Topic

4.1 A&P of Gut & Immunity

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The gut epithelium is a single layer to facilitate the absorption of nutrients and is held together with tight junctions (TJs) providing a physical barrier. If the barrier becomes damaged and tight junctions are compromised the result is leaky gut syndrome and compromise of the immune system often resulting in allergies and autoimmunity (discussed further in ‘Allergy, Intolerances and Autoimmunity’). 

The protein zonulin regulates intercellular tight junctions by loosening the tight junctions therefore causing intestinal permeability. The production of zonulin can be induced by bacteria and by a glycoprotein in wheat. Dysbiosis, excessive sugar intake particularly fructose, stress, non-steroidal anti-inflammatory drugs (NSAIDs), inflammation and nutrient deficiencies can all contribute to leaky gut. 

Given the right environment, the gut microbiota produce short-chain fatty acids including butyrate, propionic acid and acetate. These fats provide fuel for the colonocytes and support the integrity of the intestinal wall. They are produced when microbes ferment indigestible carbohydrates (fibre). Hence dietary sources of probiotics (commensal microbes) and prebiotics (the indigestible fibre for probiotics to ferment) are important in maintaining the integrity of the epithelial layer. Other nutrients important in maintaining the integrity of the epithelium are glutamine, vitamin A and vitamin D. The intestinal mucus adds a further layer of protection to the single-cell epithelial layer.

However, the gut epithelium provides more than a physical barrier. The Goblet cells within the epithelial layer secrete mucin, the major constituent of mucus. Mucin provides binding sites for microbes that can then be carried out of the body via the colon due to the flow of the mucus. In addition, the epithelial cells, Paneth cells, produce antimicrobials such as defensins, lactoferrin and lysozyme to protect against microbial penetration of the barrier. The intestinal cells also contain M cells involved in sampling antigens from the intestinal lumen and communicating with immune cells. If pathogens or antigens breach the physical barriers they will meet with gut-associated lymphoid tissue (GALT). This is a subdivision of mucosal-associated lymphoid tissue (MALT) that is present within all mucosal linings i.e. respiratory, genitourinary, etc. and consists of areas of lymphoid tissue within the gut. It is separated from the intestinal lumen by the single mucosal epithelial layer. GALT includes the loose connective tissue of the lamina propria containing macrophages, dendritic cells (DC’s), plasma cells, T cells, B cells as well as organised lymphoid structures such as Peyer’s patches. Peyer’s patches are highly populated with immune cells and act as surveillance stations, differentiating between different pathogens and antigens and communicating via chemical messengers to stimulate the correct immune response. Adjacent to Peyer’s patches are the M cells which sample antigens from the intestinal lumen and via antigen-presenting cells (APCs) pass the antigens to the immune cells within the Peyer’s patches. GALT is able to survey antigens from food and commensal bacteria and not initiate an inflammatory response yet initiate an appropriate immune response to pathogens. 

Intestinal cells also secrete intestinal alkaline phosphatase (IAP), a brush border enzyme to inactivate endotoxins. Lipopolysaccharides (LPS), known as endotoxins, are molecules found in the cell membranes of Gram-negative bacteria. They are elevated in dysbiosis and reduce the integrity of the epithelial layer by reducing the expression of tight junction proteins. 

Secretory IgA (SIgA) is the antibody IgA secreted by the mucosal tissue. It modulates the gut microbiota and protects the epithelium from damage. It is able to neutralise antigens before they penetrate the epithelial layer and hence prevent them from initiating an inflammatory response. This neutralisation occurs by a number of different processes including blocking epithelial cell receptors, entrapment in mucus and removal through peristalsis and direct effect on bacterial virulence. SIgA not only neutralises pathogenic microbes but produces biofilms (membranes) that can protect commensal microbes. SIgA production for specific antigens results from the antigen sampling by M of the Peyer’s patches. When SigA levels are low the integrity of the epithelial layer is compromised and there may be an increase in the migration of food antigens into circulation. SIgA also ‘tags’ food antigens as non-pathogenic and therefore low SIgA may lead to food antigens not being recognised as acceptable to the body resulting in intolerances and allergies. SIgA levels are reduced with stress.

Elevated levels of SIgA are associated with an upregulated immune response and can be an indication of an acute infection. Elevated levels however have also been noted in patients with chronic illness such as psoriasis, rheumatoid arthritis and Epstein Barr virus. Low levels are associated with leaky gut and gastrointestinal tract (GIT) disorders such as allergies, intolerances, inflammatory bowel disease (IBD), coeliac disease, Crohn’s disease and ulcerative colitis as well as adrenal stress. 

Nutrients supportive of increasing SIgA are prebiotics, probiotics and the polysaccharide beta-glucan. In addition, a high sugar diet and processed foods should be avoided as they will provide an environment for pathogenic bacteria and dysbiosis. This would lead to an increased requirement for SIgA. In addition as stress impacts SIgA levels, lifestyle interventions to reduce stress are beneficial. Nutrients to support the lowering of SIgA levels are antimicrobials to aid in the removal of any infection, prebiotics and probiotics to address dysbiosis and hence reduce pathogens and anti-inflammatory foods. 

The gut microbiome plays an important role in regulating multiple aspects of digestive health, from regulating peristalsis, through to housekeeping and nutrient synthesis but also our microbiota is part of our immune barrier function and innate and adaptive immune responses. The composition of the gut microbiota is unique in each individual and is impacted by age, environment, stress, genetics, diet, geographical location etc. The gut microbiota consists of 100 trillion bacteria. Diversity of the microbiota is key with no one species becoming dominant. A varied microbiome results in a flexible immune response to act on threats as appropriate. 

Commensal bacteria are concentrated in the intestinal lumen or trapped in the antimicrobial mucus. Pathogens (non-commensal microbes) are however able to penetrate the mucosal layer and be resistant to microbicides. The mucus, antimicrobial proteins and SIgA minimises microbe breach of the intestinal cell layer. If a breach does occur innate and adaptive immune responses rapidly occur. Gut homeostasis is maintained by the interaction of the microbiota and the immune system through signalling processes such as toll-like receptors (TLRs). TLRs sense in the gut abnormal microbes and induce an immune response. Gut dysbiosis is the imbalance of commensal and pathogenic microbes. Studies have shown that when germ-free animals are colonised with intestinal flora their GALT expands.

Commensal microbes reduce the ability of pathogenic bacteria to colonise by competing with them for available resources and crowding them out. The gut microbiome also aids in the maintenance of the gut epithelial barrier. Commensal microbes also secrete antimicrobials such as bacteriocins inhibiting pathogen adhesion to the epithelium. Studies show the importance of diversity of gut flora to ensure a resilient immune response and the development of disease and inflammation. 

Supporting gut microbiota through ensuring the intake of both prebiotic and probiotic foods will always be a major part of any program to enhance immunity. Whilst many studies in relation to gut flora and their role in immunity are performed with probiotic supplements, food sources of probiotics and prebiotics should be the first course of action in colonising and maintaining the gut microbiota. Probiotic supplements contain just a handful of probiotic strains and yet we live with trillions of bacterial cells. There is evidence supporting the linkage between specific probiotic strains and health conditions. However, to maintain good health and good gut flora it is important to have a constant supply of pro and prebiotic foods as probiotics have not been shown to permanently alter the microbiota.