Intestinal health and pathogen risk-reduction benefits antimicrobial management

In the dynamic world of livestock production, the increase of antimicrobial resistance and consumer demand for high-quality food has raised the interest for sustainable and ‘natural’ alternatives to AGPs to meet growth performance and feed efficiency expectations. Phytogenic compounds are on the frontline for their demonstrated benefits in this field. Moreover, phytogenic compounds supplemented at low inclusion rates have shown to be beneficial not by inhibiting pathogens, but by supporting the animal’s resilience to overcome them more effectively.

It has been almost 100 years since penicillin was discovered by Alexander Fleming. Since then, other antimicrobials and new applications other than medical treatment were developed. With that, also evolved the phenomenon antimicrobial resistance (AMR), in which bacteria experience structural or biochemical changes, becoming resistant to antimicrobials. The risk comes from the transmission of genes responsible for antimicrobial resistance from harmless bacteria to pathogen recipients.

Then mitigating AMR became a global priority, with the European Union leading the ban of antibiotics used as growth promoters in 2006. Since then, antimicrobials can only be distributed by veterinarians for therapeutic treatment.

Economical animal production will only be possible by adopting a holistic approach, enhancing intestinal resilience, supporting systemic immunity, and promoting proper biosecurity and management.

PAST AND CURRENT STATUS OF ANTIMICROBIALS IN ANIMAL PRODUCTION
According to the National Committee for Clinical Laboratory Standards of USA, in-feed antimicrobials have four applications to animal production:
(a) therapy, or the administration of an antimicrobial to a clinically diseased animal; (b) control, or the administration of an antibiotic to infected animals which exceed the baseline of morbidity and/or mortality; (c) prevention, or the administration of an antibiotic to healthy animals which are thought to be at risk; and (d) growth promotion, or the administration of an antimicrobial over a period of time enhancing the growth by improving physiological performance.

The current global annual consumption of antimicrobials per kilogram of animal product is estimated as 45 mg/kg for cattle, 148 mg/kg for poultry, and 172 mg/kg for swine. From this baseline, projections indicate that global antimicrobial consumption will increase by 67% between 2010 and 2030, from 63,151 ± 1,560 tons to 105,596 ± 3,605 tons (Ma et al., 2021). Pigs have the largest projected increase, contributing to 45% of the total increase between 2017 and 2030. Africa will have the highest expected increase by 2030 (37%). Asia is expected to increase its use of antimicrobials by 10.3% in the same period. Oceania (3.1%), North America (4.3%), and Europe (6.7%) are expected to have the smallest increase among the global regions (Tiseo et al., 2020).

IMPACT OF ANTIMICROBIALS ON ANIMALS AND HUMANS
Antibiotics are important for treatment of bacterial infections, pneumonia, urinary infections, arthritis, sepsis, and secondary infections. Their application is also valuable in protecting people more vulnerable to the harmful effects of infections: seniors over 75 years, neonates and babies with bacterial infections, patients with heart failure, diabetes, or a weakened immune system (NHS, 2023). Antibiotics are not only important for treating individuals, but also to avoid the spread of pathogens and diseases to the environment and the population.

Recent reports have revealed that the use of large amounts of antimicrobial medication could result in antibiotics residues in animal products. Although good quality milk, meat, and other related products are a prime need for supporting public health, the presence of antimicrobial residues above the maximum residue level (MRL) in food items and their subsequent consumption by consumers may cause health problems. The Food and Agriculture Organization (FAO) / World Health Organization (WHO) reported that antibiotic residues in foods of animal origin have increased beyond the permissible levels in developing countries.

SUPPORTING INTESTINAL HEALTH AND RESILIENCE OF FARM ANIMALS
The definition of “intestinal health” or “gut health” is not yet clear. It was initially proposed that gut health is the function of three major components: the diet, the mucosa, and the commensal microbiota. Later, researchers elaborated that it must include a diet that would provide sufficient nutrients, mucosa that maintains the gut integrity, and a microbial community that maintains a balanced, healthy environment (Jha et al., 2019).

Since we need to limit or remove antibiotics as growth promoters, and preventive medication or metaphylaxis, significant focus must be on precise nutrition and the concept of ideal protein, and other nutrients involved in the modulation of intestinal environment and epithelial integrity.

Excessive amounts of dietary protein reach the intestine, and the fermentation of it can produce various potentially toxic compounds (such as amines and ammonia), often associated with the growth of potential pathogenic bacteria (e.g., Clostridium perfringens) and the reduction of fecal counts of beneficial bifidobacteria (Yang et al., 2019). Similarly, formulation based on digestible rather than total amino acids reduce the non-digestible nitrogen reaching the intestine with an equivalent effect.

On the other hand, dietary amino acids requirements are defined based on growth or production performance, and those levels might not be the optimal for the vital roles they play on the small intestinal mucosa. Particularly, glutamate, glutamine, and aspartate are the major oxidative intestinal fuel. Utilization of glycine by the small intestinal mucosa to synthesize glutathione is a very important physiological pathway, and the role of glycine as a powerful cytoprotectant has also been recognized. The major end products of methionine and cysteine metabolism are glutathione, homocysteine and taurine, which play important roles in the intestinal immune and anti-oxidative responses. Threonine is highly utilized by the gut and is particularly important for mucin synthesis and maintenance of gut barrier integrity. Emerging evidence shows that arginine activates the mammalian target of rapamycin (mTOR) signaling pathway in the small intestine, integrating both intracellular and extracellular signals. It regulates gene transcription and protein synthesis, serving as a central regulator of cell metabolism, growth, proliferation and survival (LaPlante et al., 2009).

Other nutrients, like omega 3 and omega 6 poly-unsaturated fatty acids (PUFA), are essential for countless metabolic functions. Both fatty acids are needed for an adequate immune system; however, increasing the n3/n6 ratio reduces the production of the inflammatory mediators interleukin 1-β and prostaglandin E2, which is favorable to the integrity of tight junctions on the intestinal epithelium (Shin et al., 2017).

Dietary fiber (DF) stimulates the growth of beneficial intestinal bacteria, being fermented in the distal small intestine and large intestine with beneficial effects on the immune system. Microbial fermentation of DF results in the production of short-chain fatty acids (SCFA), branched-chain fatty acids (BCFA), lactate, amines, indoles, phenols, and gasses. In the absence of appropriate DF levels, proteolytic fermentation can take place in the colon, producing BCFA and potentially harmful metabolites like ammonia indoles, and phenols (Jha et al., 2019).

BIOSECURITY IN FEED AND FARM
Biosecurity practices in the feed to food chain are another fundamental tool to reduce AMR. Biosecurity helps to minimize the risk of entrance and transmission of microbial-associated pathogens, and therefore, reduces the need to use antimicrobials.

• Feed Safety
Heat treatment is a crucial processing step for feed hygiene management, preventing microorganisms from entering the feed to food chain. However, the efficacy of thermal treatment depends on the resistance of the contaminating agent and will not prevent further cross-contamination during post-processing. Thus, corrective measures need to include different approaches: intensive feed quality monitoring to assess microbial risk situations, identification of critical control points and application of feed preservatives are important tools for microbial control, contributing to inhibit the growth of molds, and mycotoxins risk management.

• Farm environment and management
The adoption of proper farm biosecurity practices can considerably reduce the risk of infections and consequent use of antimicrobials. Important measures include defining zones of restricted access, limiting visitors, intensive cleaning and disinfecting between each production cycle, implementing a proper vector (wild birds, flies and rodents) control program, and coaching farm workers on the best biosecurity practices and risk awareness.

Monitoring the water quality and ensuring hygienic conditions throughout the water system will also help reduce microbiological load in the water and prevent biofilm formation in the water lines. All these steps are critical to prevent vertical and horizonal pathogen transmission.

• Vaccination
Vaccination programs play an important role in mitigating antimicrobials use, as they block the transmission of pathogens, including potentially drug-resistant forms. However, vaccination represents a particular stressor, inducing a reaction of the immune system with temporary inflammation. This represents a costly nutritional resource and it is important to limit over-activation after vaccination to avoid a drop in growth performance. Different studies have highlighted the interest of supplementing low inclusion rates of combined phytonutrients, such as curcuminoids (present in turmeric oleoresin) and capsaicinoids (present in red chili pepper oleoresin) in boosting the effects of vaccination while limiting its negative subclinical effects (Lee et al., 2011; Awaad et al., 2019; Upadhaya et al., 2020).

ENHANCING GROWTH AND FEED EFFICIENCY
In the dynamic world of livestock production, the increase of antimicrobial resistance and consumer demand for high-quality food has raised the interest for sustainable and ‘natural’ alternatives to AGPs to meet growth performance and feed efficiency expectations. Phytogenic compounds are on the frontline for their demonstrated benefits in this field. Moreover, phytogenic compounds supplemented at low inclusion rates have shown to be beneficial not by inhibiting pathogens, but by supporting the animal’s resilience to overcome them more effectively.

The proposed mode of action of phytogenic compounds is attributed to the mitigation of gut inflammatory response, the increase of the digestive secretions and nutrient absorption (and utilization) in the gastrointestinal tract, the improvement of animals’ antioxidative status, reducing damage to intestinal cells and maintaining the integrity of the intestinal mucosal layer (Awaad et al., 2014; Bravo et al., 2014; Karadas et al., 2014; Pirgozliev et al., 2019).

An extensive number of studies in broilers demonstrated that the combination of carvacrol (present in oregano), cinnamaldehyde (present in cinnamon) and capsicum oleoresin (present in red chili pepper) has the potential to achieve similar levels of growth performance as AGPs and showed positive results in broiler carcass and meat quality (Bravo et al., 2009; Heng et al. 2017). Additional studies also showed this combination improved the nutritional value of low-metabolizable energy (ME) diets when fed to broilers. This beneficial effect seems to be mediated by decreasing the energy required for the maintenance of gastrointestinal tract, diverting more energy towards growth rather than maintenance (Bravo et al., 2011).

In poultry production, phytogenic compounds became a natural strategic tool to completely or partially replace the application of AGPs and have proved their effectiveness without involving risks to animals, consumers or the environment (Gharib et al., 2014).

POTENTIAL BENEFITS OF ANTIMICROBIAL REDUCTION AND MANAGEMENT
According to a 2019 report, the United States Center for Disease Control and Prevention (CDC) estimated that the annual cost of AMR is USD55 billion in the US, USD20 billion for health care and USD35 billion for loss of productivity. In contrast, costs related to drug-resistant bacterial infections in Europe correspond to EUR 1.5 billion/year. At the international level, it’s estimated that AMR will reduce the global gross domestic product by up to 4% and the global livestock production by up to 7.5% by 2050.

These numbers provide a very clear understanding of the benefits of minimizing the use of antimicrobials. A multi-prong approach is required for proper antibiotic management and global reduction of AMR.

References
1. Awaad M. H. H., Elmenawey M., and Ahmed K. A. 2014. Effect of a specific combination of carvacrol, cinnamaldehyde, and capsicum oleoresin on the growth performance, carcass quality and gut integrity of broiler chickens. Veterinary World 7(4): 284-290.
2. Awaad, M. H., Elmenawey, M., Shalaby, B., Mohamed, F. F., Nada, A. M., Salem, H., … & Lopez, S. (2019). Opposing of necrotic enteritis by phytonutrients and/or acidifiers in broiler chickens. IOSR JAVS, 12, 12-21. https://www.researchgate.net/publication/331990566_Opposing_of_Necrotic_Enteritis_by_Phytonutrients_andor_Acidifiers_in_Broiler_Chickens
3. Bravo D., Pirgozliev V. and Rose S. P. 2014. A mixture of carvacrol, cinnamaldehyde, and capsicum oleoresin improves energy utilization and growth performance of broiler chickens fed maize-based diet. J ANIM SCI 92:1531-1536.
4. Gharib H.B. 2014. Evaluation of using dietary phytogenics, as growth promoters, on broiler performance, under normal and subnormal temperature conditions. Egyptian J. Anim. Prod. 51(1):49-59.
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About Célia Gomes da Silva
Graduated in Animal Science with a MSc degree by the University of Trás-os-Montes e Alto Douro (Portugal) and with a double BSc degree in Animal Husbandry (The Netherlands), Célia Gomes da Silva conducted her academic research in projects related with the effect of polyphenols on in vitro rumen fermentation and mycotoxins occurrence in feed. In 2016, Célia started her path in the feed additives industry, working with a broad range of product categories applied to microbial control, feed to food safety, gut health and contributing to the development of new solutions. In 2020, she joined ADM for the position of Global Product Specialist, focusing on Phytogenic Bioactives, where she’s been actively involved in applied research, technical support, trainings to technical and sales teams and product life cycle assessment.

About Dr. Luiz W. O. Souza
With mixed expertise in animal nutrition and health, Dr. Luiz Souza has built his 20-years career with extensive work within research centers, farms and feed mills. Graduated in Brasil, he obtained further research experience in the US, and later joined the additives industry in Asia, based in Singapore. His holistic experience with swine and poultry includes in-farm management, welfare and bioclimatology, biosecurity, additives application, nutrition and formulation, good manufacturing practices, and raw material and feed quality control. Recently, Dr. Luiz joined ADM Animal Nutrition in the Vietnam office, to lead the technical sales and services in Asia.