The gut immune system consists of three lines of defense systems: barriers, innate immunity and adaptive or acquired immunity (Figure 1) that work together to give ruminant gastrointestinal tract (GIT) protection from disease. In this brief overview, I will provide some basic principles. The intestinal barrier system is probably the most overlooked defense mechanism but it eliminates 99.9% of all infections. This system is very susceptible to dehydration and changes in microbial populations. The gut mucosal immune system alone contains more than a trillion (1012) lymphocytes and has a greater concentration of antibodies than other tissues in the body. It protects against harmful pathogens but also tolerize (induces tolerance) the immune system to dietary antigens and normal microbial flora. The three defense components of the gut mucosal immune system are integrated together.
Figure 1. The three lines of gut immune defense.
Intestinal epithelium- the largest immune organ.
The first line of defense is the epithelium in the GI tract. The epithelial cells (enterocytes) function for secretion and absorption. When it comes to their immune function, they are essential. First, these cells knit themselves together with special proteins that form “tight junctions” (Figure 2). A tight junction is the physical barrier that keeps pathogens out. Healthy enterocytes will maintain that tight junction. Unhealthy epithelium becomes leaky. On the surface of the mucosa epithelium there is a physical barrier (Figure 2). There are three components of this barrier also known as the “Kill Zone” levels: mucous and mucins, antimicrobial proteins and secretory IgA. The goblet cells secrete mucous and mucins (the enterocytes also secrete mucins) that provide the initial mucous barrier (Figure 2). The mucosal barrier contains defensins [aka as antimicrobial peptides (AMP) and host defense proteins (HDP)] produced by the enterocytes. In the lamina propria, B cells produce antibody. This antibody production is driven by what happens in mucosa epithelium. The key is that for IgA to become secretory IgA—has to go through a healthy enterocyte. Enterocytes are involved in the export of IgA from the lamina propria to the lumen (Figure 2). The interesting thing about enterocytes is that they want to avoid inflammation.
Figure 2. Mucosa Epithelium and the Kill Zone. The Kill Zone is in close apposition to the gastrointestinal enterocytes and contains mucous, mucins, antimicrobial peptides (AMPs) and secretory immunoglobulin A (sIgA)(Maynard 2012). The IgA is producing by B cells in the lamina propria that have matured to become plasma cells and the IgA has to be bound by polymeric Ig receptor (pIgR) and exported by the enterocytes to the lumen to be sIgA. The lamina propria also contains different types of lymphocytes including innate lymphoid cells (ILC), natural killer (NK) cells and lymphoid tissue inducer (LTi) cells that also produce cytokines that induce AMPs. Adapted from Maynard et al., Nature 2012; 489, 231–241
On the other side of the epithelial cell in the lumen is where the microbiota (microbiome) is located. It is a collection of organisms found in the animal’s GIT and is dependent on the region of the GIT and the age of the animal. Colostrum is important for microbiome development as it increases microbiome density. The microbiome is essential for immune development and the composition will influence the host immune status. When it comes to the immune system, the lower intestinal tract is thought as being the most important part of the immune development and the microbiome interaction that occurs. The large intestine is less important.
Protection of the GIT
Having a “healthy microbiome” results in optimal GIT mucosa function. For example, certain clostridial species do a good job of producing butyrate. Butyrate and other small chain fatty acids have a calming effect and cause the GIT epithelium to be much calmer and inhibit that inflammatory response. These anti-inflammatory signals are not coming from the host side of the GIT, but from the bacteria along with metabolites. That’s why commensals are so important. They are affecting the host response. The host response is not to just the bacteria and other microorganisms, but also on microbial cell components and metabolites of bacteria. This achieves homeostasis in the GIT mucosa by inducing the protective responses to pathogens maintaining the regulatory pathways for tolerance to innocuous antigens and prevents inflammation, making for a happy gut and an animal that can more closely achieve its maximum genetic potential.
Modulation of the response–what can we learn from human medicine.
Although we have been using prebiotics, probiotics, essential oils and/or organic acids in swine production for years, the approaches have often been empirical and based on one or two components with little understanding of the mechanism of action. In looking at human medicine and the prevention and treatment of inflammatory bowel disease, there has been a more holistic multipronged approach developed (Figure 3). Like veterinary medicine, the initial approaches for prevention and/or treatment of GIT disease were pharmaceutical based with antibiotics being a major tool. Using a multipronged approach in humans has been aimed at reducing the use of exogenous corticosteroids and/or antibiotics (Figure 3, circle lower left). There are several GIT health goals from these multipronged approaches. First, maintain a healthy “kill zone” and mucosa and block specific pathogen attachment (Figure 3, center green box). Second, correct dysbiosis and restore normal microbial function (Figure 3, upper left blue box), and normalize the immune dysfunction and repair barrier defects (Figure 3, upper right lavender box). These approaches may be accomplished by using traditional approaches (probiotics, organic oils, high fiber diets, or combinations of these), cutting edge methods (fecal microbial transplants; synthetic mixtures of defined microbes, personalized for an individual’s specific microbiota profile; and personalized diets). Then there are novel experimental approaches (bacteriophages targeting key aggressive bacteria; using synthetic microbial metabolites or recombinant bacterial species) that also have promise.
Figure 3. Targeting the mucosa with nutraceuticals that specifically enhance the microbiota and improve barrier and immune function. AIEC, attaching and effacing E. coli; EGFR, epidermal growth factor receptor; FA, fatty acid; FXR, farnesoid X receptor; FMT, fecal microbial transplant; HS, hydrogen sulfide; IL-10, interleukin 10; OMV, outer membrane vesicles; SCFA, short chain fatty acids; SFB, segmented filamentous bacteria. Sartor RB, Wu GD.. Gastroenterology. 2017;152(2):327–339.e4.
In swine, we have several other unique approaches to improving GIT health in addition to the traditional approaches (probiotics, organic oils, high fiber diets, or combinations of these). These approaches including prebiotics (refined functional carbohydrates (RFC); inhibiting bacterial attachment, promoting a more anaerobic environment; blocking bacterial receptors; stimulating protective mammalian pathways}; mixtures of defined microbes based on culture and sensitivity testing that are herd specific and hen egg IgY antibodies against specific organisms. Unlike ruminants and poultry housing and pasture management systems, exposure to feces in swine is far less so there is limited farm “microbial transplant” opportunity and less ability to improve immunity from microbiome diversity.
The gastrointestinal tract is the largest immune organ of the body. The mucosal barrier- the tight junctions and the “kill zone” along with the gut mucosa and maintaining an “anti-inflammatory” state are essential for “good gut health”. The microbiome- the microorganisms in the GIT, which has more cells then the entire animal’s body, is essential for immune development, immune response, and maximizing swine productivity. Management of swine GIT immune system is not a simple process. It begins with consumption of colostrum. Stressors along with the intake of feed and hydration affect the microbiome and the intestinal epithelial cells resulting in important immune interactions. Nutraceuticals (i.e., probiotics, prebiotics, hen yolk IgY, essential oils, organic acids) aid in both microbiome stability “homeostasis” and immune function.