The gut microbiota participates in this mechanism not only as a bystander but as an active player, modulating both positively and negatively the intestinal permeability through metabolic and immune pathways. Your digestive tract is one of your main interfaces with the outside world. The intestinal mucosa is exposed to a myriad of external antigens such as food antigens, food-borne pathogens, and the symbiotic microbes that reside in the intestinal lumen. Therefore, the intestine serves as a barrier tissue whereby a monolayer of intestinal epithelial (skin-like)cells establishes a multilayered physico-chemical barrier.
The intestinal epithelial barrier helps to keep us safe and well by not allowing harmful antigens through the gut wall and into the rest of the body. To this end, intestinal epithelial cells form what are called Tight Junctions (TJs). TJ protein complexes tightly connect epithelial cells to help form an effective barrier. Think of a line of people all linking arms to make the line stronger.
The mucosal barrier also includes mucin, antimicrobial peptides, and IgA secreted by specialist cells. These molecules constitute a barrier between luminal microbes and intestinal epithelium to prevent microbes sticking to the gut wall. However, mucosal barrier dysfunction (especially the disruption of TJs) often leads to increased intestinal permeability, termed “Leaky Gut Syndrome” (LGS).
Leaky gut syndrome initiates inflammatory responses in the intestine and in tissue outside the intestine. Thus, the translocation of commensal microbes into the body disturbs immune homeostasis by inducing systemic inflammation; however, the commensal (beneficial) microbiota is important for shaping the gut immune system while they remain confined in the intestinal lumen.
Altered microbial composition, termed dysbiosis, has been implicated in mucosal barrier dysfunction and inflammatory responses, which predispose the host to systemic diseases.
Leaky Gut in Autoimmune, Metabolic, and Neurological Diseases
In cases of intestinal mucosal damage, intestinal permeability increases, and bacteria, fungi, their fragments, or antigens can translocate through the lumen. The hypothesis that an altered intestinal barrier may lead to an increased intestinal permeability and inflammatory response, and that the gut microbiota may modulate this process, has led to the concept that Leaky Gut Syndrome (LGS) and gut dysbiosis are linked to each other, and that both are involved in the pathogenesis of various gastrointestinal and systemic disorders. Indeed, intestinal barrier dysfunction has been associated with various autoimmune diseases:
- (inflammatory bowel diseases [IBDs], type 1 diabetes mellitus, coeliac disease, multiple sclerosis, etc.),
to neurological ones
- (mood disorders, autism spectrum disorders, Parkinson’s disease, Alzheimer’s disease),
This increased intestinal permeability plays the role of a primer or an aggravating factor in their evolution.
Inflammatory Bowel Diseases
Inflammatory bowel diseases (IBDs), such as Crohn’s Disease (CD) and Ulcerative Colitis (UC), are chronic disorders, and exactly why they occur is still broadly unknown. Immunological, genetic, and environmental factors, as well as changes in the gut microbiota are the most likely factors involved in the pathogenic mechanism.
Intestinal leakiness in patients with IBDs is related to dysbiosis, inflammatory response, and epithelial Tight Junction (TJ) modifications; think of that line of people with linked arms letting go of each other. The gut microbiota of patients with inflammatory bowel diseases is characterized by an increase in pro-inflammatory bacteria, such as adherent–invasive Escherichia coli or mucolytic bacteria.
During active IBDs, the expression of enterotoxigenic Bacteroides fragilis, a metalloprotease-producing bacteria, is increased, causing inflammatory diarrhea. Altered expression of tumour necrosis factor-alpha (TNF-α), transforming growth factor-beta (TGF-β), interleukin- (IL-) 17, IL-22, and IL-23, are involved in the pathogenesis of IBDs, resulting in an enhanced inflammatory response in the intestinal mucosa.
In Crohn’s Disease, mutations in NOD2 ( also called inflammatory bowel disease protein 1) cause altered expression of defensin genes, facilitating an altered antimicrobial response to the gut microbiota and translocation of bacteria across the epithelium. Studies on IBD patients also showed a metabolic reduction in Short Chain Fatty Acids (SCFA) and an increase in polyunsaturated fatty acids, including arachidonate, among dysbiotic patients, and a reduction of bile acids (BAs) conversion, with an overall pro-inflammatory effect.
Dysregulation of Tight Junction (TJ) complexes has also been demonstrated. Indeed, TNF-α is implicated in TJ modifications, and together with IL-13, promotes intestinal cell apoptosis (cell death) in Ulcerative Colitis.
Interestingly, altered intestinal permeability can be exacerbated during IBDs by a variety of external factors, but it has been shown to occur in asymptomatic patients years before the onset of clinical manifestations. In a study of 1420 first-degree relatives of CD patients, intestinal permeability was measured in vivo. The study showed that it is possible to predict the onset of Crohn’s by years with a simple urine test.
Experimental models of rheumatoid arthritis (RA) showed that the genus Lactobacillus was over represented in RA susceptible mice before the onset of arthritis; at the same time, Lactobacillus salivarius is overabundant in the oral microbiota of individuals with active RA, so it is not advisable to take a probiotic with this common strain in them. Jubair WK et al. showed that gut dysbiosis in CIA-predisposed mice was correlated with the degree of inflammation and permeability of the intestinal mucosa, with increased intestinal expression of IL-17A and IL-22. Furthermore, fecal microbiota transplantation (FMT) from RA mice to germ-free mice is associated with the development of RA. These data suggest the existence of a mucosal susceptibility for the development of RA, the so-called gut–joint axis, but further evidence is needed for possible therapeutic challenges.
Patients with ankylosing spondylitis (AS), a form of spondyloarthritis, show subclinical intestinal inflammation, which sometimes evolves into IBD, and a higher gut microbiota diversity compared to healthy subjects. A study including patients with AS and CD and healthy controls demonstrated that both AS and CD patients had high IL-23 mRNA expression in mucosal biopsy specimens. IL-23 production in response to intestinal dysbiosis and the consequent release of cytokines in the systemic circulation could be responsible for early manifestations of ankylosing spondylitis, supporting the existence of a gut–joint axis.
Systemic Lupus Erythematosus
Patients affected by systemic lupus erythematosus (SLE) are colonized by a less diverse gut microbiota, with increased abundance of Gram-negative bacteria.
In experimental models, SLE-predisposed mice showed an elevated inflammatory response secondary to increased intestinal permeability, with production of auto-antibodies and the spread of systemic inflammation, suggesting a possible pathogenic link between dysbiosis and SLE.
Patients affected by Parkinson’s disease (PD) often complain of gastrointestinal symptoms years before the diagnosis, and accumulation of α-synuclein was observed in early diagnosed or untreated patients. In addition, recent findings support the hypothesis that a-synuclein is formed in the gut and then transferred to the central nervous system via the vagus nerve.
Recently, an experimental study in mice analyzed the relationship between stress, intestinal permeability, and neuro-inflammation. Administration of rotenone, a pesticide used to induce PD in rats, together with stress, led to increased intestinal permeability with an additive effect. Indeed, rotenone and stress were able to destroy Tight Junction proteins in the intestinal mucosa.
Autism Spectrum Disorders
Children with autism spectrum disorders (ASD) often experience intestinal symptoms, such as constipation, abdominal pain and diarrhoea. Microbiota studies in these patients have shown an inverse relationship between microbiota diversity and neurological impairment.
Neuroinflammation is a recognized pattern in ASD. A human study conducted in patients affected by ASD and schizophrenia showed increased expression of two markers of neuroinflammation and blood–brain barrier impairment. In addition, reduced expression of TJ proteins was observed in the intestinal mucosa. This study could explain a possible pathological link between intestinal disorders and the development of autism.
Type 1 Diabetes
Enterovirus infections in early life represent a predisposing factor for the development of auto-antibodies associated with type 1 diabetes (T1D), probably triggering gut mucosal barrier damage. Alteration of TJs has been proposed as the hallmark of intestinal dysfunction in diabetes. Studies have shown that alterations in intestinal permeability occur before the onset of T1D. In a rat model of T1D, luminal and serum levels of ZO1 protein were higher in diabetic mice than controls, and preservation of TJ integrity by pharmacological inhibition of the ZO1 receptor was able to reduce the risk of T1D development in predisposed mice.
T1D-associated dysbiosis, particularly the lack of butyrate-producing bacteria, can further contribute to the alteration of intestinal permeability in this setting, as butyrate stimulates mucin secretion and helps maintain the integrity of TJs.
Type 2 Diabetes
In patients with type 2 diabetes (T2D), hyperglycemia promotes a pro-inflammatory condition that is related to intestinal permeability, bacterial translocation, and metabolic endotoxemia. Indeed, chronic hyperglycemia drives intestinal barrier dysregulation by direct action on gene transcription. Yes, chronic disease affects your genes!
Microbiota changes in T2D involve decreased abundance of Bifidobacteria.
Changes in the gut microbiota composition in T2D patients are also associated with reduced production of Short Chain Fatty Acids from dietary components, adversely affecting intestinal barrier function, regulation of inflammation, and lymphocyte function. This condition promotes a pro-inflammatory pathway that increases metabolic toxicity and oxidative stress, which in turn increase insulin resistance and beta-cell impairment.
Obesity is often associated with metabolic syndrome and insulin resistance. Chronic inflammation, driven by the pro-inflammatory activity of macrophages in the adipose tissue, colon, muscle, and liver, is the substrate for these conditions, and is called “meta-inflammation”. Gut dysbiosis in obesity is associated with a high Firmicutes/Bacteroidetes ratio in most studies and with an increase in potentially pro-inflammatory and invasive bacteria.
A high fat diet (HFD) promotes gut leakiness through dysbiosis, since antibiotic treatment has been shown to be effective in improving intestinal permeability and glucose homeostasis in HFD-fed mice. However, in an experimental model obesity per se was associated with increased intestinal permeability, regardless of diet
A proposed mechanism links intestinal dysbiosis, obesity, and meta-inflammation, and identifies the intestinal barrier as the trigger of an “inflammasome–microbiota axis”. In this model, dysbiosis promotes a chronic low-grade inflammation that culminates in the release of pro-inflammatory cytokines, affecting metabolic, immune, and hepatic homeostasis.
How do I find out if I have Leaky Gut?
In the first instance we can look at sympomology. Leaky gut is often linked to a range of symptoms:
- brain fog
- aching joints and muscles
- increasing food intolerances/allergies
To test for Leaky gut, there is a simple urine test. For this test, you drink a solution containing different kinds of sugars with molecules of different sizes, some of which are not usually absorbed in the intestines. Then analysts measure the sugar levels in your urine to see which ones made it through your gut wall. According to the sizes of the molecules that make it through the gut wall, the level of permeability is calculated.
There is also a blood test. This test analyzes a sample of your blood for evidence of gut bacteria infiltration. Specific antibodies and endotoxins are some of the biomarkers analysts look for.