Leaky gut and autoimmune diseases

Leaky gut and autoimmunity: An intricate balance in the individual's health and the diseased state

Damage to the tissue and destruction of functions characterize autoimmune syndromes. This article focuses on leaky gut syndrome and how it stimulates autoimmune pathogenesis. Lymphoid tissue commonly associated with the gut, along with the neuroendocrine network, cooperates with the intestinal epithelial wall, with its paracellular tight junctions, to maintain balance, tolerance, and resistance to foreign and harmful substances. The physiological regulator of paracellular tight junctions plays an important role in transferring macromolecules across the intestinal barrier and thereby maintaining equilibrium in the immune response. A new paradigm has explained the complications of disease development and suggested that the processes can be prevented if the interaction between the genetic factor and the environmental causes is hindered by restoring the intestinal wall function.

The epithelium of the gastrointestinal (GI) tract represents the largest surface that forms an interface between the human and the external environment. The lumen of the gut, which houses trillions of microbial inhabitants, plays an important role in digestion and affects the immune system. The unique anatomical architecture of the GI fine-tunes processes such as absorption and digestion, neuroendocrine networks, and immunological balance. Despite being in continuous interaction with various foodborne pathogens and antigens, the GI wall very effectively controls the invasion of microorganisms and other molecules through its paracellular space, thereby maintaining its capacity for intestinal permeability. The transfer of macromolecules is mainly controlled by the paracellular permeability of the epithelium, the regulation of which is dependent on the adapted intercellular tight junctions. A rapidly increasing number of diseases, including autoimmune diseases, are reported due to changes in intestinal permeability in relation to changes in the tight junctions. The change in permeability in the epithelial wall of the gastrointestinal tract creates an easy passage for bacteria and the substances they produce from the lumen into the bloodstream (so-called leaky gut), which provokes an immune response. Studies have well documented autoimmune diseases that arise due to the underlying phenomenal problem of leaky gut.

Autoimmune diseases, when the immune system mistakenly attacks its own tissue , are caused by some people having a strong and active immune system that is often good at fighting viruses and bacteria. However, it does so at the cost of the immune system sometimes also attacking its own body. A combination of autoimmune diseases and leaky gut occurs as a critical situation where leakage of pathogens into the body system results in autoimmunity. Maintaining a healthy gut is extremely important in preventing autoimmune diseases. This article focuses on the relationship between leaky gut and autoimmune diseases, causes of leaky gut, and factors that contribute to leaky gut healing.

Regulation of the intestinal barrier - leaky gut

The single layer of epithelial cells in the intestinal wall acts as a barrier that separates the host body (human) from the external environment. The regulation of a functional barrier is maintained by intestinal epithelial cells. The intestinal wall with the epithelial cells shows unique intercellular connections that enable nutrient and fluid absorption; However, it prevents the transfer of unwanted microbes or antigens to the underlying tissue.

The wall of epithelial cells forms a barrier between the host body and the intestinal lumen with bacteria. The functional barrier cells are held together by many tight junction proteins that prevent the entry of bacteria. The mucosa acts as a first-line defense that prevents contact between the intestinal microbiome and intestinal epithelial cells. The immune cells' role against infection further maintains homeostasis in the intestinal epithelial barrier.

Mucin, a glycosylated polymeric protein in the mucosa, also plays an important role in trapping pathogens and thereby preventing microbial colonization. The absence of a mucin layer or a disrupted mucin layer has been shown to increase the risk of intestinal inflammation. Zonulin is a substance that regulates the tight junctions in relation to fluid and macromolecular movement and exchange of leukocytes between the intestinal lumen and the bloodstream (by increasing intestinal permeability). A small intestine exposed to enteric bacteria secretes zonulin. The role of zonulin in displaying innate immunity may represent a defensive mechanism that inhibits microorganisms colonizing the small intestine.

A more simplified explanation of leaky gut:

The cells of the intestinal wall are connected to each other with links of proteins called tight junctions. This band of cells forms a cohesive mat, making the intestinal wall impermeable to fluid, larger molecules, ions and bacteria. Sometimes the intestinal wall needs to open and therefore the tight joints are not completely fixed. The tight joints are affected by a multitude of signals from your nervous system, your hormones and your immune system. This is called the barrier function. The barrier function is protected by several factors, such as healthy bacteria in the gut. Some bacteria have a stabilizing effect on the gut, while others have an effect on the barrier function.

The intestinal wall thus functions as a selective barrier, which makes sure to differentiate between the substances that are allowed to enter the body and the substances that are not. The cells of the small intestine must be able to distinguish between fatty acids, minerals, amino acids and carbohydrates in order to absorb them. At the same time, it must keep bacteria, environmental toxins, heavy metals and indigestible parts of the diet out.

However, the system can be tricked. This means that stress, allergies, intolerances, bacteria, alcohol, antibiotics and nutritional deficiencies can break up the tight joints and contribute to leaky gut (intestinal permeability or increased permeability). When this happens, an activation of the immune system occurs, which in turn can lead to inflammation and a wide range of symptoms.

Causes of leaky gut

The cause of leaky gut includes prolonged contact with an environmental pollutant, overconsumption of alcoholic beverages and unhealthy food choices. Mental stress over an extended period inhibits the immune system's ability to respond quickly and slows its ability to heal. Blood flow to the digestive organs decreases and there is an increase in the generation of toxic metabolites causing a permanent postponement of the necessary repair routine. The immune system responds in many places at the same time, and the parts of the body that are far from the intestinal system are easily affected.

The human gastrointestinal tract consists of an extraordinary chemical composition and a thick microbial atmosphere, which influences the immune responses of host cells and excites a rich medium of effector mechanisms involved in innate and acquired immune responses. Any disturbances in the structural dynamics of the microbial community and their functions in the intestinal tract (called dysbiosis) also become a cause of leaky gut conditions and ultimately the occurrence of autoimmune diseases. Microbial inhabitants of the gastrointestinal tract are unique in shaping host immunity and regulating metabolism. Recently studied data specify a serious role of gut microbiota associated with autoimmune diseases. Many Candida spp. reaching the mucosa of the gastrointestinal wall causes collapse of the epithelium lining the gastrointestinal tract.

In addition, Salmonella sp., Giardia sp., Yersinia sp., Helicobacter pylori, Blastocystis hominids, Shigella sp. and other pathogenic microbes the intestinal wall and thus cause gastrointestinal problems.

Digestive disorders or liver damage have increased the propensity for leaky gut conditions. Beverages have few nutrients but take several nutrients to metabolize. The most notable of these nutrients are B-complex vitamins. As part of the metabolism in the liver, the pollutants are either broken down or stored by the body. Excessive consumption of beverages puts stress on the liver, which interferes with digestion and damages the gastrointestinal tract. Foods low in fiber increase transit time, which increases exposure to harmful byproducts of digestion that cause irritation to the intestinal lining. In addition, processed foods contain many additives that can promote inflammation in the gastrointestinal tract. NSAIDs with acetylsalicylic acid destroy the intestinal wall, allowing microbes, food particles that are not fully digested, and impurities to pass into the bloodstream. Birth control pills and steroids also create favorable conditions for fungal nutrition, which causes damage to the mucous membrane. Chemotherapy and radiation treatments significantly disrupt the balance of the GI wall. In addition, sensitivities to certain foods and the environment can lead to the development of leaky gut syndrome.

Factors that contribute to the healing of leaky gut

In the early 1860s, microbial poisoning of the gut was believed to be a major cause of systemic disease and mental disorders, and for many decades scientists agreed. Modern studies validate this by illustrating that microflora recognized by certain receptors are essential to promote multiplication of the epithelial cells. Therefore, it accelerates the healing of the surface epithelium after being damaged and prevents inflammation. This receptor signaling is critically important to protect against pathogenic irritation and to promote tolerant conditions against commensalism (coexistence between two or more species, where one species (commensal) benefits from the other without harming it but also without being the benefit.) The gut microbiome interacts with the host cells under the influence of a highly regulated immune system involving pattern recognition receptors (PRRs) such as TLRs and NOD-like receptors (NLRs). Stimulation of TLRs increases intestinal epithelial integrity through translocation of the tight junction protein zonula occludens-1 (ZO-1) - Zonula occludens-1 ZO-1, also known as "tight junction protein-1". A pathogen recognized by specific TLRs results in several events, including stimulation of NF-κB signaling that follows an increase in cytokine production and T cell activation T cells are white blood cells that defend the body against disease-causing microorganisms. Certain t-cells learn to recognize amino acid sequences on the virus. They become memory t-cells that seek out and kill infected cells. These t- cells are activated proteins and peptides whose function is to carry chemical signals They attach to specific receptors on the target cells and are produced only when they are needed Some cytokines contribute to the immune system, and some others stimulate the formation of red and white blood cells.

The structure of the mucosa is known for its natural resistance and ability to distinguish potentially pathogenic bacteria from harmless antigens, which is realized via the arrangement of recognition receptors. The permeability of the intestinal epithelium has also been well known to be modulated by the microbiota (the microbiota is the collection of microorganisms – such as bacteria, fungi and viruses – that naturally live in the gastrointestinal tract.) and the substances it produces. The reversal of leaky gut through the administration of probiotics and prebiotics has gained momentum over the past decade. Reviews confirm reversal of leaky gut by probiotics and prebiotics (which are food for probiotics) by boosting tight junction protein production. Studies have shown that the fermentation activity of intestinal microbes exerts healing effects not only on the integrity of the intestinal epithelium but also on permeability (permeability is a term that indicates how permeable a material is to liquids and gases). These substances that the bacteria form have also been shown to modulate anti-inflammatory signals that are necessary for an adequately active immune response

The gut shows different microbial communities in different parts. Streptococcaceae and Lactobacillaceae populate the proximal region, while the distal part of the small intestine is home to Lactobacillaceae, Erysipelotrichaceae, and Enterobacteriaceae. The large intestine is inhabited by members of the Bacteriodaceae, Prevotellaceae and Clostridiaceae families. The epithelial lining of the stomach is Lactobacillaceae and Streptococcaceae. The substances produced by the bacteria are also known to become unbalanced during dysbiosis (imbalance in the intestinal flora). The term dysbiosis is often used to describe the situation that occurs when there is a structural or functional change in the intestinal microbiota configuration, which disrupts intestinal homeostasis. The infection-destroying segments of the microbiota can be completely counteracted with inflammation-exacerbating bacteria, which improves the effect in the intestinal wall of the stomach and intestinal mucosa. As further studies show, regulating the immune system is one way to fix 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, which induces autoimmunity.

Autoimmune diseases associated with leaky gut

Factors that contribute to the development of leaky gut and its relationship to autoimmune diseases are diet, genetic susceptibility and environmental conditions, which affect, among other things, the integrity of the intestinal epithelial barrier. This imbalance leads to impaired barrier integrity and contributes to several diseases.

The epithelial layer of the gastrointestinal mucosa acts as a barrier to the luminal contents of the intestine, preventing the passage of substances that can cause damage to the human body. A breach in the epithelial barrier by foreign substances from the lumen to the host sets in motion a series of events that turn the immune system against the host itself (the human) and thus present a host of autoimmune diseases such as type 1 diabetes (T1D) - type 1 diabetes is due to a lack of insulin production, multiple sclerosis (MS) - MS is a disease of the central nervous system, i.e. the brain and spinal cord, inflammatory bowel disease (IBD) - Inflammatory bowel disease includes: ulcerative colitis, Crohn's disease and colitis unclassified ("Inflammatory bowel disease unclassified" [IBD-U]), systemic lupus erythematosus (SLE) - SLE is a chronic rheumatic systemic disease characterized by inflammation/destruction and can affect largely all organs of the body.To name a few common diseases.

The situation of impaired barrier function in the mucosa of the gastrointestinal tract, resulting in even larger "holes" in the intestinal wall, manifests itself in leaky gut. Thus, substances that were originally prevented from passing (eg proteins, gluten, microbes and food antigens) can now break through the tissue, resulting in intestinal inflammation that can trigger a range of autoimmune diseases such as inflammatory bowel disease, celiac disease (gluten intolerance), autoimmune hepatitis, multiple sclerosis etc. Studies have shown that the presence of the substance zonulin increases in people with autoimmune diseases. Zonulin , also known as prehaptoglobin, is a precursor to haptoglobin and can affect the permeability of the so-called tight junctions. tight junctions in the intestine. Haptoglobin is an acute phase protein and the concentration rises during an inflammatory reaction, elevated values ​​persist for one to two weeks. The release of zonulin has been implicated in the pathogenesis of autoimmune diseases where the stimuli are bacteria, both intestinal bacteria and pathogens, and food antigens such as gluten.

Under the conditions of reduced tight-junction function, an immune response occurs after antigen stimulation. Immune cells such as antigen presenting cells (APC), T cells, T killer cells, B cells and plasma cells in the intestinal barrier are activated. Dysbiosis induced by leaky gut presents an inflammatory environment that paves the way for autoimmunity. Microbial translocation induces proinflammatory cytokines* such as IFN-γ, TNF-α and IL-13.

*When the immune system senses unwelcome invaders in the body, such as a virus or bacteria, the body produces cytokines whose task is to fight the invader. Cytokines are small proteins that send signals to the cells to act against the virus or bacteria.

Here we present a brief overview of some of the most well-known autoimmune diseases associated with leaky gut syndrome with evidence supporting that leaky gut causes autoimmunity.

Type 1 diabetes and leaky gut

T1D - diabetes type 1, an autoimmune disease mediated by self-reactive T cells, is characterized by the destruction of insulin-producing β-cells in the person's pancreas. The GI (abbreviation GI) signs of diabetes mellitus have been widely attributed to altered intestinal permeability secondary to autonomic neuropathy.

However, suggestions from other studies suggest that an increase in the permeability of the gut's joints (tight junctions) is responsible for the onset of the disease, and GI symptoms are regularly experienced by these patients. Studies in T1D models have confirmed that changes in the intestinal wall (in the large intestine) help the luminal bacteria to penetrate the extraluminal tissues. This hypothesis is reinforced by a clinical study performed in humans and in a diabetic animal model. Reports show that increased local permeability of the intestinal mucosa showed an increase in proinflammatory cytokines leading to a disrupted immune system. In both human and animal studies, gliadin, acting as an antigen, is a triggering factor linked to autoimmunity in type 1 diabetes.

Studies have shown that the pathogenesis of type 1 diabetes shows an altered gut microbiome and thus dysbiosis. Data show that gut bacteria can influence the prevention of autoimmune diabetes. Leaky gut-induced dysbiosis causes translocation of gut bacteria to pancreatic lymph nodes, whereby induction of pathogenic T helper cells contributes to type 1 diabetes. Gut microflora was shown to protect against the development of type 1 diabetes in two animal models. In addition, altered GI microbiota and the use of zonulin inhibitors were shown to improve the manifestation of type 1 diabetes in rat models of the disease.

Multiple sclerosis (MS) and leaky gut

Apart from an increase in the permeability of the blood-brain barrier, patients with multiple sclerosis were found to exhibit an increased permeability in the intestinal tight junctions, so-called. tight junctions. A quarter of the patients with multiple sclerosis had an increased permeability of the intestinal walls. Patients with multiple sclerosis and Crohn's disease show an increase in the number of peripheral B cells, a sign of antigen exposure. This further reinforces the notion of pre-existing, genetic abnormalities in small intestinal permeability, with a consequent altered antigen exposure as a pathogenic problem common to the two diseases. Bacterial infections are believed to cause multiple sclerosis, although clear epidemiological evidence is lacking. This supports the notion that commensal bacteria contribute to MS pathogenesis. Experimental autoimmune encephalomyelitis (EAE)* suggests that gut flora contribute to the development of this disease, and therapy involves the administration of probiotics (ie live beneficial bacteria) or prebiotics (fibres that stimulate the growth of beneficial bacteria).

*To study the pathogenesis behind MS, the experimental autoimmune encephalomyelitis (EAE) model is often used.

Inflammatory bowel diseases (IBD) and leaky gut

IBD, which involves Crohn's disease (CD) and ulcerative colitis (UC), occurs due to defects in the paracellular permeability of the gastrointestinal tract. The pathogenesis (Pathogenesis is the description of the onset and development of disease, and refers to which mechanisms (for example, viruses, hormonal disorders) initiate the development of the disease.) of IBD is multifactorial. In recent years, substantial evidence has supported the theory that environmental, genetic, and immunological factors initiate the autoimmune process. Despite this, most evidence points to the contribution of increased gastric (stomach) permeability to the pathogenesis of IBD. In Crohn's disease, an increase in the permeability of the intestinal epithelium precedes clinical relapse, suggesting that a defect in permeability is the first event in the onset of the disease. Reports suggest that during the development of IBD, a defective intestinal barrier shows the expression of cytokines, IFN-γ and TNF-α, which initiates inflammation. Paradoxically, this presents a situation where the disrupted immune system in the intestinal tissue triggers further leaks in the luminal wall. The state of dysbiosis plays an important role in the pathogenesis of IBD.

Ankylosing spondylitis - Bechterew's disease and leaky gut

Bechterew's disease is caused by inflammation, especially in the muscle attachments and joints. You get sore, tired and stiff. It varies how often the problems come and how painful it is. It is not possible to get rid of the disease completely, but with treatment it can be slowed down and alleviated.

The risk of getting Bechterew's disease increases if you have a close genetic relative who has the disease. The most common thing is to get sick before the age of 40. Other names for Bechterew's disease are ankylosing spondylitis and pelvospondylitis.

Ankylosing spondylitis (AS) or Bechterew's disease is a common rheumatic syndrome that clearly affects young adults. It is characterized by a stiff and painful back. The relationship between an increase in intestinal permeability and the syndrome has been clearly established. The role of dysbiosis in AS has been demonstrated by demonstrating the active participation of bacteria in modulating local and systemic immune responses. The intestinal vessels showed deterioration that caused a significant increase in zonulin levels, which affects the tight junctions in the intestinal wall, which in turn generates a leaky gut.

Systemic lupus erythematosus and leaky gut

Systemic Lupus Erythematosus (SLE) is an autoimmune inflammatory system disease that can affect several different organ systems such as musculoskeletal systems, skin and mucous membranes, blood-forming organs, kidneys, heart, lungs, blood vessels and nervous system.

SLE, a prototypical multisystem autoimmune disease is characterized by a hyperactive immune response that causes severe and persistent inflammation. Although the etiology of SLE is unclear, various genetic and environmental factors are involved in the occurrence of the disease. Increased bacterial lipopolysaccharide* uptake via the intestinal lumen promotes the development and progression of SLE. Dysbiosis induced by leaky gut increases inflammatory macrophage activity that damages the tissues in SLE. Improvement in the commensal (symbiotic) intestinal microbiota through dietary supplementation of probiotics or dietary supplementation with prebiotics (food for probiotic bacteria) significantly improves the occurrence of the disease.

*Lipopolysaccharides (LPS) are molecules consisting of fatty acids (lipids) and complex carbohydrates (polysaccharides). They occur on the surface of gram-negative bacteria. The immune system recognizes bacteria with the help of LPS, and free LPS therefore provokes a strong immune reaction. When bacteria die, large amounts of LPS are released, and the immune response to this can cause disease symptoms worse than the disease itself. For that reason, LPS are traditionally classified as toxins, even though the bacteria do not produce LPS with the aim of poisoning their host, but to build up their cell wall.

Heal a leaky gut

Many studies have shown that a leaky gut paves the way for the development of autoimmune diseases. Therefore, the healing of leaky gut improves the symptoms of these diseases, it is therefore important to reduce its occurrence in order to prevent autoimmune diseases. The process of healing the gut has also been investigated, with both short-term and long-term measures. Short-term measures to heal the gut include cutting foods rich in gluten, dairy and sugar from the diet. Additionally, raw foods eaten in moderation and consumption of tea and bone broth (rich in collagen) and collagen supplements are essential to healing a leaky gut. In the long term, it is important to maintain good gut health to prevent autoimmune diseases. In addition, food or dietary supplements with prebiotics contribute to establishing the intestinal flora. Thus, the introduction of probiotics and prebiotics into the daily diet can increase the health of the gut microbiome by reducing gut permeability, healing a leaky gut.

Treatment with Bacteroides fragilis has been shown to reduce pathogen translocation which further improves the diseased state. Bacteroides fragilis is part of the normal microbiota of the human colon and is generally commensal, but can cause infection if it is displaced into the bloodstream or surrounding tissue after surgery, illness or trauma. The role of B. fragilis has predominantly been shown to alter the microbial flora and improve the intestinal barrier function. Since most autoimmune diseases involve microbiota imbalance and immune system hyperactivity, systemic immunomodulation through an external supply of substances that either supplement internal microbiota or promote their proliferation is possible. Such a measure to increase the body's own microflora has been achieved with probiotics and prebiotics. Probiotics (i.e. healthy microflora) and prebiotics (i.e. fibers that promote the proliferation of probiotics) improve the intestinal environment when ingested, prevent colonization by pathogenic microbes and regulate immune function. They reduce the permeability of the intestinal mucosa and as such provide health benefits to the human body. The introduction of probiotics (mostly lactobacilli) modulates the gut microbiota and reduces the incidence of autoimmune diseases such as IBD and type 1 diabetes. The most common prebiotic dietary supplement derived from plants is inulin. Dietary supplementation with inulin increases the growth of Bifidobacterium spp., in addition to improving glucose homeostasis. Homeostasis is about the body's ability to stay stable in a certain state, despite external changes. Homeostasis is therefore often life-determining.

Dietary supplements with prebiotics and probiotics - effective dietary supplements to heal a leaky gut

Autoimmune diseases are influenced by heredity, environment, pollution and altered gut microbiota. 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 factors presented in the pathogenesis of autoimmune diseases. The traditional model of autoimmune pathogenesis related to a particular genetic constitution and contact with environmental triggers has recently been challenged by the introduction of a third component: impaired GI function. In type 1 diabetes, gliadin can contribute to loss of stomach wall function and can cause autoimmune reactions in genetically predisposed individuals. This new theory suggests that once the autoimmune process is triggered, it does not continue automatically, but rather can be moderated or even reversed by inhibiting the constant interplay between the genetic factor and the environment. Because tight junctions are dysfunctional components of this interaction, new therapeutic approaches are aimed at restoring intestinal barrier function by providing inventive and unexplored approaches to treating these diseases. Instead of treating the symptoms and diseases that occur in connection with a leaky gut, studies have shown that a diet or dietary supplement with prebiotics or probiotics could heal a leaky gut and in turn improve or prevent the symptoms or diseases that may arise due to a leaky gut. intestinal.