LEAKY GUT, DYSBIOSIS & THE MICROBIOME IN AUTOIMMUNITY
The human gastrointestinal system is maintained by a mucosal barrier. This specialised barrier allows nutrient absorption but blocks entry to harmful antigens such as food proteins, pathogens and toxins. The mucosal barrier consists of three layers:
1) The Mucosal Layer
A complex polymeric network of highly glycosylated mucins which forms a physical and biochemical layer to keep organisms away. It includes two layers, the inner and outer mucus layer. In a healthy gut, the inner mucus layer is impregnable to any commensal microorganisms. However, the outer mucus layer is more exposed and provides a habitat for commensal microorganisms.
2) Intestinal epithelial cells
A single layer of cells that are linked together by tight junction proteins. It is composed of different types of cells, such as goblet and M cells, which have different functions. The intestinal epithelial cells create a physical barrier to the lamina propria, and also play a role in intestinal immunity against pathogenic bacteria and their components (e.g., lipopolysaccharides, LPS).
3) Intestinal Immune Cells
There are many types and large volumes of immune cells in the intestines, which kill foreign pathogens and maintain homeostasis. Macrophages and Dendritic cells are the main antigen-presenting cells found under the Intestinal Epithelial Cells, which can identify potential pathogens. Adaptive immune cells (Tcells and B cells) stimulated by specific antigens may initiate an immune response to any antigens entering the bloodstream across the gut barrier. Th17 cells are crucial for protecting the intestinal mucosal barrier from pathogens. TH17 cells are implicated in Autoimmune conditions particularly if they become imbalanced with Tregs which play a crucial role in the gut to retain immune tolerance.
LEAKY GUT
If any abnormalities or dysfunction occurs in the mucosal barrier such as a break down of the tight junctions between the epithelial cells, then intestinal permeability may increase, this is called a “leaky gut.” Tight junction damage can be transcellular which involves big areas of the lining to be destroyed, or paracellular where small gaps between junctions exist. A leaky gut allows translocation of external antigens (toxins, microbes, food, commensal bacteria) into the host causing local and systemic immune responses. In genetically predisposed individuals, this may trigger the development of autoimmune disease.
The Mucosal Barrier of the Gastrointestinal System
Intestinal homeostasis is maintained by three immunological barriers: mucus layer (first barrier), epithelium layer (second barrier), and immune cell layer (third barrier).
Reference: (Yue, B.; Luo, X.; Yu, Z.; Mani, S.; Wang, Z.; Dou, W., 2019)
doi.org/10.3390/microorganisms7100440
Causes of Leaky Gut
Prolonged contact with an environmental contaminants, overconsumption of inflammatory foods, alcohol, medications, mental stress for extended periods, infections and dysbiosis can all contribute to leaky gut over time.
Reference: (Paray BA, Albeshr MF, Jan AT, Rather IA., 2020)
doi.org/10.3390/ijms21249770
Microbiota
The human gastrointestinal tract hosts over one hundred trillion microorganisms, 10 to 20 times greater than the number of cells in a body, includes 1000 different species, including bacteria, fungi, yeast, viruses encompassing approx 5,000,000 genes. This ecosystem is called the gut microbiome. Gut microbiota facilitate digestion, storing nutrients, secreting vitamins, activating metabolic functions, and shaping intestinal architecture.
The microbiota is separated from intestinal epithelial cells by a physical-chemical barrier composed of mucus, mucin glycoproteins, and multiple antibacterial molecules and secretory IgA. The SIgA has many functions to modulate the Immune response in the gut as well as support immune cells ie. it prevents dendritic cells from over-reacting. In healthy conditions, all gut microbial species are in a mutualistic or commensal symbiotic state contributing to a perfect and constant homeostasis where the interaction between gut microbiota, intestinal epithelial cells, and the mucosal immune system creates an environment which controls harmful foreign pathogens.
Short chain fatty acids are produced by the microbiome bacteria when we eat fibre e.g. butyrate, propionate and acetate. These have an impact on modulating TReg cells, provide fuel to improve diversity of the microbiome and also can help with keeping the gut barriers in tact. So eating fibre can support the microbiome intensely and also promote immune tolerance.
Modern influences on the microbiome include; stress, pesticides, herbicides, fungicides, GMO foods, lack of fermented foods, medications, smoking, pro-inflammatory diet, environmental xenobiotics, hormone imbalances, antibiotic use in livestock. These have all been shown to reduce the diversity of the microbiome and make it less efficient. A suboptimal microbiome can cause an over reactive mucosal response, with significant reactions to foods, intestinal permeability, Small Intestinal Bacterial Overgrowth, loss of oral tolerance and even Autoimmunity.
Microbiome diversity is very important for Immune Tolerance and Autoimmunity.
Dysbiosis
Dysbiosis is an alteration in the composition of the microbiome which changes the balance between pathogen and commensal (friendly) bacteria causing a disturbance to homeostasis of the gut. A loss of beneficial microbes, expansion of bad bacteria, and loss of diversity of bacteria can lead to dysbiosis. Dysbiosis has been implicated in mucosal barrier dysfunction and inflammatory response. Studies reveal that both Leaky gut and dysbiosis are evident in patients with Autoimmune diseases.
During healthy, homeostatic status the microbiota is composed of diverse organisms known to benefit the host. However, environmental threats, such as antibiotic use can lead to disruptions in the balance of the microbial community. These disruptions can cause loss of beneficial organisms to the host and subsequent overgrowth of bad bacteria that can potentially cause inflammation and disease.
If dysbiosis is present with a leaky gut, endotoxemia can occur. Bad bacteria produce Lipopolysaccharides (LPS) which bind to receptors in body tissues to cause systemic inflammation which will then drive or flare Autoimmunity. Therefore it is important for any Autoimmune patients to ensure they have a healthy microbiome and also to be focused on repairing a leaky gut. In recent years, several diseases and dysfunctions have been linked to intestinal dysbiosis, including inflammatory bowel disease.
Autoimmune responses induced by dysbiosis and Leaky Gut.
Microbiota reinforce epithelial barrier and regulate the mucosal immune response to maintain symbiotic relationship in the intestine. Environmental factors can cause dysbiosis, which impairs epithelial barrier function and elicits proinflammatory response. Microbial adhesion to epithelial cells and the induction of proinflammatory cytokines further damage Tight Junction integrity, leading to Leaky gut. Leaky gut enhances bacterial translocation to the systemic circulation. Translocated bacteria can initiate or worsen Autoimmune responses. Food particles, toxins etc can cause cross reactivity leading to Autoimmunity.
Reference: (Kinashi Y, Hase K., 2021)
doi: 10.3389/fimmu.2021.673708
