Bilal Ahmad Paray, Mohammed Fahad Albeshr, Arif Tasleem Jan, and Irfan A. Rather
Published 21st December 2020
“Damage to the tissue and the ruining of functions characterize autoimmune syndromes.
This review centers around leaky gut syndromes and how they stimulate autoimmune pathogenesis.
Lymphoid tissue commonly associated with the gut, together with the neuroendocrine network, collaborates with the intestinal epithelial wall, with its paracellular tight junctions, to maintain the balance, tolerance, and resistance to foreign/neo-antigens.
The physiological regulator of paracellular tight junctions plays a vital role in transferring macromolecules across the intestinal barrier and thereby maintains immune response equilibrium.
A new paradigm has explained the intricacies of disease development and proposed that the processes can be prevented if the interaction between the genetic factor and environmental causes is barred by re-instituting the intestinal wall function.
The latest clinical evidence and animal models reinforce this current thought and offer the basis for innovative methodologies to thwart and treat autoimmune syndromes.”
The gastrointestinal (GI) tract’s epithelium represents the largest mucosal lining that provides an interface between mammalian host and the external environment.
The lumen of the gut harboring trillions of microbial inhabitants plays a vital role digestion and influences the immune system.
The outstanding anatomical architecture of the GI fine-tunes processes like absorption and digestion of food, neuroendocrine networking, and immunological balance.
Despite being in continuous interaction with various foodborne pathogens and antigens, the GI lining very efficiently checks invasion by microorganisms and other molecules through its paracellular space, thereby maintaining its capability of intestinal permeability…
… The transfer of macromolecules is controlled principally by epithelia’s paracellular permeability, whose regulation is dependent on the attuned intercellular tight junctions.
A fast-rising number of illnesses, including autoimmune diseases, are reported due to intestinal permeability changes relative to changes in tight junctions (TJs).
The change in permeability of the GI tract’s epithelial lining creates an easy passage for commensal bacteria and their products from the lumen into the bloodstream (referred to as the leaky gut), thereby evoking immune response.
Studies have well documented autoimmune diseases that arise due to the underlying phenomenal problem of the leaky gut.
An autoimmune disease occurs when the immune system produces autoantibodies against self-antigens, causing assault on body tissue. An association of autoimmune diseases and leaky gut has emerged as a critical situation wherein the leakage of pathogens into the body system results in autoimmunity.
As such, maintenance of the healthy gut goes a long way in preventing autoimmune diseases.
This review focuses on the relationship between the leaky gut and autoimmune diseases, causes of leaky gut, factors contributing to the healing of leaky gut, and a prospectus of ongoing research being carried out on the topic.”
Intestinal Barrier Regulation:
“… Mucin, a highly glycosylated polymeric protein in the mucous layer, also plays an important role in trapping pathogens thereby preventing microbial colonization.
The absence of a mucin layer, or a disturbed mucin layer has been seen to make animals vulnerable to intestinal inflammation. The remarkable study on zonula occludens toxin (Zot) enterotoxin elaborated by Vibrio cholera showed that it reversibly opened TJs, which potentiated our knowledge of the regulation of the paracellular pathway.
Zonulin, being the eukaryotic counterpart, has been known to regulate TJs in relation to fluid and macromolecular movement and the exchange of leukocytes between the lumen of intestine and the bloodstream (by increasing intestinal permeability).
Small intestines exposed to enteric bacteria secreted zonulin. The role of zonulin in displaying innate immunity may represent a defensive mechanism that inhibits microorganisms that colonize the small intestine.”
Causes of Leaky Gut:
“The cause of leaky gut includes prolonged contact with an environmental contaminant, overconsumption of alcoholic beverages, and unhealthy food choices.
Mental stress for an extended period inhibits the capacity of the immune system to respond speedily and slows down its ability to heal. The flow of blood to digestive organs is reduced, and there is an increase in the generation of toxic metabolites that cause a permanent deferral of the necessary repair routine.
The immune system responds to many places at once, and the parts of the body located far away from the intestinal system are easily affected.
The vertebrate GI tract comprises an extraordinary chemical composition and a thick microbial atmosphere, which influence the immune reactions of host cells and excite a rich medium of effector mechanisms involved in innate and acquired immune responses.
Any perturbations in the structural dynamics of the microbial community and their functions within the intestinal tract (referred to as dysbiosis) also become a cause of leaky gut condition and, ultimately, the occurrence of autoimmune diseases…
Beverages have few nutrients but take several nutrients to metabolize. The most notable of these nutrients are B-complex vitamins.
As part of metabolism in the liver, the contaminants are either broken down or stockpiled by the body. The abuse of overconsumption of beverages puts stress on the liver, which upsets the digestive ability and harms the GI tract.
Food with little fiber increases transit time, thereby increasing exposure to harmful by-products of digestion that cause irritation of the gut mucosa. Additionally, processed foods contain many additives capable of promoting inflammation of the GI tract.
Non-steroidal medicines, aspirin, and Motrin mutilate the brush borders, permitting microbes, food particles that are not wholly digested, and contaminants to go into the bloodstream.
Birth control drugs and steroids also form favorable conditions for fungi nourishment, which cause damage to the lining. Chemotherapy and radiation treatments significantly disrupt the balance of the GI wall.
Additionally, sensitivity to certain foods and the environment could lead to the development of leaky gut syndrome.”
Factors Contributing to the Healing of Leaky Gut:
“… The reversal of leaky gut through administration of probiotics and prebiotics has gained momentum in the last decade.
Reviews confirm the reversal of leaky gut by probiotics through augmentation of TJ protein production.
Studies have shown that the fermentation activity of gut microbes exert healing effects not only on the intestinal epithelium integrity but also permeability.
Fermentation products have also been shown to modulate anti-inflammatory signals necessary for an adequate active immune response…
The term dysbiosis is commonly used to describe the situation that arises whenever there is a structural or functional change in gut microbiota configuration, which disturbs homeostasis of the gut.
Fermentation products are also known to become imbalanced under dysbiosis. The infection-destroying segments of microbiota may altogether be countered with inflammation-aggravating germs, improving the wall effect of the gastrointestinal mucosa and straightening the interaction with inflammation-causing constituents of the immune system.
As further studies show, regulating the immune system is one way of fixing a leaky gut. Dysbiosis upregulates the expression of TLRs on antigen-presenting cells (APCs) and disturbs the T-cell balance.
Reports indicate that dysbiosis promotes the production of neo-antigenic determinants of self-proteins, thereby evoking autoimmunity.”
Autoimmune Diseases Associated with Leaky Gut:
“… The situation of impaired barrier function in the mucosal lining of the GI tract, which results in even larger holes in the lining, manifests in leaky gut.
Thus, things that were initially barred from passing through (e.g., proteins, gluten, microbes, and food antigens) can now breach through the tissue as well as systemic circulation, resulting in intestinal inflammation that may trigger an array of autoimmune diseases such as inflammatory bowel disease, celiac diseases, autoimmune hepatitis, multiple sclerosis, etc.
We have accumulating evidence in support of the presence of overexpressed zonulin in subjects with autoimmune diseases.
Zonulin has been recognized as pre-haptoglobin (HP)2. The release of zonulin has been implicated in the pathogenesis of autoimmune diseases where the stimuli are bacteria, both the gut commensals and pathogens, and food antigens like gluten.
Under the conditions of compromised TJ function, an immune response ensues after antigen stimulation. The immune cells such as antigen-presenting cells (APCs), T-cells, T killer cells, B-cells, and plasma cells in the intestinal barrier get activated.
Dysbiosis induced by leaky gut presents an inflammatory environment that paves the way to autoimmunity. Microbial translocation induces pro-inflammatory cytokines such as IFN-γ, TNF-α, and IL-13…”
“Ankylosing spondylitis (AS) is a common rheumatic syndrome that distinctively affects young adults. It is characterized by a stiff and painful back.
The connection between an increase in the permeability of the intestines and the syndrome has been plainly established.
Using a proteomic method, an investigation of the serum protein summaries of AS patients and healthy controls from a Chinese AS family has been conducted.
A group of four massively expressed protein spots was clearly witnessed in every AS patient’s summary and consequently recognized as isoforms of HP.
The role of dysbiosis in AS has been demonstrated by showing the active participation of ileal bacteria in modulating local and systemic immune responses.
The gut vasculature showed impairment that caused a significant rise in zonulin levels, which affected the TJs.”
Healing the Leaky Gut:
Many studies have revealed that a leaky gut paves the way to the development of autoimmune diseases. Therefore, healing the leaky gut suppresses the symptoms of these diseases; as such, decreasing its occurrence is vital to the prevention of autoimmune diseases.
The process of healing the gut has also been looked into, with both short-term and long-term measures. Short-term measures to heal the gut include discontinuing foods rich in gluten, dairy, and sugar from the diet.
Additionally, raw foods eaten in moderation and consumption of tea and bone broth are vital to healing.
In the long term, maintaining good gut health is crucial to the prevention of autoimmune diseases by sustaining proper gut health. Similarly, terraforming is a long-term method of preventing leaky gut.
Furthermore, the addition of prebiotics helps in establishing the gut flora by creating a fresh system of operation in the gut.
Thus, the inclusion of probiotics and prebiotics in the daily diet can augment gut microbiome health by reducing intestinal permeability.
Treatment with Bacteroides fragilis has been shown to decrease the pathogen translocation that further ameliorates the diseased state.
The role of B. fragilis has been predominantly shown to change the microbial flora and improve the barrier function of the intestine. As most autoimmune diseases involve the imbalance of the microbiota and hyperactivity of the immune system, systemic immune modulation through an extraneous supply of substances that either supplement internal microbiota or promote their proliferation is possible.
One such measure to increase resident microflora has been achieved using probiotics and prebiotics. Probiotics (i.e., healthy microflora) and prebiotics (i.e., food compounds promoting the proliferation of probiotics) improve the gut environment on administration, prevent the colonization of pathogenic microbes, and regulate immune function.
They reduce the permeability of the gut lining and, as such, confer health benefits to the host. The introduction of probiotics (most of the lactobacilli) modulates the gut microbiota and decreases the occurrence of autoimmune diseases such as IBD and T1D.
The most common prebiotic supplement derived from plants is inulin. The supplementation of diet with inulin enhances the growth of Bifidobacterium spp., besides improving glucose homeostasis.”
“Autoimmune disorders are facilitated by heredity, the environment, contaminants, and altered gut microbiota. Acting as fueling forces in the facilitation of autoimmune disorders, there has been fantastic advancement in our understanding of the interplay among these factors.
Genetic predisposition, exposure to triggering environmental factors, and damage to intestinal wall function, secondary to poor functioning of paracellular tight junctions, appear to be crucial ingredients presented in the pathogenesis of autoimmune diseases. The traditional model of autoimmune pathogenesis relating to a particular genetic constitution and contact with environmental triggers has lately been challenged by the inclusion of a third component: damaged GI function.
In T1D, gliadin can contribute to the loss of stomach wall function and can prompt the autoimmune reaction in genetically prone persons.
This recent theory suggests that as soon as the autoimmune process is triggered, it is not auto-continuing, but can rather be moderated or even overturned by inhibiting the constant interplay between the genetic factor and the environment.
Since tight junctions are components of reduced functioning in this interaction, new healing approaches are aimed at reinventing the gut barrier function, providing inventive, unexplored methods for the treatment of these cataclysmic diseases.
We emphasize on more studies involving the application of probiotics that can show the reversal of dysbiosis aiming at disease attenuation.
Keeping in view of the cost-effectiveness of these treatment modalities, autoimmune diseases in coherence with leaky gut can be well handled, and we sincerely foresee a future approach to focus on more of such studies.”