The term immunonutrition originated from some human studies conducted in the 1950s and suggests a link between malnutrition and the occurrence of infections (Shetty, 2010). From the 1970s onwards, this concept began to be broken down into four general guidelines on how nutrition can impact the immune response:

– Malnutrition (especially protein-energy related) and nutrient deficiencies.

– Nutrition as a determining factor on the immune capacity of newborns and older people.

– The influence of obesity and excessive intake of nutrients on the individual’s immunocompetence.

– How interactions between nutrition and immunity impact clinical medicine and public health (Chandra, 1993).

In the 1980s and 1990s, other studies investigating population monitoring data for decades corroborated this concept. Since then, the immunonutrition in humans has been investigated in many broader aspects and is considered a multifactorial science since nutrition is related to nutrient digestion and absorption in the gastrointestinal tract, microbiota, immune system, organs involved in the inflammatory processes (and their secondary effects), nervous system, hormone production, etc. This concept has been understood and applied to animal nutrition for a long time due to the advances in knowledge of nutrition and health. However, the term immunonutrition has been effectively applied in recent years.

It is essential to understand that, besides being responsible for the digestion and absorption of nutrients, the gastrointestinal tract is a crucial organ for the immune response. Approximately one-quarter of the intestinal mucosa comprises lymphoid tissue, and over 70% of it consists of immune cells (Wershil & Furuta, 2008). Gut-associated lymphoid tissue (GALT) is the main component of mucosal-associated lymphoid tissue (MALT). It is also a significant immune cell source that monitors and protects intestinal mucosa layers. GALT is continuously exposed to dietary antigens, microbiota, and pathogens (Dalloul & Lillehoj, 2006). Then, the development and maturation of the immune system can be affected by external factors (environment, diet) and factors inherent to the animal (genetics, age).

These factors also impact the microbiota and intestinal health. The intestinal microbiota has many functions in the organism and plays a vital role in the gut-brain axis bidirectional communication (Cryan & Dinan, 2012). In other words, the central nervous system (CNS), via the hypothalamus-pituitary axis, can be activated in response to stress factors, thus releasing cortisol (Image 1, below). Cortisol affects the immune cells, releasing pro-inflammatory cytokines, influencing intestinal permeability, and leading to microbiota changes (Landeiro, 2016).

Image 1. The microbiota-gut-brain axis scheme (Verduci et al., 2020).

Besides having the function of absorbing nutrients, the intestinal epithelium acts as a physical barrier. If intestinal permeability is impaired, microorganisms and lipopolysaccharides (LPS) can pass through the lamina propria, activating the immune cells and releasing pro-inflammatory cytokines, which will affect the central and enteric nervous systems (Gareau et al., 2008). Several physiological changes may result from these responses, including fever, metabolic inefficiency, skeletal muscle catabolism, and synthesis of acute phase proteins (Korver, 2006). Also, an impact on energy and nutrients used for growth or maintenance may be observed.

Therefore, the pro-inflammatory response caused by any of the abovementioned factors can result in compromised immunocompetence. The animals must develop their immune response and protection abilities throughout life, i.e., these abilities are modulated each day since the metabolic cost vs. an induced immune response is low and directly affects the maintenance of metabolic homeostasis.

According to the established concept of immunonutrition, amino acids (glutamine, arginine, cysteine, taurine), nucleotides, lipids (monounsaturated and polyunsaturated fatty acids, omega-3 fatty acids), vitamins (A, C, and E) and trace minerals (zinc and selenium) (McCowen & Bistrian, 2003) are classified as immunonutrients. Some immunomodulating substances are not absorbed like nutrients but can directly or indirectly modify the immune system response, such as prebiotics, probiotics, and phytogenic compounds.

β-glucans are among the most studied immunonutrients in the literature and are derived from the yeast cell wall (β-1,3 and 1,6-glucans). Their mode of action consists of recognizing phagocytic or antigen-presenting cells (APC) in the lamina propria just below the intestinal epithelial cells. These cells have a toll-like receptor on their surface, which recognizes microbial patterns and induces an immediate innate immune response. After this activation and phagocytosis, the phagocyte presents a processed antigen fragment and stimulates a chain response (Image 2, below). Pro-inflammatory cytokines are released and activate the production, release, and mobilization of additional phagocytic cells and proliferation of goblet cells (mucus production), among other effects. The recognition of pathogens and antigens by the innate immune system triggers immediate innate defenses and the activation of an adaptive immune response (Lee & Iwasaki, 2007).

Image 2. β-glucans modo of action scheme.

Activating the innate immune system by β-glucans is known as immunomodulation since there is no damage to the intestinal epithelium or invasion of epithelial cells. The result is putting the innate immune system cells on alert and preparing the animal to face the day-by-day challenges with low metabolic costs. This is a key factor in diets for:

– Young animals (puppies) in which the immune organs are under development and immune response are under maturation. Vaccination in this period is a great challenge, as it is essential to succeed in the face of immunological immaturity and maternal antibodies (Klein et al., 2014). During the first year of age, alterations in the quantity and proportion of circulating leucocytes will impact general immunocompetence. It is also related to genetic breed determination factors (Day, 2007).

– Special diets for animals with intestinal problems or diseases that may unbalance the intestinal microbiota or cause depression in the immune response (chronic problems).

– Senior diets due to the immune system’s susceptibility in advanced ages.

– General adult diets to support the daily challenges.

These benefits can be measured by quantifying antigen-presenting cells circulating in the blood, helper T and cytotoxic T lymphocytes, immunoglobulins (Bonato et al., 2020), vaccine titers, and others. Thus, effects on maintaining intestinal permeability may also be observed since, as mentioned previously, there is a close relationship between the microbiota, intestinal permeability, and the immune system.

Given the complexity of the associated factors, there is still much to be studied about the microbiota-intestine-brain axis. However, using immunonutrients, individually or associated, has been proven to promote benefits for the health, welfare, and growth of the animals. Therefore, it is crucial to fully understand their mode of action to enable the correct application in each phase and type of diet.

References

• Bonato, M.A; Borges, L.L.; Ingberman, M.; Fávaro Jr. C.; Mesa, D.; Caron, L.F.; Beirão, B.C.B. Effects of the yeast cell wall on immunity, microbiota, and intestinal integrity of Salmonella-infected broilers. Journal of Applied Poultry Research, 29:545-558, 2020.
• Chandra, R. Nutrition and the immune system. Proceedings of the Nutrition Society, 52(1): 77-84, 1993.
• Cryan, J.F.; Dinan, T.G. Mind-altering microorganisms: the impact of the gut microbiota on brain and behavior. Nature Reviews Neuroscience, 13(10): 701–712, 2012.
• Dalloul, R.A.; Lillihoj, H.S. Poultry coccidiosis: recent developments in control measures and vaccine development.  Expert Rev. Vaccines, v. 5, p.143-163, 2006.
• Day, M.J. Immune System Development in the Dog and Cat. Journal of Comparative Pathology, v. July,2007, p. S10-S15, 2007.
• Gareau, M.G.; Silva, M.A.; Perdue, M.H. Pathophysiological mechanisms of stress-induced intestinal damage. Current Molecular Medicine, 8(4): 274–281, 2008.
• Klein, R.P; Lourenço, M.L.G; Moutinho, F.Q.; Takahira, R.K; Lopes, R.S; Martins, R.R; Machado, L.P.; Silveira, V.F.; Ferreira, H. Imunidade celular em caninos neonatos – do nascimento ao 45° dia de idade. Arq. Bras. Med. Vet. Zootec., v.66, n.3, p.745-756, 2014.
• Korver, D.R. Overview of the Immune Dynamics of the Digestive System. Journal of Applied Poultry Research, 15:123–135, 2006.
• Landeiro, J.A.V.R. Impacto da microbiota intestinal na saúde mental. Tese (Doutorado em Ciências Farmacêuticas) – Instituto Superior de Ciências da Saúde Egas Moniz, Almada, Portugal, 81p, 2016.
• Lee, H. K.; A. Iwasaki. Innate control of adaptive immunity: dendritic cells and beyond. Semin. Immunol., n. 19, p.48-55, 2007.
• McCowen K.C; Bistrian B.R. Immunonutrition: problematic or problem solving? The American Journal of Clinical Nutrition, 77(4):764–70, 2003.
• Shetty, P. Nutrition, immunity e infection. Paper­back: 224 pages; Publisher: CABI Publishing; 1 edition 2010.
• Verduci, E.; Carbone, M.T; Borghi, E.; Ottaviano, E.; Burlina, A.; Biasucci, G. Nutrition, Microbiota and Role of Gut-Brain Axis in Subjects with Phenylketonuria (PKU): A Review. Nutrients 2020, 12, 3319, 2020.
• Wershil B.K.; Furuta G.T. Gastrointestinal mucosal immunity. Journal of Allergy and Clinical Immunology, n. 121, p. 380-383, 2008.

 

Melina Bonato, Ph.D. – Global R&D and Technical Manager, ICC Animal Nutrition
Céline Villart – European Technical Supervisor, ICC Animal Nutritiom