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Animal Nutrition Conference of Canada 2021
The following technical article is related to the event::
Animal Nutrition Conference of Canada 2021

Immunometabolism: The Potential Cause of and Solution to Our Most Pressing Poultry Problems in Health and Infectious Disease

Published on: 8/25/2021
Author/s : Ryan J. Arsenault / Assistant Professor, Department of Animal and Food Sciences, University of Delaware, Newark, DE, USA.

Poultry, and chicken specifically, have been a research model organism for decades. Much of our most fundamental and consequential discoveries in immunology and disease have come from the study of poultry. These discoveries cross the research spectrum from oncogenes to B-cells. At the same time chickens have been aggressively, and successfully, bred for greater growth and feed efficiency. While this breeding has been an indisputable success in terms of food animal production, it has had consequences in terms of emerging and re-emerging disease challenges in poultry. These challenges have a common theme in the form of the recent research perspective called immunometabolism. Immunometabolism refers to the interconnectedness of immune responses and metabolic processes. We can use an immunometabolic perspective to better understand poultry disease, both infectious and not. Immunometabolism has pointed to potential mechanisms of woody breast, the tolerance of chicken toward Salmonella, and the devastating effects of coccidiosis and necrotic enteritis. The challenges that we face in growing poultry ever more efficiently is coupled with greater restrictions on how poultry production is managed. These challenges of immunometabolism are also an opportunity. An integrated metabolic and immunologic perspective allows us to more fully understand disease pathogenesis and the mechanism of action of effective disease interventions. Importantly, it also opens up an entirely new world of possible solutions, nutritional and metabolic solutions, to the pressing health and disease problems in poultry.

Poultry Immunity
The poultry immune system is in many ways the “standard” vertebrate immune system, which is what makes it such a good model for immune research, though there are several key differences when compared to other agricultural species. Indeed, much of our fundamental understanding of immunology has come from the study of poultry, specifically chickens. Discoveries including retroviruses, oncogenes, interferon, vaccine development and B-cells have come from chicken studies (Stern, 2005; Taylor Jr and McCorkle Jr, 2009; Weiss, 1998). The vertebrate immune system is comprised of two branches, the evolutionarily more ancient innate immune system and the vertebrate-evolved adaptive immune system (Chaplin, 2010). The innate immune system involves non-specific barriers and responses, barriers such as skin and mucus, and responses such as inflammation and temperature increase (fever). The innate response is very rapid to immediate, and generally non-specific, recognizing patterns associated with pathogens rather than individual microbes. The adaptive immune system is a more recent evolutionary development, is cell-mediated or humoral, and extremely specific, though slower to respond to antigen insult. Receptors, initially low affinity, found on T- and B-cells result in stimulation and cellular expansion leading to an antigen-specific respond that can distinguish between close serovars. The adaptive immune system can generate an active response or tolerance to commensals and maintains an immune memory for subsequent antigen exposure.
Historically, nutrition and/or metabolism and immunology were treated as distinct research disciplines, and the significant cross-talk between the two was underestimated. With the emerging field of immunometabolism, where immunity and metabolism are considered part of an integrated whole, the connections are beginning to be unraveled (Mathis and Shoelson, 2011). There has been a veritable explosion in research related to immunometabolism in recent years. A Google Scholar search for “immunometabolism” conducted in February 2020 for papers published between 1900-2010 generated 361 citations, while that same search for papers published between 2010-2020 generated 5,850 citations. 
The impact of nutrition on immune potential has been known for decades, and nutritional studies in poultry that determined the limiting nutrients in effective immune responses allowed us to understand the nutritional building blocks of a proper immune system (Klasing, 2007). One aspect of the nutrition-immune dynamic that was clearly shown was that engaging the innate immune system is very energetically costly, though it is not costly to establish the system in the first place, while the adaptive immune system response is energetically efficient, though costly to establish the system beforehand (Klasing, 2007). The innate response causes an increase in thermogenesis, an invasion of effector cells, increase in blood supply, generation of expanded innate immune cells, production of cytokines and chemokines, among other changes, all placing significant energy and resource demands on the organism requiring enhanced metabolism and nutrient consumption. The adaptive immune system is already, in the main, established before an immune insult, a repertoire of antigen presenting cells, T-, and B-cells are present and ready to respond, for example. When the antigen receptor system is engaged a specific clonal expansion of B-cells and the engagement of a controlled T-cell response places less of a metabolic burden on the host. Following an initial adaptive response and the establishment of immune memory toward the antigen, there is almost no nutritional consequences to a secondary response to that same antigen (McDade et al., 2016). The activation of an immune cell, such as a macrophage or T-cell, has metabolic consequences for that cell. The reverse is also true; the alteration of metabolism in an immune cell can alter that cells immune response or potential. Shifting a macrophage from a predominantly glycolytic metabolic state to a predominantly oxidative phosphorylation-based metabolism shifts the cell from a proinflammatory M1 phenotype to an anti-inflammatory M2 phenotype (He and Carter, 2015). This phenomenon is also true of T-cells, shifting metabolism can result in either an effector T-cell (glycolytic) or T-regulatory (T-reg) cell (oxidative phosphorylation) (Mockler et al., 2014).
The Modern Broiler and Disease
Breeding and Immunometabolism
The modern broiler (meat production) chicken has been aggressively, selectively bred for feed efficiency for many decades. When Cecile Steele serendipitously started the United States broiler industry on her farm in Sussex County, Delaware (Williams, 1998), a chicken grew to 1.13 kg in 112 days, now a modern commercial broiler grows to 2.84 kg in 47 days (National Chicken Council). The modern broilers feed to meat gain ratio is now 1.8 kg-to-kg, the most efficient terrestrial agricultural animal. This fantastic increase in productivity and efficiency, 80% of which is due to genetic selection (Havenstein et al., 2003), has had an impact on the immune system of these birds, in addition to their metabolism.
The chicken disease coccidiosis, caused by the Eimeria parasite, is one of the major production loss diseases in the poultry industry. The total cost to the industry is estimated at $2.4 billion U.S.D (Quiroz-Castañeda and Dantán-González, 2015). Eimeria enters orally and invades and destroys the epithelium of the chicken gut, this leads to reduced feed intake, bloody diarrhea, reduced weight gain and can proceed to death. Different species of Eimeria preferentially invade different segments of the gut, E. acervulina develops in the duodenum, E. maxima and E. mitis develop in the middle part of the small intestine, E. tenella develops in the caeca, E. brunetti develops in the caeca and lower intestine, and E. necatrix develops in the small intestine (Quiroz-Castañeda and Dantán-González, 2015). A vaccine for coccidiosis is available; it incorporates various species of Eimeria at a low dose to expose the immune system to the parasite, resulting in subsequent protection. Groups, including Wang, et al., have shown that even the Eimeria containing vaccine has an impact on bird weight gain (Wang et al., 2019). Our group compared the heritage breed Athens-Canadian Random Bred (ACRB) broiler chicken that represents 1957 genetics with a modern broiler chicken following coccidia vaccination and found that that in the ACRB there was an induction of apoptosis/inhibition of cell growth, and in the modern broiler, there was an induction of cell growth related signaling. The apoptosis response may represent an attempt to restrict pathogen growth and spread, as Eimeria is an intracellular pathogen. Following a pathogenic dose of Eimeria the ACRB again induced apoptosis and initiated a glycolytic response while the modern broilers did not show these responses. These results highlight the immunometabolic differences following pathogen challenge due to the differing genetics of these two lines of chickens. 
In general, chickens are refractory in their immune response to the Salmonella species of greatest health concern to humans (Kogut and Arsenault, 2017). This results in a foodborne illness problem as Salmonella harboured in the chicken gut or organs can contaminate poultry products and result in human illness. Our group and others have determined that if Salmonella is given early in a chick’s life they will generate an inflammatory response to the bacteria. This response manifests in several ways: an interleukin (IL)-6 to TGF-B transition around day 4, induction of Wnt signaling, and the activation of NFκB (Kogut and Arsenault, 2015). After 4 to 7 days post-hatch, a transition occurs in chickens where anti-inflammatory IL-10 is expressed and there is an increase in T-reg cells, both resulting in reduced immune response (Shanmugasundaram et al., 2015). We determined that one mechanism of this transition is the inhibition of glycogen synthase kinase 3β (GSK3β) and thus glycolysis by Salmonella infection (Kogut et al., 2014). With GSK3β inhibited, there is a decrease in expression of pro-inflammatory cytokines and an increase in antiinflammatory cytokine IL-10. The result being a tolerance of Salmonella in the gut of infected chickens.
Table 1. Summary of the immunometabolic changes occurring in the chick following exposure to Salmonella. Adapted from (Kogut and Arsenault, 2017)
Summary of the immunometabolic changes occurring in the chick following exposure to Salmonella. Adapted from (Kogut and Arsenault, 2017)
Wooden Breast 
Wooden breast is a myopathy that involves the pectoral muscle of commercial broiler chickens (Papah et al., 2018). The disorder is characterized by abnormally firm muscle, resulting in an undesirable consistency of the meat, which affects meat quality traits. Expression profiling of the muscle tissue comparing wooden breast to normal breast muscle tissue has shown a variety of immune and metabolic changes occurring in the abnormal (“wooden”) muscle cells (Papah et al., 2018). These changes include an increase in inflammatory response, metabolic dysregulation of lipids and fatty acids and connective tissue remodeling abnormalities. In addition to breeding for rapid growth and feed efficiency, breeders in the United States have selected broiler chickens for the development of large breast muscle, as these cuts of meat are the most desirable in the U.S. market. This puts the pectoral muscle under significant metabolic and physical stress as it rapidly grows, growing out of proportion to the rest of the chicken body. As a result, there are alterations in immune responses to this metabolic program in some chicken strains resulting in abnormal muscle deposition.

The Challenge and the Opportunity
In both animal production and human health, the interactions between immunity and metabolism can appear to be a significant challenge. In humans, issues with obesity can lead to chronic immunological diseases, including autoimmune diseases. The demands of animal agriculture production, greater yield with fewer inputs, places significant metabolic strain on animals, thus impacting their immune potential and susceptibility to disease. However, this immune-metabolism interplay can also be viewed as an opportunity. The dichotomy that once stated that the solutions to growth and to disease are distinct no longer apply. Using the knowledge we are gaining in immunometabolism we can expand our intervention repertoire to include solutions across the spectrum from nutrition changes to drugs. To date, the greatest advances using this perspective have come in cancer research. Tumors switch their metabolic program as they grow and divide uncontrollably, targeting this metabolic program can aid in the treatment of several types of cancer. Effector and helper T-cells can be inhibited by 2-Deoxy-D-glucose [2DG] or rapamycin by inhibiting glycolysis or mTOR, respectively (Mockler et al., 2014). These approaches may be applicable to infectious or metabolic disease such as activating an immune response with etomoxir, which inhibits the development of Tregs or metformin, which activates lipid oxidation. In animal production, with nearly total control of the diet formulations, we may be able to feed-in proper immune potential or feed-out excess inflammation in certain circumstances. Our research on postbiotics have shown that feeding the beneficial metabolites of a probiotic fermentate can modulate the gut immune response, not diminish or stimulate, to improve growth and resistance to pathogen challenge (Johnson et al., 2019). Thus, rather than the extreme solution advocated by some to return to slow growth, inefficient animal production systems, a nutritional or feed additive corrective to the current challenges may allow us to keep the dramatic gains we have attained in animal production while further improving the health, wellbeing and disease resistance of our domestic animals.
Published in the proceedings of the Animal Nutrition Conference of Canada 2020. For information on the event, past and future editions, check out https://animalnutritionconference.ca/.

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