high xylanase stability in pelleted feed over a 2-month feed storage period at>40°C, with humidity around 65%.

Conclusions

As feed mills continue to operate at higher conditioning temperatures and longer retention times, enzyme heat stability has become a critical success factor in modern feed production. Intrinsically heat-stable xylanase offers a practical and reliable solution to this challenge by maintaining enzyme activity through pelleting without the need for coatings or post-pelleting liquid application systems.

By relying on its native protein structure rather than external protection, intrinsically thermostable xylanase delivers consistent post-pelleting recovery, uniform distribution in feed, and predictable nutritional performance across different feed mills and processing conditions. This reliability translates into improved nutrient utilization, better gut health support, and reduced cost per kilogram of meat or eggs produced.

From an operational standpoint, intrinsically heat-stable xylanase simplifies enzyme application, reduces dependence on specialized equipment, and minimizes the need for over-formulation or safety margins. These advantages help feed manufacturers and integrators improve efficiency, lower risk, and achieve more consistent results, especially under demanding commercial pelleting conditions.

In summary, intrinsically heat-stable xylanase aligns well with the evolving needs of today’s feed industry, offering a robust, cost-effective, and future-ready enzyme solution for high-performance animal production systems.

References:

Bedford, M. R., and A. J. Cowieson. 2009. “Phytate and Phytase Interactions.” In Proceedings of the 17th European Symposium on Poultry Nutrition, 7–13. Edinburgh, UK.

Eeckhout, M., M. De Schrijver, and E. Vanderbeke. 1995. “The Influence of Process Parameters on the Stability of Feed Enzymes during Steam Pelleting.” In Proceedings of the 2nd European Symposium on Feed Enzymes, 163–169. Noordwijkerhout, The Netherlands.

Engelen, G. M. A. 1998. Technology of Liquid Additives in Post-Pelleting Applications. Wageningen, The Netherlands: Wageningen Institute of Animal Science.

Gilbert, T. C., and G. Cooney. 2011. “Thermostability of Feed Enzymes and Their Practical Application in the Feed Mill.” In Enzymes in Farm Animal Nutrition, 2nd ed., edited by M. R. Bedford and G. G. Partridge, 249–259. Wallingford, UK: CABI.

Kwakkel, R. P., P. L. van der Togt, and K. A. B. M. Holkenborg. 2000. “Bio-Efficacy of Two Phytase Formulations Supplemented to a Corn–Soybean Broiler Diet.” In Proceedings of the 3rd European Symposium on Feed Enzymes, 63–64. Noordwijkerhout, The Netherlands.

By Ilinca Anghelescu, Dr. Andreas Michels, Predrag Persak

Our understanding of how nutrition influences growth and resilience in poultry has greatly expanded in recent years. It is now clear that animal performance stems to a large extent from a balance between metabolism, immune function, and the gut microbiome. These systems interact continuously, and even small nutritional or environmental changes can shift the animals’ physiological response. This growing knowledge has encouraged the development of nutritional strategies and feed components that work through adaptive, non-antibiotic mechanisms. One recent proposed explanation for these responses has rapidly gained ground: hormetic modeling.

Hormetic modeling describes how small or moderate doses of nutritional components can activate beneficial adaptive responses (improved resilience or metabolic efficiency), while excessive doses become harmful. This idea parallels, largely speaking, Paracelsus’s famous principle: “The dose makes the poison.” In poultry nutrition, such hormetic patterns are well recognized in nutrients like trace elements (selenium, zinc) and specific amino acids (for example, arginine). At optimal levels, these nutrients support antioxidant defense, growth, and immune balance, whereas excessive intake may cause oxidative or metabolic stress

This review examines the hormetic principle and its application to modern poultry/swine feeding concepts, exploring how balanced nutrient design and controlled inclusion of bioactive compounds can strengthen cellular adaptation, improve stress tolerance, and enhance production efficiency.

How do AGPs actually work?

Despite AGP’s widespread historical use, the precise mechanisms by which subtherapeutic doses of antibiotics enhance animal productivity remained poorly understood. Recent advances in systems biology and mitochondrial research propose new answers, much needed to develop future advanced nutritional systems.

The traditional explanations for AGP efficacy have focused primarily on antimicrobial effects:

• reducing nutrient competition from microorganisms
• decreasing harmful bacterial metabolites
• improving gut wall morphology (thinner gut wall ➡ better nutrient absorption)
• preventing subclinical infections

However, these mechanisms alone could not fully explain why different classes of antibiotics with diverse mechanisms of action produce similar growth-promoting effects (Gutierrez-Chavez et al., 2025).

Niewold (2007) hypothesized that the primary mechanism of AGPs is non-antibiotic anti-inflammatory activity, reducing the energetic costs of chronic low-grade inflammation. Inflammation diverts nutrients from growth toward immune responses, with cytokine production (particularly IL-1β, IL-6, and TNF-α) suppressing anabolic pathways (Kogut et al., 2018). AGPs appear to selectively inhibit pro-inflammatory cytokine production without completely suppressing immune function.

A paper published in 2024 by Fernandez Miyakawa et al. proposes that antibiotics at subtherapeutic levels act primarily through mitochondrial hormesis and adaptive stress responses, and not simply through antimicrobial activity. In this model, mitochondria act as bioenergetic hubs and signaling centers. Low-dose antibiotics trigger mild mitochondrial stress, which triggers the activation of adaptive protective pathways.  This in turn induces mitokine release, leading to systemic adaptive responses improving growth, feed efficiency, and disease tolerance.

Mechanism of action in the hormetic model of AGP efficiency

Hormesis is a biphasic mechanism whereby high doses are toxic, but low doses stimulate adaptive responses and are beneficial. In the case of AGPs, Fernandez Miyakawa et al. propose that low doses stimulate growth, stress resistance, and cellular repair.

Key signaling pathways

As Bottje et al. (2006, 2009) shows, efficient animals often have mitochondrial inner membranes that are less permeable to protons and other ions, allowing for more effective coupling between electron transport and ATP synthesis, which reduces energy loss through proton leak and maximizes the production of ATP per oxygen molecule consumed. Lower membrane permeability is influenced by factors like decreased membrane surface area per protein mass, specific membrane protein content (such as adenine nucleotide translocase), and fatty acid composition in the membrane phospholipids, all contributing to a tighter barrier that prevents unregulated electron or proton flow and supports higher energetic efficiency. Such features make mitochondria in efficient species more capable of maintaining membrane integrity and ATP generation, especially when facing environmental stress, as seen in freeze-tolerant animals whose mitochondria do not undergo damaging permeability transitions under extreme conditions.

Nrf2

Many AGPs interfere with mitochondrial protein synthesis and electron transport chain. At subtherapeutic levels, they cause a mild ROS increase, which triggers the activation of redox-sensitive transcription factor Nrf2. Since Nrf2 regulates over 250 antioxidant, detoxification, and anti-inflammatory genes, the result is improved cell survival, redox balance, and tolerance to stress.

Mitokine production

Mitokines are “signaling molecules that enable communication of local mitochondrial stress to other mitochondria in distant cells and tissues” (Burtscher 2023). Through fibroblast growth factor 21 (FGF21), growth differentiation factor 15 (GDF15), adrenomedullin2 (ADM2) etc, these stress signals are released systemically and coordinate tissue-wide responses, leading to improved growth and resilience.

Inflammation and disease defense

While the negative side of antibiotic growth promoters is well researched and understood (Rahman et al., 2022), science can advance by isolating the positive effects and attempting to offer different pathways to the same benefits. One such lesson can be derived from understanding inflammation pathways and responses.

Chronic low-grade intestinal inflammation is common in modern poultry production, due to diet, microbiota shifts, high metabolic demands etc. This inflammation diverts energy from growth to immune responses.

AGPs reduce the energy costs of this inflammation in three main ways:

• Reduces inflammation through adaptive stress response
• Raising the threshold to trigger inflammation
• Promoting overall resilience, rather than simply killing pathogens

Fernandez Miyakawa et al. suggest, in this emerging model, that disease defense can operate two different actions: resistance to health challenges through reduction of the pathogen load (which is driven by the immune system and is energy costly); and overall resilience by reducing host damage without reducing the pathogen load. AGPs, the authors claim, mainly promote resilience by enhancing mitochondrial stress responses and tissue repair, i.e. more precisely:

• Direct mitochondrial stimulation in intestinal epithelial cells
• Systemic mitokine signaling coordinating organism-wide adaptive responses
• Selective microbiota modulation enhancing beneficial host-microbe interactions
• Improving resilience without immune system costs
• Metabolic optimization supporting growth and feed efficiency

In this context, “metabolic optimization” refers to the enhancement of metabolic processes within livestock or poultry to support efficient growth, feed conversion, and physiological resilience, without relying on immune-mediated pathways that are energetically costly. Scientific evidence shows that metabolic optimization involves improving nutrient assimilation, promoting more efficient energy production in tissues (such as mitochondrial ATP synthesis), and minimizing wasteful metabolic byproducts, resulting in reduced feed intake per unit of growth and better utilization of dietary nutrients (Rauw 2025, El-Hack 2025).

Function of feed additives and feed components

Feed additives and feed components in many ways represent the complete other side of the spectrum from antibiotics, but are there some features where antibiotics and feed additives come close in their functions? There is a good case to be made for certain feed additives ultimately working in the animal to achieve similar benefits to the desirable, non-medicinal usage of AGP´s. Especially with the emergent model of AGP mechanism described above, it is worth discussing how certain feed additives can support the same end goal: promoting animal resilience.

Lillejhoj et al (2018), Gutierrez-Chavez et al. (2025) and others outline the end-results such products must achieve:

• Growth performance & feed conversion efficiency
• Promotion of animal productivity under real-world conditions
• Support gut homeostasis
• Non-adverse effect on the immune system
• Reduction of oxidative stress
• Support organism in mitigation of enteric inflammatory consequences

Within the hormetic model, possibly the most important systemic benefit is, in one phrase, promoting resilience. Phytomolecules have long been used, in human and animal medicine, for the same end goal. The mechanisms described below should naturally be seen with caution, as phytomolecule microbiome effects can be subtler and context-dependent. However, the substantiating literature has been increasingly accumulating on these specific topics.

1. Immunometabolic regulation

Phytomolecules demonstrate remarkably similar anti-inflammatory effects to what Niewold (2007) suggested was a primary mechanism of AGPs: non-antibiotic anti-inflammatory activity, reducing the energetic costs of chronic low-grade inflammation. Inflammation diverts nutrients from growth toward immune responses, with cytokine production (particularly IL-1β, IL-6, and TNF-α) suppressing anabolic pathways (Kogut et al., 2018). AGPs appear to selectively inhibit pro-inflammatory cytokine production without completely suppressing immune function. A similar effect can be observed with various types of phytomolecules, which significantly reduced pro-inflammatory and/or increased anti-inflammatory cytokine expression in animals challenged with several pathogens. The anti-inflammatory mechanism appears to involve inhibition of NF-κB activation and modulation of MAPK signaling pathways (Kim et al., 2010; Long et al., 2021).

2. Mitochondrial hormesis and energy metabolism

Fernández Miyakawa et al. (2024, see above) proposed that AGPs exert growth-promoting effects through mitochondrial hormesis – subtherapeutic antibiotic doses induce mild mitochondrial stress, triggering adaptive responses that enhance mitochondrial function, energy metabolism, and cellular resilience. This mechanism, while requiring further validation, explains why different antibiotics with diverse targets produce similar growth outcomes.

The mitochondrial stress response involves activation of the IL-6 receptor family signaling cascade, which regulates metabolism, growth, regeneration, and homeostasis in liver and other tissues (Perry et al., 2024). Subtherapeutic antibiotic exposure activates proteins involved in growth and proliferation through IL-6R gp130 subunit signaling, including JAK, STAT, mTOR, and MAPK pathways.

Phytomolecules demonstrate similar mitochondrial effects. Perry et al. (2024) showed that increased activity of AMPK, mTOR, PGC-1α, PTEN, HIF, and S6K can also be available via phytomolecule activity, suggesting enhanced anabolic metabolism.

Capsicum oleoresin supplementation in broilers increased jejunal lipase and trypsin activity, enhanced ileal amylase activity, improved jejunal morphology, and modulated immune organ development, indicating enhanced digestive efficiency and nutrient utilization (Li et al., 2022).

Compounds such as vanillin, thymol, eugenol have been shown to improve glucose and lipid metabolism through TRPV1 activation and mitochondrial function enhancement (Gupta et al., 2022; Zhang et al., 2017).

3. Gut microbiota modulation

AGPs selectively reduce specific microbial populations, particularly Lactobacillus species that produce bile salt hydrolase (BSH). Since BSH reduces fat digestibility and thus weight gain, AGP-mediated reduction of BSH-producing bacteria enhances energy extraction and growth (Lin, 2014; Bourgin et al., 2021).

Recent research by Zhan et al. (2025) using single-molecule real-time 16S rRNA sequencing demonstrated that therapeutic antibiotic doses (lincomycin, gentamicin, florfenicol, benzylpenicillin, ceftiofur, enrofloxacin) significantly altered chicken gut microbiota composition, with Pseudomonadota and Bacillota becoming dominant phyla after exposure. Different antibiotics produced distinct temporal effects on microbial diversity and community structure.

Phytomolecules exert targeted antimicrobial effects while promoting beneficial bacteria. Dietary supplementation with 800 mg/kg Capsicum extract in Japanese quails reduced cecal counts of pathogenic bacteria (Salmonella spp., E. coli, coliforms) while modulating Lactobacilli populations (Reda et al., 2020).

In pigs, 80 mg/kg natural capsicum extract increased cecal propionic acid and total volatile fatty acid concentrations, with increased butyric acid in the colon – indicating enhanced fermentation by beneficial bacteria (Long et al., 2021).

Capsicum and Curcuma oleoresins altered intestinal microbiota composition in commercial broilers challenged with necrotic enteritis, reducing disease severity through microbiome modulation (Kim et al., 2015).

Capsaicin demonstrates selective antimicrobial activity, inhibiting pathogenic Gram-negative bacteria while favoring development of certain Gram-positive bacteria. The antibacterial mechanism involves induction of osmotic stress and membrane structure damage (Adaszek et al., 2019; Rosca et al., 2020).

4. Intestinal barrier function and gut health

AGPs have been associated with improved intestinal morphology, including increased villus height and reduced crypt depth, which enhance absorptive capacity (Gaskins et al., 2002).

Phytomolecules produce similar or superior effects. Capsicum extract (80 mg/kg) in pigs increased ileal villus height and upregulated MUC-2 gene expression, indicating enhanced gut barrier function and integrity. The improved barrier function correlated with reduced diarrhea incidence (Liu et al., 2013; Long et al., 2021).

Allium hookeri extract increased expression of tight junction proteins (claudins, occludins, ZO-1) in LPS-challenged broiler chickens, demonstrating direct enhancement of barrier integrity (Lee et al., 2017).

5. Oxidative stress mitigation

Oxidative stress impairs growth by damaging cellular components and triggering inflammatory responses. AGPs reduce oxidative stress indirectly through anti-inflammatory effects and microbiota modulation (Bortoluzzi et al., 2021).

Phytomolecules possess direct antioxidant properties. Capsicum extract (50 mg/kg) in heat-stressed quails reduced serum and ovarian malondialdehyde (MDA) while increasing superoxide dismutase (SOD) and catalase (CAT) activities. Ovarian transcription factors showed decreased NF-κB and increased Nrf2 and HO-1 expression (Sahin et al., 2016).

A mixture of herbal extracts including pepper reduced thiobarbituric acid reactive substances and MDA in broiler liver and muscle, while increasing glutathione peroxidase (GSH-Px) activity and improving antioxidant enzyme expression (Saleh et al., 2018).

Capsicum extract (80 mg/kg) in pigs increased total antioxidant capacity, SOD, and CAT while reducing MDA levels, demonstrating robust antioxidant effects (Long et al., 2021).

Standardization and controlled release: Critical success factors

A major criticism of phytomolecules has been inconsistent efficacy across studies. However, this variability largely reflects differences in:

• Active compound concentrations
• Bioavailability and stability
• Dosing precision
• Product quality and standardization

Microencapsulation is one of the technologies that address the standardization and bioavailability challenges. It protects volatile compounds from degradation during feed processing and storage, with encapsulated essential oils showing significantly higher retention compared to unprotected forms (Stevanović et al., 2018). By creating a protective barrier around active ingredients, microencapsulation enables controlled release in specific regions of the gastrointestinal tract, improving absorption efficiency and reducing dose variability (Bringas-Lantigua et al., 2011). The technology also masks unpalatable flavors that can reduce feed intake while standardizing active ingredient concentrations through precise manufacturing processes (Gharsallaoui et al., 2007). Studies demonstrate that spray-dried microencapsulated essential oils achieve encapsulation efficiencies exceeding 93% with minimal loss during storage (Hu et al., 2020), and can be engineered for enzyme-mediated release to ensure bioactive delivery at optimal intestinal sites (Elolimy et al., 2025).

Mechanistic synthesis: An integrated model

The evidence indicates that both AGPs and phytomolecules operate through an integrated network of effects:

1. Primary Level: Selective antimicrobial effects modify gut microbiota composition
2. Secondary Level: Reduced microbial metabolites (ammonia, endotoxins) decrease inflammatory signaling
3. Tertiary Level: Reduced inflammation conserves energy for growth; enhanced barrier function improves nutrient absorption
4. Quaternary Level: Mitochondrial hormesis and metabolic optimization increase energy efficiency
5. Systemic Level: Improved immunometabolic homeostasis supports optimal growth

This integrative model explains why multiple antibiotics with different mechanisms produce similar growth outcomes: they converge on common pathways regulating immunometabolism and mitochondrial function (Fernández Miyakawa et al., 2024).

Phytomolecules operate through the same mechanistic framework but with potential advantages:

• Multiple bioactive compounds providing redundancy
• Antioxidant effects enhancing stress resilience
• Lower AMR selection pressure
• Potential prebiotic-like effects supporting beneficial microbiota

Safety and antimicrobial resistance considerations

Antibiotic exposure significantly disrupts gut microbiota diversity and stability, with effects persisting beyond withdrawal periods. The study by Zhan et al. (2025) demonstrated that different antibiotics produce varying degrees of microbiota disruption, with florfenicol and gentamicin showing the strongest and most persistent effects.

In contrast, phytomolecules generally do not generate resistance through the same mechanisms as antibiotics. Some phytochemicals may actually enhance antibiotic efficacy and resensitize resistant bacteria through structural modifications of bacterial membranes (Khameneh et al., 2021; Suganya et al., 2022).

However, one study reported increased correlation between antibiotic resistance genes (ARGs) and mobile genetic elements in pig feces after mushroom powder supplementation, suggesting that certain phytogenic compounds may increase ARG mobility (Muurinen et al., 2021). This emphasizes the need for continued surveillance of phytomolecule effects on resistance gene dynamics.

Capsaicinoids and capsinoids have well-established safety profiles. Capsiate, a non-pungent analogue of capsaicin, exhibits substantially lower toxicity while maintaining similar metabolic and growth-promoting effects (Gupta et al., 2022). No adverse effects on animal health or product quality have been reported at recommended dosages in reviewed studies.

Future directions and research needs

Despite substantial progress, several areas require further investigation:

1. Mechanistic refinement: Detailed characterization of signaling pathways, particularly the IL-6R/gp130 cascade and mitochondrial stress responses
2. Precision formulation: Development of combinations optimized for specific production stages, environmental conditions, and disease pressures
3. Bioavailability optimization: Advanced delivery systems ensuring consistent active compound release and absorption
4. Microbiome-host interaction mapping: High-resolution characterization of microbial community shifts and their functional consequences
5. Economic validation: Large-scale production trials assessing cost-effectiveness compared to AGPs and disease management costs

Conclusions

The scientific evidence demonstrates that standardized phytomolecules operate through well-characterized biological mechanisms that substantially replicate those of AGPs:

1. Anti-inflammatory effects reducing energetic costs of immune activation
2. Mitochondrial hormesis enhancing energy metabolism and cellular resilience
3. Selective microbiota modulation supporting beneficial bacteria while controlling pathogens
4. Intestinal barrier enhancement improving nutrient absorption and reducing translocation
5. Antioxidant activity mitigating oxidative stress and supporting immune function

When properly standardized and formulated for controlled release, phytomolecules deliver growth promotion, feed efficiency improvements, and disease resistance comparable to AGPs, while potentially offering advantages in AMR risk profile, stress resilience, and consumer acceptance.

The mechanistic convergence between AGPs and phytomolecules, coupled with demonstrated efficacy in controlled trials, provides producers with confidence that science-based phytomolecular interventions represent legitimate alternatives to AGPs. Success depends on product standardization, appropriate dosing, and understanding that phytomolecules work through fundamental biological pathways rather than undefined or mystical mechanisms.

As the livestock industry continues to navigate the post-AGP era, standardized phytomolecules offer a scientifically sound, mechanistically validated approach to maintaining animal performance, health, and welfare while addressing antimicrobial resistance concerns.

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Zhan, Ru, et al. “Effects of Antibiotics on Chicken Gut Microbiota: Community Alterations and Pathogen Identification.” Frontiers in Microbiology, vol. 16, 2025, article 1562510. https://doi.org/10.3389/fmicb.2025.1562510

Zhang, Y., et al. “Effects of Vanillin, Thymol, and Eugenol on Glucose and Lipid Metabolism via TRPV1 Activation.” Journal of Agricultural and Food Chemistry, vol. 65, no. 13, 2017, pp. 2719 – 2727.

By Dr. Inge Heinzl, Editor, and Predrag Persak, Regional Technical Manager North Europe

For profitable pig production, efficient energy metabolism is essential. Every kilojoule consumed must be wisely spent – on maintenance, growth, reproduction, or defense. An impacted energy metabolism due to disease or stress impacts animal performance and farm profitability.

Different faces of energy

Energy metabolism determines how efficiently pigs convert feed into body mass. The Gross energy (GE) of the diet, which the use of a calorimeter can determine, is progressively reduced by losses in feces (→digestible energy – DE), urine, gases (→metabolizable energy – ME), and heat, resulting in the →net energy (NE), which is then available for maintenance and performance (growth, milk…).

The requirements for maintenance include the minimum energy that an organism needs to maintain essential functions under standardized conditions and at complete rest. This includes respiration, thermoregulation, tissue turnover, and immune system activity. Only energy in excess of these needs is available for performance. The ratio between additional retained energy and additional energy intake defines the incremental efficiency of nutrient utilization. Under normal conditions, healthy, fast-growing pigs display high incremental efficiencies for both protein and energy deposition by channeling energy efficiently into lean tissue and approximately 25-30% of the metabolizable energy from the feed is used for maintenance, 20-25% for lean gain, and the rest for fat deposition, driving daily gain and carcass quality (Patience, 2019).

However, disease, immune stress, and suboptimal environmental conditions can disrupt this delicate balance, diverting nutrients from growth to survival processes (Obled, 2003). The activation of the immune system leads to reduced feed efficiency, slower growth, and inferior meat quality.

Disease generates costs

The health challenge of disease causes energy loss through several key mechanisms (Patience, 2019).

1. The activation of the immune system becomes an energetic priority. It consumes significant amounts of energy and nutrients, such as glucose and specific amino acids, to produce immune cells and acute-phase proteins, such as haptoglobin and CRP, and to combat pathogens. The nutrients are redirected away from performance toward immune defense, i.e., less energy available for growth performance or even a mobilization of body reserves (fat deposits). A study conducted by Huntley et al. (2017) showed a 23.6% higher requirement for metabolizable energy to activate and maintain the immune system, resulting in a 26% lower ADG.
2. Physiological responses to disease, such as fever (heat production), shivering, or increased physical activity due to discomfort or listlessness, require energy.
3. Additional lower feed intake due to reduced appetite, leading to less energy consumption and intensifying the problem of energy repartitioning.

Environmental challenges are energy-consuming

Besides environmental conditions that cause disease due to high pathogenic pressure, environmental challenges are often related to thermoregulation.

1. Cold stress

In the case of cold stress, the ambient temperature falls below the pig’s lower critical temperature. The animal must spend extra energy to produce heat and maintain a constant body temperature. Alternatively, it can achieve this through shivering (muscle friction generates heat) and the release of thyroid hormones, which increase the metabolic rate and boost body temperature. Another possibility is huddling with other pigs. If the pigs eat more to gain extra energy for warmth, they increase production costs.

2. Heat stress

Excessive temperature leads to heat stress, and the animals attempt to cope through several mechanisms. Increased respiratory evaporation by panting is energy-intensive. Other possibilities are lying spread out on cool surfaces (conduction), seeking shade, and reducing physical activity to minimize heat production. To reduce metabolic heat production, pigs decrease their feed intake; however, this results in an energy deficit and likely mobilizes body reserves, especially in lactating sows.

3. Poor housing and management

High ventilation rates, draughts, wet floors, high stocking densities, and, too often, mixing of pigs are other stressors that require adequate energy-consuming responses. Also, an environment that facilitates excessive heat loss, e.g., through cold concrete floors, constrains the pigs to expend more ME to compensate. Poor-quality air with high levels of harmful gases, such as ammonia or hydrogen sulfide, or dust can lead to respiratory issues and energy expenditure for immune defense.

What are the detailed consequences?

Energy required for immune defense cannot be used for the production of meat, milk, or eggs. Several energy-consuming processes are triggered during an immunological challenge.

Glucose, an important energy source

Several scientists (Spurlock, 1997; Rigobelo and Ávila, 2011) have stated that glucose is primarily used to meet the increased energy demands of an activated immune system. According to Kvidera et al. (2017), the reason might be that stimulated leucocytes change their metabolism from oxidative phosphorylation to aerobic glycolysis (Palsson-McDermott and O’Neill, 2013). A trial conducted by Kvidera et al. (2017) confirmed the high need for glucose. In their trial with E. coli LPS-challenged crossbred gilts, they measured the amount of glucose required to maintain normal blood glucose levels (euglycemia). They calculated that an acutely and intensely activated immune system requires 1.1 g of glucose/kg body weight0.75/h. As they obtained similar results in ruminants (Kvidera et al., 2016 and 2017), they regard this glucose requirement as conserved across species and physiological states. In a confirming study, McGilvray and coworkers (2018) observed a significant (P<0.01) decrease in blood glucose in pigs after injection of E. coli LPS.

A further energy-consuming process is the increase in body temperature (fever): To increase body temperature by 1°C, the metabolic rate must be raised by 10-12.5% (Evans et al., 2015). 

Influence on protein metabolism

Stimulation of the immune system in growing pigs may lead to a redistribution of amino acids from protein retention to immune defense. Amino acids are needed as a ‘substrate’ to synthesize immune system metabolites, such as acute-phase proteins (e.g., haptoglobin, a-fibrinogen, antitrypsin, lipopolysaccharide-binding protein, C-reactive protein, and others (Rakhshandeh and De Lange, 2011)), immunoglobulins, and glutathione (Reeds and Jahoor, 2001). This impacts the requirements for amino acids quantitatively but also qualitatively, i.e., the amino acid profile. Various studies indicated an increased need for Methionine, cysteine, branched-chain amino acids (BCAAs), aromatic amino acids, Threonine, and Glutamine during immune system stimulation (Reeds et al., 1994; Melchior et al., 2004; Calder et al., 2006; Rakhshandeh and de Lange, 2011; Rakhshandeh et al., 2014).

If the required amino acids are not available, they must be either synthesized or obtained from body protein. This costs energy, leads to muscle mass degradation, and causes an imbalance in amino acid levels. Excess amino acids are catabolized, resulting in an increase in blood urea nitrogen (BUN). McGilvray et al. (2018), e.g., observed a 25% increase in BUN in their study, in which they stimulated pigs’ immune systems with LPS.

Another possibility is using amino acids as energy sources. L-Glutamine, for example, is a crucial energy source for immune cells and the primary energy substrate for mucosal cells (Mantwill, 2025).

Carcass and meat quality

As already mentioned, immune stimulation or disease leads to protein degradation. Plank and Hill (2000) reported a loss of up to 20% of body protein (mainly skeletal muscle) in critically ill humans over 3 weeks. This protein degradation influences carcass yield and quality by reducing the amount of muscle meat.

Another effect is a decrease in the muscle cross-sectional area of fibers and a significant shift from the myosin heavy chain (MHC)-II towards the MHC-I type (Gilvray et al, 2019)

How can feed additives support pigs in health challenges?

Health challenges can occur due to infections by bacteria, viruses, fungi, or protozoa, as well as due to myco-, exo-, or endotoxins. Phytomolecules-based and toxin-binding can help animals cope with these health challenges.

Phytomolecules have several health-supporting effects

Phytomolecules can support animals in the case of a health challenge by directly fighting bacteria – antimicrobial effect (Burt, 2004; Rowaiye et al., 2025), scavenging free radicals – antioxidant effect (Saravanan et al., 2025; Dhir, 2022), or mitigating infection – anti-inflammatory effect (Saravanan et al., 2025). 

A trial with the phytomolecules-based product Ventar D demonstrated its antimicrobial and microbiome-modulating effects (Heinzl, 2022). The product clearly reduced the populations of Salmonella enterica, E. coli, and Clostridium perfringens but spared the beneficial lactobacilli.

The anti-inflammatory effects of phytomolecules inhibit the activity of pro-inflammatory cytokines and chemokines from endotoxin-stimulated immune cells and epithelial cells (Lang et al., 2004; Lee et al., 2005; Liu et al., 2020), and there is an indication that the anti-inflammatory effects might be mediated by blocking the NF-κB activation pathway (Lee et al., 2005). A trial confirmed this thesis by showing a dose-dependent reduction of NFκB activity in LPS-stimulated mouse cells (-11% & -54% with 50 & 200 ppm Ventar D, respectively) (Figure 1).

Additionally, Ventar D increases interleukin-10, a cytokine with anti-inflammatory properties, and decreases interleukin-6, a pro-inflammatory cytokine. The result is a dose-dependent decline in the ratio of IL-6 to IL-10 (Figure 2), indicating the effectiveness of the product.

The effects of Ventar D, which support the immune system and redirect energy to enhance growth performance, result in higher daily gains and improved feed conversion. This was observed in a trial conducted on a commercial farm in Germany, using, on average, 26-day-old weaned piglets with a mean body weight of approximately 8 kg. Just after weaning, young animals experience stress (new feed, new groups, and separation from the dam) and are more susceptible to disease.

Two groups of piglets were fed either the regular feed of the farm (Control) or the regular feed + 100 g Ventar per MT of feed. The results for final weight and FCR are shown in Figures 3 and 4

Toxin-binding products support animals against health challenges caused by toxins

As mentioned, various toxins, including myco-, endo-, and exotoxins, can harm animals. The danger of mycotoxins lurks in many feeds, and exo- and endotoxins derive from bacteria. Toxin-binding products, possibly supplemented with phytomolecules that support health (e.g., liver protection), can help animals cope with these challenges.

Solis Max 2.0, a toxin solution containing bentonite and phytomolecules, showed excellent binding performance for myco- and endotoxins (Figures 5 and 6).

Trial with endotoxins

Two samples were prepared: one with only 25 EU (1 EU equivalent to approximately 100 pg or 10,000 cells) of LPS of E. coli O55:B5 LPS/mL solution, and one with the same concentration of LPS but also containing 700 mg Solis Max 2.0/mL.

Solis Max 2.0 bound about 80% of endotoxin.

Trial with mycotoxins

In another in vitro trial, the binding capacity of Solis Max 2.0 for six different kinds of mycotoxins was evaluated. For that purpose, samples with 800 ppb AFB1, 400 ppb OTA, 800 ppb DON, 300 ppb T2, 2,000 ppb FB1, or 1,200 ppb ZEN were prepared, and Solis max was added at two inclusion rates, one corresponding to 1 kg/t, the other to 2 kg/t. The binding capacities ranged from 40.7% for OTA to 96% for AFB1, with the lower inclusion rate, and from 61.5% for OTA to 99% for AFB1, with the higher inclusion rate.

Health support by toxin-binding solutions improves performance

The mitigating effects of Solis Max concerning the negative impact of toxins are also reflected in performance. A trial involving 24 female weaned piglets was conducted to evaluate the mitigating effects of Solis Max in the event of a challenge with a naturally contaminated diet (3,400 ppb of DON and 700 ppb of ZEA). Solis Max was added to one half of the challenged piglets. The addition of Solis Max to the contaminated diet not only compensates for growth performance parameters, such as weight gain and feed conversion, but also for Vulva and tail necrosis scores. The results are shown in Figures 7-11.

Tools are available to prevent the unnecessary expenditure of energy for immune protection

As the various references in the article demonstrate, health challenges such as pathogens or toxins not only spoil the appetite of animals but also require energy due to the activation of the immune system. Products based on phytomolecules, as well as toxin solutions, can help animals cope with these challenges and conserve energy for improved performance.

References:

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Burt, Sara. “Essential Oils: Their Antibacterial Properties and Potential Applications in Foods—a Review.” International Journal of Food Microbiology 94, no. 3 (August 2004): 223–53. https://doi.org/10.1016/j.ijfoodmicro.2004.03.022. 

Calder, Phillip C. “Branched-Chain Amino Acids and Immunity ,.” The Journal of Nutrition 136, no. 1 (January 2006). https://doi.org/10.1093/jn/136.1.288s. 

Dhir, Vivek. “Emerging Prospective of Phytomolecules as Antioxidants against Chronic Diseases.” ECS Transactions 107, no. 1 (April 24, 2022): 9571–80. https://doi.org/10.1149/10701.9571ecst. 

Evans, Sharon S., Elizabeth A. Repasky, and Daniel T. Fisher. “Fever and the Thermal Regulation of Immunity: The Immune System Feels the Heat.” Nature Reviews Immunology 15, no. 6 (May 15, 2015): 335–49. https://doi.org/10.1038/nri3843. 

Heinzl, Inge. “Efficient Microbiome Modulation with Phytomolecules.” EW Nutrition, June 9, 2023. https://ew-nutrition.com/pushing-microbiome-in-right-direction-phytomolecules/. 

Huntley, Nichole F., John F. Patience, and C. Martin Nyachoti. “Immune Stimulation UPS Maintenance Energy Requirements.” National Hog Farmer.com, September 28, 2017. https://www.nationalhogfarmer.com/hog-health/immune-stimulation-ups-maintenance-energy-requirements. 

Kvidera, S. K., E. A. Horst, M. Abuajamieh, E. J. Mayorga, M. V. Sanz Fernandez, and L. H. Baumgard. “Technical Note: A Procedure to Estimate Glucose Requirements of an Activated Immune System in Steers.” Journal of Animal Science 94, no. 11 (November 1, 2016): 4591–99. https://doi.org/10.2527/jas.2016-0765. 

Kvidera, S.K., E.A. Horst, M. Abuajamieh, E.J. Mayorga, M.V. Sanz Fernandez, and L.H. Baumgard. “Glucose Requirements of an Activated Immune System in Lactating Holstein Cows.” Journal of Dairy Science 100, no. 3 (March 2017): 2360–74. https://doi.org/10.3168/jds.2016-12001. 

LANG, A. “Allicin Inhibits Spontaneous and Tnf-$alpha; Induced Secretion of Proinflammatory Cytokines and Chemokines from Intestinal Epithelial Cells.” Clinical Nutrition, May 2004. https://doi.org/10.1016/s0261-5614(04)00058-5. 

Lee, Seung Ho, Sun Young Lee, Dong Ju Son, Heesoon Lee, Hwan Soo Yoo, Sukgil Song, Ki Wan Oh, Dong Cho Han, Byoung Mog Kwon, and Jin Tae Hong. “Inhibitory Effect of 2′-Hydroxycinnamaldehyde on Nitric Oxide Production through Inhibition of NF-ΚB Activation in RAW 264.7 Cells.” Biochemical Pharmacology 69, no. 5 (March 2005): 791–99. https://doi.org/10.1016/j.bcp.2004.11.013. 

Liu, S. D., M. H. Song, W. Yun, J. H. Lee, H. B. Kim, and J. H. Cho. “Effect of Carvacrol Essential Oils on Growth Performance and Intestinal Barrier Function in Broilers with Lipopolysaccharide Challenge.” Animal Production Science 60, no. 4 (January 22, 2020): 545–52. https://doi.org/10.1071/an18326. 

Liu, S. D., M. H. Song, W. Yun, J. H. Lee, H. B. Kim, and J. H. Cho. “Effect of Carvacrol Essential Oils on Growth Performance and Intestinal Barrier Function in Broilers with Lipopolysaccharide Challenge.” Animal Production Science 60, no. 4 (January 22, 2020): 545–52. https://doi.org/10.1071/an18326. 

Mantwill, Elke. “Eiweiß & Immunsystem.” sportärztezeitung, April 10, 2025. https://sportaerztezeitung.com/rubriken/ernaehrung/9197/eiweiss-immunsystem/. 

McGilvray, Whitney D, David Klein, Hailey Wooten, John A Dawson, Deltora Hewitt, Amanda R Rakhshandeh, Cornelius F de Lange, and Anoosh Rakhshandeh. “Immune System Stimulation Induced byEscherichia ColiLipopolysaccharide Alters Plasma Free Amino Acid Flux and Dietary Nitrogen Utilization in Growing Pigs1.” Journal of Animal Science 97, no. 1 (October 11, 2018): 315–26. https://doi.org/10.1093/jas/sky401. 

Melchior, D., B. Sève, and N. Le Floc’h. “Chronic Lung Inflammation Affects Plasma Amino Acid Concentrations in Pigs.” Journal of Animal Science 82, no. 4 (April 1, 2004): 1091–99. https://doi.org/10.2527/2004.8241091x. 

Obled, C. “Amino Acid Requirements in Inflammatory States.” Canadian Journal of Animal Science 83, no. 3 (September 1, 2003): 365–73. https://doi.org/10.4141/a03-021. 

Palsson‐McDermott, Eva M., and Luke A. O’Neill. “The Warburg Effect Then and Now: From Cancer to Inflammatory Diseases.” BioEssays 35, no. 11 (September 20, 2013): 965–73. https://doi.org/10.1002/bies.201300084. 

Pastorelli, H., J. van Milgen, P. Lovatto, and L. Montagne. “Meta-Analysis of Feed Intake and Growth Responses of Growing Pigs after a Sanitary Challenge.” Animal 6, no. 6 (2012): 952–61. https://doi.org/10.1017/s175173111100228x. 

Patience, John. “One of the Most Important Decisions in Swine Production: Dietary Energy Level – Dr. John Patience by The Swine It Podcast Show.” Spotify for Creators, December 2, 2019. https://anchor.fm/swineitpodcast/episodes/One-of-the-most-important-decisions-in-swine-production-dietary-energy-level—Dr–John-Patience-e99j9u. 

Plank, Lindsay D., and Graham L. Hill. “Sequential Metabolic Changes Following Induction of Systemic Inflammatory Response in Patients with Severe Sepsis or Major Blunt Trauma.” World Journal of Surgery 24, no. 6 (June 2000): 630–38. https://doi.org/10.1007/s002689910104. 

Rakhshandeh, A., and C.F.M. de Lange. “Evaluation of Chronic Immune System Stimulation Models in Growing Pigs.” Animal 6, no. 2 (2012): 305–10. https://doi.org/10.1017/s1751731111001522. 

Rakhshandeh, A., and C.F.M. De Lange. “Immune System Stimulation in the Pig: Effect on Performance and Implications for Amino Acid Nutrition.” Essay. In Manipulating Pig Production XIII, 31–46. Werribee, Victoria, Australia: Australasian Pig Science Association Incorporation, 2011. 

Rakhshandeh, Anoosh, John K. Htoo, Neil Karrow, Stephen P. Miller, and Cornelis F. de Lange. “Impact of Immune System Stimulation on the Ileal Nutrient Digestibility and Utilisation of Methionine plus Cysteine Intake for Whole-Body Protein Deposition in Growing Pigs.” British Journal of Nutrition 111, no. 1 (January 14, 2014): 101–10. https://doi.org/10.1017/s0007114513001955. 

Reeds, P., and F. Jahoor. “The Amino Acid Requirements of Disease.” Clinical Nutrition 20 (June 2001): 15–22. https://doi.org/10.1054/clnu.2001.0402. 

Reeds, Peter J, Carla R Fjeld, and Farook Jahoor. “Do the Differences between the Amino Acid Compositions of Acute-Phase and Muscle Proteins Have a Bearing on Nitrogen Loss in Traumatic States?” The Journal of Nutrition 124, no. 6 (June 1994): 906–10. https://doi.org/10.1093/jn/124.6.906. 

Rigobelo, E. Cid, and F. A. De Ávila. “Hypoglycemia Caused by Septicemia in Pigs.” Essay. In Hypoglycemia – Causes and Occurrences., 221–38. London, UK: InTechOpen, 2011. 

Rowaiye, Adekunle, Gordon C. Ibeanu, Doofan Bur, Sandra Nnadi, Ugonna Morikwe, Akwoba Joseph Ogugua, and Chinwe Uzoma Chukwudi. “Phyto-Molecules Show Potentials to Combat Drug-Resistance in Bacterial Cell Membranes.” Microbial Pathogenesis 205 (August 2025): 107723. https://doi.org/10.1016/j.micpath.2025.107723. 

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EW Nutrition brings global poultry leaders together to chart “New Frontiers in Poultry Production”

24 October 2025 – Hurghada, Egypt. This week, EW Nutrition’s conference “New Frontiers in Poultry Production” gathered together 250 partners, customers, and peers from 40 countries.

Over three days, the participants heard talks on the critical topics of the industry. The hosts outlined a coherent vision and market approach: from Jan Wesjohann’s opening on EW Group’s long-term vision and EW Nutrition’s role in the holding company, to CEO Jan Vanbrabant, Marie Gallissot, and Madalina Diaconu’s presentations on the market challenges that EW Nutrition is solving.

Guest speakers included distinguished leading practitioners and key opinion leaders. Day 1 of the conference brought to the stage Prof. Dr. Saadia Nassik from Rabat University on the role of practical mitigation tools for antimicrobial resistance, Marcin Wolak on applied biosecurity best practices, Al Ajban/Al Ain’s Dr Mohammad Ezzat on preventive tools for poultry health, Jaroslaw Wilczinski on enteropathies in poultry production, Rani Ahmad from our sister company Hygiena on food safety hazards and solutions.

Day 2 started with Aviagen’s Murat Yakar with a clear overview of best practices in poultry production and a challenging perspective from Rainbow Chicken’s Brett Roosendaal on nutritional issues and solutions. Lohmann’s Jurek Grapentin then outlined trends in layer genetics, and Prof. Dr. Necmettin Ceylan, from Ankara University, presented holistic strategies to alleviate heat stress.

Both days ended with panel discussions where all speakers answered questions from the audience, moderated by EW Nutrition’s regional directors and event hosts, Radek Nigrin and Jedrzej Standar. On day 3, the discussions continued in more informal settings, allowing participants to network and collect more information while enjoying the impressive local history and natural offerings.

The conference showcased the industry’s potential for growth, both in geographical expansion, in genetic performance, and in better solutions allowing for safe, sustainable, affordable animal protein.

 

Conference Report
By M. Rosenthal, Global Application Manager Swine, EW Nutrition GmbH

Sustainability is essential for the long-term survival of our planet. In pig production, sustainability involves maintaining economically viable outputs while simultaneously safeguarding animal health and welfare and minimizing environmental impact. The goal is to produce pork that is profitable, ethical, and has a minimal ecological footprint.

Phytomolecules, the bioactive constituents of plant-derived essential oils, play a promising role in advancing this goal. With multifunctional gut health benefits including antimicrobial, anti-inflammatory, antioxidant, and digestive-supportive properties, phytomolecules help maintain gut health and reduce the need for antibiotics. By improving feed efficiency, enhancing resilience, and supporting intestinal integrity, phytomolecules contribute to both sustainability and efficiency in pig production systems.

Targeting sustainability in pig production

Achieving sustainability in pig production requires a balanced approach that considers three key perspectives: those of the producer, the pig, and the environment.
For the producer, sustainable pig production must be profitable to ensure the long-term viability of the industry. This includes factors such as efficient feed conversion, optimized production practices, and fair market prices.

Another aspect is the maintenance of animal health and well-being, which is essential for optimal pig performance and can be achieved by providing appropriate housing, nutrition, and veterinary care, as well as minimizing stress and disease.

From an environmental perspective, minimizing negative impacts, such as greenhouse gas emissions, water pollution, and land degradation, is a key objective. Various strategies, such as improved manure management, efficient nutrient utilization, reuse of farm resources like manure and water, and the use of by-products from other industries as feed ingredients, can be applied.

Strategy for efficient pig production

Historically, pig production has relied heavily on the use of antibiotics to control enteric pathogens, promote gut health, and enhance growth. While effective in the short term, this practice led to unintended consequences, including the emergence of antimicrobial resistance (amr), disruption of microbiota across multiple organ systems, difficulties in manure management, and environmental contamination.

These outcomes triggered societal concern, regulatory interventions, and economic pressure, prompting a shift away from routine antibiotic use. The industry now faces increasing expectations for environmentally responsible practices, reduced dependence on antibiotics, and cost-effective, sustainable solutions.
Achieving both efficiency and sustainability in pig production requires a holistic, system-wide approach that includes an innovative, solution-oriented mindset, optimized management practices, and the adoption of effective gut health antibiotic alternatives.

The foundation of efficiency – the gut

The pigs gastrointestinal tract is the largest and most vulnerable interface between the pig and its external environment. It is a highly organized ecosystem comprised of epithelial cells, the mucosal immune system, and a diverse microbiome consisting of both beneficial commensal microbes and potentially harmful pathogens.
The functions of the gut include nutrient absorption, chemosensing of nutrients and other compounds, immune defence, and balancing the highly diverse microbiome within this complex environment (Furness et al. , 2013). Disruption of this ecosystems homeostasis can impair not only gut function and health but also negatively affect the overall well-being and growth efficiency of the pig.

When evaluating antibiotic alternatives to support this ecosystems homeostasis in the face of challenges, considerations include safety for humans, animals, and the environment, cost-effectiveness, antimicrobial efficacy, the ability to increase nutrient availability, and to modulate immune activation and inflammation.

Functional feed additives commonly utilized in pig nutrition, alone or in combination, include organic acids, probiotics, immunoglobulins, medium-chain fatty acids, and phytomolecules.

Phytomolecules: supporting gut health and performance

Phytomolecules are the bioactive components of plant-derived essential oils. Due to the variability in phytomolecule content and the presence of volatile and astringent components in essential oil extracts, utilizing commercial phytomolecule products is recommended. Proprietary formulations utilize encapsulation or matrix technology to protect the phytomolecules from damage or loss during storage, processing, and passage through the stomach.

Extensive research in humans and animals has identified phytomolecules as having antimicrobial, anti-inflammatory, antioxidative, and coccidiostatic properties. They enhance digestibility and immunity, promote gut health through differential modulation of bacterial populations, and reduce inflammation and oxidative stress (Brenes et al., 2010; Puvaca et al. , 2013; Chitprasert et al., 2014). Phytomolecules most researched and utilized in pig feed additives to date include terpenes (e. G., carvacrol and thymol) and phenylpropenes (e.g., cinnamaldehyde and eugenol).

1. Direct antimicrobial activity of phytomolecules

Phytomolecules such as carvacrol and thymol provide broad-spectrum antimicrobial activities against Gram- and Gram+ bacteria, fungi, and yeast and are regarded as promising alternatives to antibiotics in swine production systems (Lambert et al., 2001; Delaquis et al., 2002; Abbaszadeh et al., 2014).

Phytomolecules directly target bacterial cells through multiple mechanisms, with the cell wall and membrane being major sites of action. The lipophilic structure of phytomolecules enables their entry through bacterial membranes among the fatty acid chains, causing the cell wall and membranes to expand and become more fluid. This damage collapses the cell wall and cytoplasmic membrane, resulting in the destruction of membrane proteins, the coagulation of the cytoplasm, and a reduction in proton motive force. The result is leakage of vital intracellular contents and death of the bacterial cell (Cox et al., 1998; Faleiro, 2011; Nazzaro et al., 2013; Yap et al., 2014). For example, thymol and carvacrol can damage the outer membrane of Salmonella typhimurium and Escherichia coli o157: h7 (Helander et al., 1998).

A further direct antimicrobial action involves phytomolecules acting as trans-membrane carriers, exchanging a hydroxyl proton for a potassium ion, resulting in dissipation of the ph gradient and electrical potential over the bacterial cytoplasmic membrane. The result is a reduced proton motive force and the depletion of the intracellular adenosine triphosphate (APT) pools. Loss of potassium further inhibits bacterial function as it is needed for the activation of cytoplasmic enzymes to maintain osmotic pressure and regulate intracellular pH. (Wendakoon et al., 1995).

In summary, the primary direct antimicrobial mechanism of action for terpene and phenylpropene phytomolecules is related to their effects on cell walls and cytoplasmic membranes, and energy metabolism of pathogenic bacteria.

2. Indirect antimicrobial activity of phytomolecules

Phytomolecules indirectly impact the physiological functioning and virulence capability of pathogenic bacteria through the interference of quorum-sensing (QS). QS involves pathogenic bacteria producing signaling molecules that are released based on cell numbers. The detection of these molecules regulates pathogen population behavior such as attachment, biofilm formation, and motility, i. e. , virulence (Greenberg, 2003; Joshi et al., 2016).

QS mechanisms require signal synthesis, signal accumulation, and signal detection, providing three opportunities for QS inhibitors to disrupt pathogenic bacteria from causing disease (Czajkowski and Jafra, 2009; Lasarre and Federle, 2013). Eugenol and carvacrol have been extensively studied for their QS inhibition activities (Zhou et al., 2013; Burt et al., 2014).

3. Combinations increase efficacy

Additional antimicrobial effects can be seen when different phytomolecules are combined, and/or applied with other functional additives such as organic acids (Souza et al., 2009; Hulankova and Borilova, 2011). Zhou et al. (2007) reported that carvacrol or thymol in combination with acetic or citric acid had a better efficacy against S. typhimurium when compared to the individual phytomolecule or organic acid. In recent studies, results have shown in vivo efficacy of such synergistic dietary strategies in pigs (Diao et al., 2015; Balasubramanian et al., 2016). The combined inclusion of phytomolecules and organic acids in pig diets before slaughter may hinder Salmonella shedding and seroprevalence (Walia et al., 2017; Noirrit et al., 2016).

4. Phytomolecules are more than antimicrobials

In addition to acting as antimicrobials, phytomolecules enhance production efficiency through multiple complementary mechanisms, including direct anti-inflammatory, antioxidative, digestive, and gut barrier-supportive effects.

Anti-inflammatory effects: Gut inflammation in pigs not only compromises intestinal function and barrier integrity but also has a direct negative impact on growth performance and overall health. Chronic or excessive immune activation diverts energy away from productive processes such as growth and feed efficiency.

Phytomolecules have demonstrated the ability to modulate immune responses by influencing key cell-signalling pathways involved in inflammation. For example, compounds such as cinnamaldehyde and carvacrol can modulate the activity of critical transcription factors, including nuclear factor erythroid 2 2-related factor 2 (Nrf2) and nuclear factor kappa B (NF-κB). Through this dual action, phytomolecules can simultaneously activate antioxidant defences and suppress pro-inflammatory signalling, thereby reducing intestinal inflammation and supporting improved performance outcomes (Krois-mayr et al., 2008; Wondrak et al., 2010; Zou et al., 2016).

Antioxidant effects: oxidative stress is a major biological challenge in modern swine production systems, where high-performance animals are frequently exposed to stressors such as weaning, disease challenges, heat stress, mycotoxin exposure, transport, and overcrowding. These stressors promote the generation of reactive oxygen species (ROS), and when ROS production exceeds the capacity of the pig’s antioxidant defence systems, oxidative stress occurs.

This imbalance can negatively affect growth, immunity, muscle integrity, feed intake, milk yield, and reproductive performance, including increased abortion rates in gestating sows (Zhou et al., 2013; Burt et al., 2014). As a result, there is growing interest in the use of natural antioxidant compounds, particularly phytomolecules, to counteract these detrimental effects. For example, carvacrol and thymol (1:1 ratio) at 100 mg/kg dietary supplementation reduced weaning-associated oxidative stress by decreasing TNF-α mRNA expression in the intestinal mucosa (Wei et al., 2017).

Additionally, carvacrol supplementation in the diets of late gestation and lactating sows under oxidative stress conditions significantly improved piglet performance (Tan et al., 2015).

Digestive function: The gastrointestinal tract functions not only as a site for nutrient absorption but also as a sensory organ. Specialized chemosensors in the gut monitor the concentration and composition of nutrients, playing a crucial role in the regulation of digestive enzyme secretion, gut peptide release, feed intake, and nutrient absorption and metabolism.

Studies in weaner piglets have shown that certain phytomolecules can stimulate the secretion of digestive enzymes and enhance gastrointestinal function (Maenner et al., 2011; Li et al., 2012).

Tight junctions and gut barrier integrity: The intestinal epithelium functions as a highly dynamic and selective barrier, facilitating the absorption of fluids and solutes while preventing the translocation of pathogens and toxins into underlying tissues. This barrier function occurs through intercellular tight junctions. During episodes of mucosal inflammation, the integrity of these junctions can be compromised, leading to increased intestinal permeability, reduced nutrient absorption, and systemic immune activation and inflammation.

Research has shown that phytomolecules can enhance transepithelial electrical resistance and upregulate the expression of tight junction proteins, reducing epithelial permeability and maintaining a functional barrier, even under inflammatory conditions (Yu et al., 2020; Kim and Kim, 2019).

Sustainable efficiency in pig production supported by in-feed phytomolecules

As the pig industry moves away from reliance on in-feed antibiotics, the need for sustainable, efficient, and health-focused production strategies has never been greater. Modern pig production systems must respond to societal expectations, regulatory mandates, and environmental pressures, while still maintaining profitability and high animal welfare standards.

Central to this transformation is a holistic approach-one that includes a shift in mindset among stakeholders, optimized management across all production domains, and the strategic use of effective antibiotic alternatives. The gastrointestinal tract, as the core of nutrient absorption and immune defence, is a critical control point for supporting health and performance.

Phytomolecules and other functional feed additives have demonstrated potential to enhance gut integrity, reduce inflammation, combat oxidative stress, and improve nutrient utilization. While no single solution can fully replace antibiotics, targeted combinations of these compounds have shown the most consistent success in promoting gut health and sustainable performance.

With continued innovation, collaboration, and science-based application of these alternatives, the industry is well-positioned to achieve its goals of profitable, ethical, and ecologically responsible pork production for the future.

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By Dr. Inge Heinzl, Editor EW Nutrition

Gut health is a critical factor in poultry production, influencing growth performance, feed efficiency, and overall bird health. A well-functioning digestive system ensures optimal nutrient absorption and ultimately contributes to economic sustainability in poultry farming.

However, another essential function of the gut is its significant role in immune defense, as evidenced by the fact that 80% of all active immune cells are in the gut. It is essential for the organism to keep a sensitive balance by eliminating invading pathogens while maintaining self-tolerance to avoid autoimmunity. Being 1.5 to 2.3 m long and with a big contact area to the external environment, the gut is the first line of defense when pathogens have orally entered the organism. For this purpose, the intestine has several specialized cells and a plethora of diverse microorganisms – the microbiome.

A balanced gut environment, therefore, enhances resistance to diseases, helps prevent infections, and reduces the need for antibiotics.

Which tools are available in the gut to counteract pathogenic attacks?

The gut wall, per se, has several fixed tools to fight pathogenic offenses, such as the mucus layers and the epithelium with highly specialized cells. Figure 1 shows in detail the different parts of the gut immune system.

1. Mucus layers

The mucus layers form the first host-derived line of defense. They help trap invasive bacteria and facilitate their removal via luminal flow. The protective properties may depend on whether the mucin is neutral or acidic, sialylated or sulfated (Broom and Kogut, 2018). The glycoprotein mucins forming the mucus layer (mainly MUC2 in the small and large intestine and MUC5ac in the proventriculus) are produced by the goblet cells, part of the intestinal epithelium just beneath.

2. Intestinal epithelium

The one-layered intestinal epithelium represents a physical barrier and consists of normal enterocytes, as well as specialized cells. All the cells are closely linked by tight junctions, consisting of claudin, occludin, and junctional adhesion molecules (JAM).
The following diverse specialized cells protect the organism from pathogenic attacks:

2.1 Proliferating stem cells

These cells are ready to replace damaged epithelial cells in the case of inflammation.

2.2 Paneth cells

Paneth cells are situated at the bottom of the Lieberkühn crypts, neighboring the stem cells in the jejunum and the ileum. Paneth cells have different tasks:
In normal conditions, they maintain homeostasis by regulating the microbiome’s composition via the secretion of antimicrobial peptides, which are accumulated in apically oriented secretory granules, performing phagocytosis and efferocytosis. Additionally, the Paneth cells provide niche factors for the intestinal stem cell compartment, absorb heavy metals, and preserve the integrity of the intestinal barrier. If one or more of these functions are impaired, intestinal and systemic inflammations or infections can develop (Wallaeys et al., 2022). The number of Paneth cells and their diameter can be enhanced via feeding. Agarwal et al. (2022) noticed a significant increase in the number and diameter of Paneth cells after feeding quinoa soluble fiber and/or quercetin 3-glucoside.

2.3 M cells

M cells (M coming from microfold and indicating the structure) are specialized epithelial cells localized along the antimesenteric border in the epithelium of the ileum. They are crucial for the immune system and an essential part of the gut-associated lymphoid tissue (GALT), a sub-system of the mucosa-associated lymphoid tissue (MALT).
M cells play an important role in the function of the immune system. They act as a transport system for antigens. They sample antigens (macromolecules, bacteria, viruses, small parasites) via the apical membrane. After the phagocytosis of the foreign organism/substance, the antigen gets through the cell and is consigned to cells of the adaptive immune system (e.g., the B-cells) at the basal side. The exact transport and the handover to the cells of the adaptive immune system are still unclear. It is also not clarified whether the antigens are processed inside the cells.

2.4 Dendritic cells

Dendritic cells are a kind of leucocyte derived from the bone marrow. Immature dendritic cells have a star-like shape. They are specialized to identify, uptake, transport, process, and present antigens to other immune system cells on their surface. To identify and uptake harmful substances/microbes, they carry receptors on their surface that recognize the attributes often occurring in pathogenic viruses, bacteria, and fungi. After contact with the antigen, the cell moves to secondary lymphoid tissue, and in the intestine, this is predominantly Mucosa-Associated Lymphoid Tissue (MALT). Arriving as mature and not phagocytizing dendritic cells, they present the antigens of the pathogens to the T-lymphocytes. For this purpose, they use cell surface proteins (MHC proteins). This presentation, together with co-stimulators and cytokines, activates naïve T-lymphocytes to develop into the relevant T-cell (fighting viruses, bacteria…) and proliferate, leading to the clearance of the pathogen.
On the other hand, dendritic cells can also suppress an immune reaction if the “suspicious subjects” are harmless or belong to the organism. Dendritic cells are the most potent antigen-presenting cells of the immune system.

2.5 Goblet cells

Goblet cells originate from pluripotent stem cells and are located between the enterocytes in the inner mucus layer of the intestine. Goblet cells develop and mature rapidly after hatching due to external stimuli such as environmental and dietary factors, but also intestinal microbiota (Duangnumsawang et al., 2021). They derive their name from their goblet-like appearance. The basal site is thin, but the cell gets thicker toward the apical side. In the thicker cell organisms, vesicles with mucins are stored and explosively released to the surface by exocytosis.

The mucins (MUC2) are viscous, slime-forming substances consisting of a protein string bound to many sugar chains. Due to their oligosaccharide chain structure, they offer adhesion binding sites for intestinal commensal bacteria and enhance probiotic colonization (Liu et al, 2020). They have a high water-binding capacity, which is responsible for their slimy and protective characteristics. In the case of inflammation, mucin production can increase strongly.

By providing bicarbonate for proper mucin unfolding in the small intestine, goblet cells help maintain homeostasis and the intestinal barrier function. Furthermore, goblet cells can form goblet cell-associated passages (GAPs) and deliver luminal substances to the antigen-presenting cells in the underlying lamina propria that can start an adaptive immune response (Knoop and Newberry, 2018).
As with Paneth cells, the number of goblet cells also increases by feeding quinoa soluble fibers.

2.6 Neuroendocrine cells

Enterochromaffin cells are neuroendocrine cells found in the epithelium of the whole digestive tract, mainly in the small intestine, the colon, and the ceca. They belong to the enteric endocrine system, are part of the diffuse neuroendocrine system, and produce 95% of the serotonin in the organism. Enterochromaffin cells act as chemo- and mechanosensors. They react to free fatty acids, amino acids, and other chemicals as well as physical forces occurring during peristaltic activity in the gut, thus modulating the secretion of water and electrolytes as well as gut motility and visceral sensation of pain (Linan-Rico et al., 2016; Diwakarla et al., 2018).

Serotonin, on its side, has been shown to affect the composition of the gut microbiota (Kwon et al., 2019) and to modulate bacterial physiology (Knecht et al., 2016). Gut-derived serotonin is responsible for immune responses (Baganz and Blakely, 2012) but also for the regulation of other functions such as bone development (Chabbi-Achengli et al., 2012), gut motility, and platelet aggregation (Berger et al., 2009). A deficient serotonergic system can cause psychopathological behaviors such as feather pecking.

3. Last but not least – the microbiome

The poultry gut microbiome consists of bacteria, fungi, protozoa, and viruses. Beneficial microbes, such as Lactobacillus, Bifidobacterium, and Bacteroides, contribute to gut health and immunity. 

On the one hand, microbes are involved in digestion and nutrient synthesis. They assist in breaking down fiber, producing short-chain fatty acids, and synthesizing essential vitamins. On the other hand, they contribute to immune defense:

Beneficial bacteria (BB) prevent the colonization of harmful microbes:
The bacteria inhabiting the poultry gut act against pathogens by competing with them for nutrients and binding sites at the intestinal mucosa.

Beneficial bacteria prevent/reduce inflammation and stabilize the intestinal mucosa
Abaidullah et al. (2019) showed in their review how beneficial bacteria influence the immune response to diverse viruses (AIV, IBDV, MDV, NDV).
Bacteria such as Collinsella, Faecalibacterium, Oscillibacter, etc., increase the release of IFN-α, IFN-β, and IL-22. These substances control virus replication and repair mucosal tissue damage. Other bacteria, such as Clostridium XIVa or Firmicutes, provoke T-cells to produce anti-inflammatory cytokines to suppress inflammation. By promoting the antimicrobial peptides such as MUC, TFF, ZO, and tight junction proteins comprised of claudins, occludin, and zona occludens mRNA expression, Bacteroides, Candidatus, SMB53, Parabacteroides, Lactobacillus, Paenibacillus, Enterococcus, and Streptococcus spp. inhibit pathobiont colonization and translocation, and suppress inflammation. Butyrate succinate and lactate, produced by Faecalibacterium and Blautia spp., provide energy and reduce inflammation.
Bacteroides fragilis produce bacterial polysaccharides that communicate with the immune system and influence the transformation of CD4+ (T-helper cells) and Foxp3+ cells (the master transcription factor of regulatory T cells in mammals, but also present in chicken (Burkhardt et al., 2022)). 

“Negative” bacteria increase inflammation and enhance viral shedding
Clostridium Cluster XI, Salmonella, and Shigella downregulate the anti-inflammatory and tight junction-stabilizing substances, which would be increased by the beneficial bacteria and increase IFN-γ and IF-17A to cause mucosal inflammation and tissue damage, as well as increased virus replication and fecal shedding. Further bacteria, which enhance mucosal and GIT inflammation, are Desulfovibrionaceae, producing hydrogen sulfides, Vampirovibrio, Clostridium cluster XIVb, and the genus Rumicoccus. They induce the pro-inflammatory cytokines IL-6 and IL-1β. The latter three bacteria also increase viral shedding. Salmonella typhimurium and Campylobacter jejuni also achieve higher viral shedding by decreasing viral-specific IgG and IgA production (Abaidullah et al., 2019)

Factors impairing intestinal immune defense

As the previous paragraph indicates, an imbalance of the intestinal microbiome called dysbiosis makes chickens more prone to diseases such as necrotic enteritis (Stanley et al., 2014). Several factors are disturbing the balance in the microbiome (Heinzl,  2020):

• An abrupt change of feed
• High contents of non-starch polysaccharides increase viscosity, decrease passage rate, lower the digestibility of other nutrients, and serve as nutrients for, e.g., Clostridium perfringens
• High protein levels can also serve as a substrate for pathogens and cause a shift in the balance of the intestinal flora
• Finely ground feed does not stimulate the gizzard muscles to do their work. pH increases, transit time decreases, and pathogenic microbes such as Salmonella, Campylobacter, and Clostridia proliferate.
• Stress (heat or cold stress, re-assembling of groups, high stocking densities)
• Mycotoxins

However, besides all these factors causing an overgrowth of commensal bacteria such as E. coli, ingested pathogens such as Marek’s or Newcastle Disease viruses can also cause this imbalance.

Immune defense in the gut – an interplay of different tools that must be protected

The first line of defense, the intestine, comprises different tools working together to fight pathogens and harmful substances. Besides the mucus layers and the specialized cells, the intestinal microbiome plays an essential role in immune defense by competing with pathogens for nutrients and binding sites, enhancing the secretion of anti-inflammatory substances, and stimulating the production of interferons, which fight the pathogens. However, several factors can impact the balance of the microbiome and cause dysbiosis. The best protection of this sensitive equilibrium can support the organism in defending against diseases and maintaining immunity and performance. Understanding the interplay between microbiota, immune function, and nutrition allows for effective strategies to enhance poultry health while reducing reliance on antibiotics. Future research will continue to provide insights into optimizing gut-immune interactions in poultry production.

References

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Marcobal, A., P. C. Kashyap, T. A. Nelson, P. A. Aronov, M. S. Donia, A. Spormann, M. A. Fischbach, and J. L. Sonnenburg. “A Metabolomic View of How the Human Gut Microbiota Impacts the Host Metabolome Using Humanized and Gnotobiotic Mice.” The ISME Journal 7, no. 10 (June 6, 2013): 1933–43. https://doi.org/10.1038/ismej.2013.89. 

Stanley, Dragana, Shu-Biao Wu, Nicholas Rodgers, Robert A. Swick, and Robert J. Moore. “Differential Responses of Cecal Microbiota to Fishmeal, Eimeria and Clostridium Perfringens in a Necrotic Enteritis Challenge Model in Chickens.” PLoS ONE 9, no. 8 (August 28, 2014). https://doi.org/10.1371/journal.pone.0104739. 

Wallaeys, Charlotte, Natalia Garcia‐Gonzalez, and Claude Libert. “Paneth Cells as the Cornerstones of Intestinal and Organismal Health: A Primer.” EMBO Molecular Medicine 15, no. 2 (December 27, 2022). https://doi.org/10.15252/emmm.202216427. 

Yano, Jessica M., Kristie Yu, Gregory P. Donaldson, Gauri G. Shastri, Phoebe Ann, Liang Ma, Cathryn R. Nagler, Rustem F. Ismagilov, Sarkis K. Mazmanian, and Elaine Y. Hsiao. “Indigenous Bacteria from the Gut Microbiota Regulate Host Serotonin Biosynthesis.” Cell 163, no. 1 (September 2015): 258. https://doi.org/10.1016/j.cell.2015.09.017.

Recently, The Poultry Site’s Sarah Mikesell interviewed Predrag Persak, EW Nutrition’s Regional Technical Manager for Northern Europe. The conversation covered topics as wide as sustainability and challenges in poultry production, and as narrow as intestinal permeability. Thanks to The Poultry Site for the great talk!

Watch the video

Sarah Mikesell, The Poultry Site: Hi, this is Sarah Mikesell with The Poultry Site, and today we are here with Predrag Peršak. He is the Regional Technical Manager for Northern Europe with EW Nutrition. Thanks for being with us today, Predrag.

Predrag Peršak, EW Nutrition: Nice to be here, Sarah. Thank you for inviting me.

SM: Very good. It’s nice to visit with you. And today, Predrag and I are in Berlin, Germany, at an exclusive event for the poultry industry called Producing for the Future, which is sponsored by EW Nutrition. You are one of our speakers today, Predrag, so I’m going to ask you just a few questions to let everybody know a little bit about your presentation.

You’ve described animal nutrition as “never boring and never finished.” What makes this field so dynamic and constantly evolving for you?

PP: I’ve been in animal nutrition for about 25 years. And in those 25 years, I would say that not even half a year passed without something extraordinary happening. From genetics to animal husbandry, especially here in Europe, we also have a lot of pressure from consumers and slaughterhouses to adapt production to the needs of the customers.

Sustainability, sourcing raw materials, and the variety of raw materials available in Europe – and the constant development of new ones – make life for an animal nutritionist very, very interesting. It’s also very challenging, and through these challenges you learn a lot.

So, applying what we learned 20 years ago is simply not enough anymore. For someone who wants to be challenged every day with new things, this is definitely the right industry to be in – especially now.

SM: Excellent. Can you explain your holistic approach to animal nutrition and how considering multiple factors benefits practical applications on farms?

PP: The concept of a holistic approach in animal nutrition is not new. But for me – being both a veterinarian and a nutritionist – it means having deeper insight into the animal itself, into all the metabolic processes, and also into the external influences: husbandry, genetics, diseases, and management. Looking at how all of these interact, we can only really solve problems by looking at the animal as a whole system.

The same applies to feed production. You cannot look at a feed mill as just one compartment. You have to look at sourcing raw materials, their quality, how they are processed – milling, pelleting, and other technologies – and then see how that feed performs on the farm.

So, a holistic approach can be applied both from the animal perspective and from the feed production perspective, across all steps and processes. This is something we use and promote daily in our work with customers.

SM: Very good. You’ve worked with unconventional protein and fiber sources. We’re hearing a lot more about that recently. What are those, and what potential do they bring to animal nutrition?

PP: When I talk about unconventional protein and fiber sources, we need to remember that the global feed production scene is very diverse. What applies in the U.S. or Brazil does not necessarily apply in Europe or the Far East.

Here in Europe, we try to use not by-products but co-products of food production. For example, different fractions of rapeseed or sunflower meal, which are widely produced in Europe but not often used by mainstream nutritionists due to certain limitations. By finding the right processing methods and combining them with technologies, we can make these unconventional materials usable in mainstream nutrition.

The same goes for fiber sources. Both fermentable and structural fibers are increasingly important for intestinal and digestive development, as well as for overall animal health. So, processing fibers in ways that maximize usability while minimizing negative effects is a big part of my work.

SM: From a cost standpoint for producers, are those lower-cost inputs, or just alternatives they need to look at?

PP: In Germany we have a perfect expression for this: “yes and no.” There is always pressure on price, especially in poultry, because food must be accessible to everyone. But at the same time, food must not harm the environment or human health, and we should use all resources not fit for humans but still usable for animals.

So, it’s not only about cost – about availability and sustainability. Working with just two, three, or five raw materials for a long time is not the way forward. The way forward is to think of everything that can be used properly, for the benefit of the animals, and ultimately to produce enough food for the world.

Also, using locally available products is important. Feed production is very diverse around the world—raw materials in Southeast Asia differ completely from those in Europe, Brazil, or the U.S. Using technologies to enable the use of locally produced by-products makes production not only sustainable, but also economically viable for local communities. That’s really the core of the feed industry: using what is produced locally.

SM: Interesting. Very cool. How does your interdisciplinary work across poultry, pigs, and ruminants give you unique insights that might be missed with a narrower focus?

PP: I come from a small feed mill in a small country, Croatia. There, you don’t have deep specialization by species or even by category, as you find in larger markets. Specialization has its advantages, but it can also limit creativity and “outside-the-box” thinking.

By working with ruminants, I learned about fermentation processes – knowledge that can be applied to pigs and even to poultry. For example, fermentation can reduce anti-nutritional factors, allowing higher inclusion levels of certain raw materials in poultry diets.

With pigs, fermentation of fibers – especially in piglets – is crucial, and some of that knowledge could be applied to turkeys, where we still face health issues.

So, working across species demands a lot – it leaves little time for other things – but it opens up unique perspectives and cross-species applications that benefit the entire livestock industry.

SM: I was talking with someone yesterday about mycotoxins – there’s a lot of research in pigs but less in poultry. That’s kind of what you’re talking about, right? Applying knowledge across species?

PP: Absolutely. We’re focused now on poultry, but we can learn from poultry too – not only about feeding but also about farm management, biosecurity, and more. These lessons can also apply to pigs or ruminants.

It’s all holistic – you cannot solve everything with nutrition alone. It’s always a package.

SM: You presented today about the importance of intestinal permeability. Why is it important, and how can understanding it impact animal health and performance outcomes?

PP: Intestinal permeability is one of the key features we use to describe gut health. Personally, I’m very practical. For 20 years we’ve talked about “gut health,” but the real question for veterinarians and nutritionists is: what do we actually do with that knowledge?

In my presentation, I explained intestinal permeability as a “point of no return” in gut health. When leaky gut develops, everything else can deteriorate – faster or slower – but it won’t return to normal without intervention.

By comparing how different stressors or pathogens impact intestinal permeability, we can better understand severity and decide where to focus. Nutritionists already pay attention to thousands of factors, but we need to identify the most impactful ones. That was my key message: focus on the most important drivers.

SM: And leaky gut has really become something the whole industry is talking about, right? I’ve even seen it in human health – my doctor has posters about it.

PP: Exactly. Across cows, pigs, and poultry, leaky gut is getting a lot of attention. It’s a physiological or pathophysiological feature that marks the point of no return.

We can talk about dysbiosis and all the causes, but once you reach leaky gut, you understand where intervention is needed. And it’s not just hype. For example, recently Nature published research showing certain types of human bone marrow conditions are linked to leaky gut and microbial influence on blood processes.

So, this is not a passing trend. It’s fundamental. And once we solve one issue, another door opens. That’s why this industry is never boring.

SM: Very good. Well, thank you for all the information today, Predrag.

PP: Thank you, Sarah. It was a pleasure to talk with you.

Watch the video on The Poultry Site.

By Dr. Inge Heinzl, Editor EW Nutrition and
Marie Gallissot, Global Manager Feed Quality Solutions EW Nutrition

Antibiotic resistance is a growing global health concern, making infections more complicated to treat and increasing the risk of disease spread, severe illness, and death. While overuse and misuse of antibiotics are the primary causes, recent research has uncovered another unexpected contributor: mycotoxins. Among these, deoxynivalenol (DON), a toxin commonly found in contaminated grains, has been shown to significantly alter gut microbiota and promote antibiotic resistance. This article examines how DON impacts gut bacteria, influences antibiotic resistance, and highlights why this issue warrants urgent attention.

Mycotoxins – originators of antimicrobial resistance?

Actually, it would be logical…

Alexander Fleming discovered Penicillin when he returned after the summer holidays and saw that a mold had grown on the agar plate he had prepared. Around the mold, Staphylococcus was unable to proliferate. The reason was a substance produced by the mold – penicillin, which, like other toxins produced by molds, is a mycotoxin. In his article about the origin of antibiotics and mycotoxins, Shier (2011) stated that antibiotics and mycotoxins share considerable similarities in structure, metabolic roles, and biosynthesis.

A short excursus to antimicrobial resistance

In general, the primary mechanisms of resistance involve the prevention or limitation of the antimicrobial substance’s uptake, modifying the drug target, inactivating the drug, or facilitating its discharge with efflux pumps.

There are two types of resistance: natural resistance, which is further divided into intrinsic and induced resistance, and acquired resistance.

Intrinsic resistance is a “characteristic” of a bacterial species and is not dependent on antibiotic exposure. An example is the reduced permeability of the outer membrane of gram-negative bacteria, which prevents certain antibiotics from entering.

Induced resistance, however, needs to be initiated by antibiotics. Here, multidrug-efflux pumps can be mentioned.

The third one, acquired resistance, refers to the process by which bacteria acquire genetic material, the resistance genes, from other bacteria that are resistant. The mechanisms include vertical transfer to daughter cells and horizontal transfer, such as the transfer from dead bacteria to living ones, by viruses, or the transfer of plasmids (Reygaert, 2018).

Deoxynivalenol (DON) promotes resistance in gut microbiota

A Chinese group of researchers (Deng et al., 2025) examined for the first time the influence of DON on the intestinal microbiota of chickens. One of the most alarming findings is DON’s ability to enhance antibiotic resistance. It contributes to this issue in several ways:

1. Encouraging resistant bacteria – By disrupting microbial balance, DON provides a survival advantage to bacteria that carry resistance genes.
2. Activating resistance genes – Studies suggest that DON can increase the expression of genes that help bacteria withstand antibiotics.
3. Enhancing gene transfer – Bacteria can share resistance genes through horizontal gene transfer. DON appears to promote this process, making antibiotic-resistant strains spread more rapidly.
4. Weakening antibiotic effectiveness – DON-induced changes in the gut environment can reduce the effectiveness of antibiotics, making treatments less successful.

A further indication that mycotoxins can enhance resistance is the significant overlap in the geographical distribution of antimicrobial-resistant bacteria and genes with that of mycotoxins, as noted by Deng et al.

Which protection mechanisms do bacteria have against mycotoxins?

In the case of mycotoxins, bacteria employ similar molecular mechanisms to those used against antibiotics. In an in vitro experiment, Hassan et al. (2019) challenged Devosia mutans, a gram-negative bacterium, with DON in the growth medium. DON inhibits protein synthesis, induces oxidative stress, and compromises cell membrane integrity in eucaryotic cells. Hassan et al. asserted three adaptive mechanisms as the response to the challenge:

1. Activation of cellular membrane proteins (adenosine 5’-triphosphate-binding cassette -ABC- transporters) responsible for the unidirectional transport of substrates, either outward or inward. These ABC transporters can work as drug efflux pumps.
2. Production of DON-specific deactivation enzymes, thereby engaging a toxin-specific pyrroloquinoline quinone-dependent detoxification pathway. This enables the bacterial isolate to transform DON to a non-toxic stereoisomer.
3. Upregulation of auxiliary coping proteins, such as porins (transmembrane proteins involved in metabolite exchange), glutathione S-transferases, and phosphotransferases, both of which are likely involved in the detoxification of xenobiotics.

Public health implications and preventive measures

Given the widespread presence of DON in food and animal feed, its potential role in antibiotic resistance poses a serious threat. The combination of increased bacterial resistance and weakened antibiotic efficacy could lead to more difficult-to-treat infections. This is particularly concerning in hospital settings, where antibiotic-resistant infections already cause high mortality rates.

To address the issue, several strategies can be implemented:

1. Reducing DON contamination: Implementing improved agricultural practices, such as crop rotation, the use of fungal-resistant crop varieties, and maintaining proper storage conditions, can help limit fungal growth and DON production.
2. Monitoring food and feed supply – Strict regulations and testing for DON contamination in grains and animal feed are essential to minimize human and animal exposure.
3. Effective mycotoxin risk management at feed mill and farm levels: Using tools such as MasterRisk and effective products combatting mycotoxins.
4. Maintaining gut health: A healthy diet rich in fiber, probiotics, and gut health-supporting feed supplements, such as Ventar D or products from the Activo line, may help counteract some of the adverse effects of DON on gut microbiota.
5. Developing new treatments: Research into alternative therapies and new antibiotics is crucial to combat the rise of antibiotic resistance.

Antimicrobial resistance: Be aware of the mycotoxins!

The connection between mycotoxins, such as DON, and antibiotic resistance underscores the need for a broader perspective on public health and food safety and once again brings the “One Health Concept” into focus. While antibiotic overuse remains the primary driver of resistance, environmental factors, such as exposure to mycotoxins, should not be overlooked. By increasing awareness, enhancing food safety regulations, and investing in research, we can take steps to mitigate this emerging threat and safeguard the effectiveness of antibiotics for future generations.

References:

Deng, Fengru, Chuying Yao, Linyu Ke, Meichan Chen, Mi Huang, Jikai Wen, Qingmei Chen, Jun Jiang, and Yiqun Deng. “Emerging Threat to Antibiotic Resistance: Impact of Mycotoxin Deoxynivalenol on Gut Microbiota and Clonal Expansion of Extensively Drug-Resistant Enterococci.” Environment International 197 (March 2025): 109353.
https://doi.org/10.1016/j.envint.2025.109353.

Hassan, Yousef I., Jian Wei He, Dion Lepp, and Ting Zhou. “Understanding the Bacterial Response to Mycotoxins: The Transcriptomic Analysis of Deoxynivalenol-Induced Changes in Devosia Mutans 17-2-E-8.” Frontiers in Pharmacology 10 (November 14, 2019).
https://doi.org/10.3389/fphar.2019.01098.

Reygaert, Wanda C. “An Overview of the Antimicrobial Resistance Mechanisms of Bacteria.” AIMS Microbiology 4, no. 3 (2018): 482–501.
https://doi.org/10.3934/microbiol.2018.3.482.

Shier, W. Thomas. “On the Origin of Antibiotics and Mycotoxins.” Toxin Reviews 30, no. 1 (January 28, 2011): 6–30.
https://doi.org/10.3109/15569543.2011.550862.

Smith, William P., Benjamin R. Wucher, Carey D. Nadell, and Kevin R. Foster. “Bacterial Defences: Mechanisms, Evolution and Antimicrobial Resistance.” Nature Reviews Microbiology 21, no. 8 (April 24, 2023): 519–34.
https://doi.org/10.1038/s41579-023-00877-3.

by Ajay Bhoyar, Global Technical Manager, EW Nutrition

Anyone working with today’s fast-growing broiler chicken knows that it is a sensitive creature – and so is its gut health. Thanks to continuous improvements in terms of genetics and breeding, nutrition and feeding, as well as general management strategies, broiler production has tremendously upped performance and efficiency over the past decades. It is estimated that, between 1957 and 2005, the broiler growth rate increased by over 400%, while the feed conversion ratio dropped by 50%.

These impressive improvements, however, have come at the cost of intense pressure on the birds’ digestive system, which needs to process large quantities of feed in little time. To achieve optimal growth, a broiler’s gastrointestinal tract (GIT) needs to be in perfect health, all the time. Unsurprisingly, enteric diseases such as necrotic enteritis, which severely damages the intestinal mucosa, hamper the intestines’ capacity to absorb nutrients and induce an inflammatory immune response.

The modern broiler’s gut – a high-performing, but sensitive system

However, in a system as high performing as the modern broiler’s GIT, much less can lead to problems. From when they are day-old chicks up to slaughter, broilers go through several challenging phases during which they are more likely to show impaired gut functionality, e.g. after vaccinations or feed changes. Good management practices go a long way towards eliminating unnecessary stressors for the animals, but some challenging periods are unavoidable.

The transition from starter to grower diets is a classic situation when nutrients are very likely to not be well digested and build up in the gut, fueling the proliferation of harmful microbes. Immunosuppressive stress in combination with an immature intestinal microflora results in disturbances to the bacterial microbiota. At “best”, this entails temporarily reduce nutrient absorption, in the worst case the birds will suffer serious intestinal diseases.

Phytomolecules – the intelligent alternative to antibiotics

To safeguard performance during stressful periods, poultry producers need to anticipate them and proactively provide effective gut health support. For many years, this support came in the form of antibiotic growth promoters (AGP): administered prophylactically, they were effective at keeping harmful enteric bacteria in check. However, due to grave concerns about the development of antimicrobial resistance, non-therapeutic antibiotics use has been banned in many countries. Alternatives need to focus on improving feed digestibility and strengthening gut health, attacking the root causes of why the intestinal microflora would become unbalanced in the first place.

Phytomolecules are secondary metabolites active in the defense mechanisms of plants. Studies have found that certain phytomolecules stimulate digestive enzyme activities and stabilize the gut microflora, “leading to improved feed utilization and less exposure to growth-depressing disorders associated with digestion and metabolism” (Zhai et al., 2018). With other trials showing positive effects on broilers’ growth performance and feed conversion, the research indicates that phytomolecules might also specifically support chickens during challenging phases.

The effect of phytomolecules on broilers during a challenging phase

A study was conducted over a period of 49 days on a commercial broiler farm of an AGP-free integration operation in Japan. The farm reported gut health challenges in the second and third week of the fattening period due to vaccinations and changes to the animals’ diets. The trial included 15504 Ross 308 broilers, divided into two groups. The negative control group included a total of 7242 birds, kept in another house.

All the birds were fed the standard feed of the farm. The trial group (8262 birds) received Activo Liquid, which contains a synergistic combination of phytomolecules, administered directly through the drinking water. Activo Liquid was given at an inclusion rate of 200ml per 1000L of water (3.3 US fl oz per gallon of stock solution, diluted at 1:128), from day 8 until day 25, for 8 hours a day.

The results are summarized in Figure 1:

Figure 1: Improved broiler performance for Activo Liquid group (day 49)

The Activo Liquid group clearly showed performance improvements compared to the control group. Livability augmented by 1.5%, while the feed conversion rate improved by 3.2%. This resulted in a more than 5% higher score in terms of the performance index.

Challenging times? Tackle them using phytomolecules

Poultry producers take great care to eliminate unnecessary sources of stress for their birds. Nonetheless, during their lifecycle, broiler chickens face challenging periods during which the balance of the intestinal microflora can easily become disturbed, with consequences ranging from decreased nutrient absorption to full-blown enteric disease.

The trial reviewed here showed that, after receiving Activo Liquid, broilers raised without AGPs showed encouraging performance improvements during a challenging phase of feed changes and vaccinations. Likely thanks to the activation of digestive enzymes and a stabilization of the gut flora, the broilers showed improved livability and feed conversion, thus delivering a much more robust performance during a critical phase of their lives. In times where the non-therapeutic use of antibiotics is no longer an option, phytomolecules allow poultry farmers to effectively support their animals during challenging times.

References

Photo Source: Aviagen

Adedokun, Sunday A., and Opeyemi C. Olojede. “Optimizing Gastrointestinal Integrity in Poultry: The Role of Nutrients and Feed Additives.” Frontiers in Veterinary Science 5 (January 31, 2019): 348.

Jamroz, D., T. Wertelecki, M. Houszka, and C. Kamel. “Influence of Diet Type on the Inclusion of Plant Origin Active Substances on Morphological and Histochemical Characteristics of the Stomach and Jejunum Walls in Chicken.” Journal of Animal Physiology and Animal Nutrition 90, no. 5-6 (March 23, 2006): 255–68. 

Tavárez, Marcos A., and Fausto Solis De Los Santos. “Impact of Genetics and Breeding on Broiler Production Performance: a Look into the Past, Present, and Future of the Industry.” Animal Frontiers 6, no. 4 (October 1, 2016): 37–41.

Zhai, Hengxiao, Hong Liu, Shikui Wang, Jinlong Wu, and Anna-Maria Kluenter. “Potential of Essential Oils for Poultry and Pigs.” Animal Nutrition 4, no. 2 (June 2018): 179–86.

Zuidhof, M. J., B. L. Schneider, V. L. Carney, D. R. Korver, and F. E. Robinson. “Growth, Efficiency, and Yield of Commercial Broilers from 1957, 1978, and 20051.” Poultry Science 93, no. 12 (December 2014): 2970–82. 

 

Press Release

EW Nutrition awarded the 2019 “Outstanding Contribution Award” for reducing antibiotic resistance in the layer industry

On August 28-29, the BBS & Excellent Product Award Ceremony for Reducing Antibiotic Resistance for the Layer Industry was held in Guangzhou.

China’s Ministry of Agriculture and Rural Affairs reiterated that, starting from January 1, 2020, China’s livestock industry will face the challenge of reducing antibiotic resistance. For layer-breeding enterprises, food safety is the bottom line, and the production of safe eggs without drug residue is the most basic requirement.

The introduction of the new policy is also an opportunity for industrial upgrading. To further discuss the topic, the technical organization of Guangdong’s poultry industry invited well-known domestic and international experts and representatives of leading layer enterprises in China, totaling more than 500 people. On this occasion, EW Nutrition received the 2019 Outstanding Contribution Award for reducing antibiotic resistance in the layer industry.

Mr. Wang Deshu, EW Nutition’s Sales Director for China, was honored to receive this prestigious award, which reinforces EW Nutrition’s vision: mitigating the impact of AMR by providing comprehensive animal nutrition solutions. He took the opportunity to restate his eagerness to cooperate with the government in its endeavor to eliminate the use of AGPs by 31 December 2020.

EW Nutrition Sales Director Mr. Wang Deshu

EW Nutrition

EW Nutrition GmbH, an affiliate of EW Group, is a German-based company with offices and affiliates around the world, holding a strong science-based product portfolio in the field of innovative feed additives. EW Nutrition offers holistic solutions for antibiotic reduction, young animal nutrition, gut health management, toxin risk management and more, including a complex range of services in these areas.

Press contact
Caroline Gong (Marketing Manager, China, EW Nutrition)
Email:   caroline.gong@ew-nutrition.com
Phone:  +86 021 6042 8390