Over the past twenty years research has shown that the digestive system does much more than digest food and absorb nutrients. Gone are the days when the importance of the gastrointestinal (GI) tract can best be appreciated by studying enzymes, acids, bile, and peristalsis. Approximately seventy percent of the body’s immune system is found integrated into the intestines. That makes the GI tract the largest organ of the immune system and a major player in overall immune function. And this makes sense given the fact that the surface area of the adult human GI tract is 30 to 40 square meters, making it the largest interface between the inside of the body and the microbes and toxins of the outside world.1
There are many components involved in the interaction between the digestive system and the body’s immune system, such as the liver, the gut-associated lymphoid tissue (GALT), the GI microbiome, and the mucosal barrier which consists of the enterocytes, their receptors, and the tight junctions between them.
The Liver’s Role in GI-related Immunity
One organ of the digestive system that is often overlooked as a key component of the body’s immune function is the liver. It is ideally positioned to detect, capture, and clear bacteria, viruses, and unwanted macromolecules entering the body via the gut, and it acts as an important barrier between the body and the outside world.2 The liver contains the largest collection of phagocytic cells in the body. Its default immune status is anti-inflammatory and immunotolerant, and yet it is capable of mounting a robust immune response when needed. The balance between immunity and tolerance is essential to liver function.2
The GALT Role in Immunity
The GALT begins development in the fetus and becomes functional only after the epithelial cells encounter microorganisms in the gut lumen.3 The GALT is the largest mass of lymphoid tissue in the body. It consists of Peyer’s Patches and the mucosa associated lymphoid tissue (MALT). The cells of the GALT include B and T lymphocytes, macrophages, and antigen-presenting cells, dendritic cells from the immune system and specialized epithelial cells called M Cells. The GALT processes antigens from food or commensal bacteria without mounting an inflammatory response but also recognizes and responds to pathogens. The key to keeping the balance between these two responses is the GI microbiome.4
When the GALT encounters a pathogen, either a dendritic cell or an M Cell endocytoses the antigen and transports it to a naïve T lymphocyte that migrates from the bloodstream into the GALT. The presentation of the antigen to the naïve T lymphocyte causes cellular activation, proliferation, and differentiation into either effector cells or memory cells. Effector cells activate macrophages and B lymphocytes, then reenter the circulation in search of their cognate antigens. Thus, they travel beyond the gut. Some end up in distant lymphoid tissue while most travel to sites of infection and inflammation that contain the original antigen. When the effector cells are re-presented with cognate antigen, cytokines are released causing the recruitment of PMNs, monocytes, and lymphocytes into the interstitium to engulf and destroy the invading microorganisms. Memory cells may exist for years in the absence of antigen which leads to an enhanced immune response after antigen challenge.5
The GI Microbiome and Immunity
Over millennia, the GI immune system co-evolved with the microbiome within it. The GI microbiome consists of communities of bacteria, viruses, and fungi that inhabit the gut. These microbes are needed for a healthy immune system and their balance affects many aspects of the body’s natural defenses.
The understanding of the GI microbiome in relation to the immune system began with the work of the Russian-born biologist and “Father of Natural Immunity,” Elie Metchnikoff (1845-1916). Metchnikoff was the first to recognize the importance of white blood cells in fighting disease and was awarded the 1908 Nobel Prize in medicine for his efforts. He noticed that peasants consuming fermented foods were healthier than their city counterparts and he reasoned it was the bacteria in the fermented foods they ate that gave them the advantage. In fact, Metchnikoff coined the word “probiotic” and understood that the “good” bacteria in the GI tract must outnumber the “bad” bacteria. He warned that, “death begins in the colon.”
Exploring the bacteria of the GI tract involves two main techniques. Culture methods have identified over 500 species, and modern molecular techniques, such as ribosomal RNA sequencing (known as metagenomics), determined the presence of more than another 1000 species. The populations of bacteria vary throughout the GI tract with the different environments from the stomach through the colon.8
The gut microbiota have specific immunomodulatory properties. These microbes significantly affect the development and function of both innate and adaptive immunity. The absence of a balanced microbiota hinders the maturation of the immune system. Furthermore, differences in the microbiomes of individuals provide a plausible explanation about their differential response to vaccination.9
The balance of bacteria in the gut can be thrown off by the administration of antibiotics and other medications including proton pump inhibitors, N-SAIDs, antidepressants, and laxatives.10,11 The unhealthy imbalance and loss of diversity of intestinal microbes is known as dysbiosis, and this condition can last for months or years after a course of antibiotics.12,13 Dysbiosis often leads to a breakdown of the tight junctions between enterocytes, a condition known as leaky gut syndrome, which allows bacteria and toxins to enter the circulation and causing all manner of autoimmune diseases.14 Multiple studies show that probiotics decrease intestinal permeability and have a beneficial effect on the systemic immune system.15-22
Nutrition and the GI Immune System
An animal’s diet has a powerful effect on the GI microbiome.23 Even short-term exposure to bisphenol A (BPA), a common toxin found in canned dog foods, has been show to cause fecal microbiome alterations.25
There are several notable functional foods that facilitate the health of the liver and gut, and therefore the body’s immune system. For example, buckwheat (aerial parts and seed) is a source of rutin, a phytonutrient that protects against free radicals and free radical-induced DNA damage. It is also a source of fiber which acts as a prebiotic in the digestive tract to support a healthy GI microbiome. Finally, buckwheat has been found to increase circulating levels of glutathione, an important detoxifying molecule which supports liver function.26
Another helpful food is Spanish black radish, which is a member of the cruciferous vegetable family. This root vegetable has high levels of glucosinolates, phytonutrients that are not only responsible for the distinctive scent of cruciferous vegetables but also supportive of liver, gallbladder, and digestive health.27 Spanish black radish supports phase I and II liver detoxification enzymes and helps to eliminate toxins more efficiently.28 It also supports digestion by stimulating bile function.29
Beets are a source of nitrates which convert to nitric oxide (NO) in the body. NO is a signaling molecule involved in vascular function and immunity as well as a defense molecule against invading pathogens. Beets also deliver phenolics which provide oxidation support and betalains for a healthy inflammatory response.30 Beets are also rich in betaine which acts as a methyl donor for proper genetic expression, detoxification, and healthy homocysteine levels. Furthermore, betaine regulates urea and electrolyte balance and modulates immune function during stress.31
Brussels sprouts are known for their sulfur-containing glucosinolates as well as their content of phenolic compounds and carotenoids. They are being studied for their immune modulating properties.32 Brussels sprouts are also a source of sulfur, required for hepatic detoxification, and their metabolites are rapidly conjugated to glutathione in the liver.33
Finally, chlorophyll extract, which is the green pigment found in plants, has antioxidant and anti-inflammatory properties. It may support wound repair, red blood cell activity, and healthy hemoglobin levels.34 Chlorophyll extract has also been shown to modulate the gut microbiota in a mouse model.35 This kind of microbiota modulation has been proven to be important for the attenuation of certain immune responses related to chronic inflammation.36
The GI tract is the largest organ of the immune system. Its structure and complicated interactions with the microbiome effects all aspects of the body’s overall immune function. Dysbiosis of the GI microbiome can lead to leaky gut syndrome which has deleterious effects on the immune system, while probiotics reduce intestinal permeability and improve the immune system. A natural diet and certain functional foods can improve the GI microbiome, intestinal and liver function, and ultimately the body’s immune function.