How Your Gut Health Affects Your Disease Risk

A chain reaction in your gut can leave you vulnerable to chronic inflammatory disease

The critical importance of gut health is getting more attention. A significant proportion of your immune system resides in your gastrointestinal tract, which means optimizing your gut microbiome will have far-reaching effects on your physical health and emotional wellbeing.

Mounting scientific evidence also continues to suggest a large component of nutrition centers on nourishing health-promoting bacteria in your gut (and elsewhere in and on your body). Take care of these beneficial bacteria and you’ll keep harmful microbes in check and shore up your protection against chronic disease.

Disease Begins in Your Gut

Research has linked ADHD, autism, learning disabilities, obesity, diabetes, Parkinson’s disease, and other conditions to the health of the gut microbiome. A 2020 scientific review by Alessio Fasano, director of the Center for Celiac Research at Massachusetts General Hospital, goes so far as to say that all inflammatory disease begins in the gut.

Part of the blame is laid on excessive hygiene. In other words, we’re “too clean” for our own good. This “cleanliness” strips away a healthy microbiome and leaves room for unwelcome bacteria to grow.

Your diet also plays a crucial role in your microbiome and can affect several factors, including the release of zonulin, a group of proteins that affect the lining of your intestinal tract. Fasano’s paper specifically addresses the role of zonulin-mediated gut permeability in the pathogenesis of chronic inflammatory diseases. Gut permeability refers to how easily substances moving through the digestive tract can leak through the intestinal wall. If the intestinal wall is “leaky,” these substances seep into the body and can trigger inflammation.

Research across several fields—including human genetics, the gut microbiome, and proteomics (the study of proteins)—suggests gut permeability plays a key pathogenic role in the development of chronic inflammatory diseases (CIDs). Zonulin, meanwhile, plays a key role in gut permeability.

Bacteria, Not Genes, Rule Your Health Destiny

Aside from the microbes themselves, Fasano writes that the condition of your intestinal mucosa—the inner lining of the intestinal wall where much of the gut microbiome resides —is of critical importance.

“It plays a pivotal role through its dynamic interactions with a variety of factors coming from our surrounding environment, including microorganisms, nutrients, pollutants, and other materials,” Fasano explains.

Fasano points out that we simply don’t have enough genes to account for the myriad chronic diseases that can beset us. Genes also cannot explain the timing of disease onset. To solve these mysteries, we must look to the microbiome, he says.

“It is the interplay between us as individuals and the environment in which we live that
dictates our clinical destiny,” writes Fasano.

As the innermost layer of the intestinal wall, your mucosal mucosa comes in direct contact with the food you eat and contaminating substances you ingest. Zonulin can cause the intestinal mucosa to become too permeable, leading to leaky gut.
“Pre-clinical and clinical studies have shown that the zonulin family, a group of proteins modulating gut permeability, is implicated in a variety of CIDs, including autoimmune, infective, metabolic, and tumoral diseases. These data offer novel therapeutic targets for a variety of CIDs in which the zonulin pathway is implicated in their pathogenesis,” Fasano writes.
However, while zonulin is a biomarker of gut permeability and plays a pathogenic role in
many chronic inflammatory diseases, it should be noted that not all CIDs are caused by
leaky gut.

Proposed Chain of Events Leading to CID

The graphic below was included in Fasano’s review but originated from an earlier paper, titled “Zonulin, a Regulator of Epithelial and Endothelial Barrier Functions, and Its Involvement in Chronic Inflammatory Diseases.” It was co-written by Fasano and Craig Sturgeon and details the “proposed chain of events leading to chronic inflammatory disease.”

Under normal circumstances, a healthy homeostasis is maintained in your gut lining such that when an antigen is encountered, no excess immune reaction occurs. Antigens are molecules or molecular structures that alert your body to an outside pathogen and trigger an immune response.

Under No. 2 in the graph, gut dysbiosis is setting in (i.e., an imbalance in the number and diversity of your gut microflora), causing excess production of zonulin, which, in turn, makes the gut lining more permeable.

According to Fasano, the two most powerful triggers of zonulin release are bacteria overgrowth and gluten. Zonulin is produced in response to bad bacteria—it helps flush the bacteria out by opening up the tight junctions—so bacteria overgrowth makes sense. But why does it respond to gluten?

Interestingly enough, the zonulin pathway misinterprets gluten as a potential harmful component of a microorganism. That’s why gluten triggers zonulin release. While not mentioned by Fasano, the herbicide glyphosate also triggers zonulin, and is 10 times more potent than gluten.

The subsequent permeability allows microbiota-derived antigen and endotoxin to migrate from the lumen (the hollow tube at the center of the intestinal tract that food and waste pass through) to the lamina propria (the connective tissue that is part of the mucous membrane lining your intestine), thereby triggering inflammation.

As the process continues to worsen (No. 3 in the graph), your adaptive immune response kicks in, triggering the production of proinflammatory cytokines, including interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α). These cytokines further worsen gut permeability, thus creating a vicious cycle. Eventually (No. 4), mucosal tolerance is completely broken, resulting in the onset of a chronic inflammatory disease

Chronic Inflammatory Diseases Linked to Leaky Gut

The specific chronic inflammatory disease that ultimately emerges at the end of all this depends in part on your genetic makeup, in part on the types of exposures you’ve had, and in part on the composition of your gut microbiome.

“The pathogenesis of a variety of CIDs seems to involve mutually influenced changes in gut permeability/Ag trafficking, immune activation, and changes in composition/function of the gut microbiome,” Fasano writes.

A chain reaction starting from an imbalance in the number and diversity of your gut microflora (aka gut dysbiosis) spurs the release of zonulin, which leads to leaky gut, which causes the release of pro-inflammatory cytokines.
These cytokines then cause increased gut permeability and spur a vicious loop that leads to a massive influx of dietary and microbial antigens triggering the activation of T cells, warns Fasano.

T cells play a central role in the adaptive immune response and if they are being overactivated because of a massive influx of antigens, they can damage healthy tissues.

“Depending on the host genetic makeup, activated T cells may remain within the GI tract, causing CID of the gut … or migrate to several different organs to cause systemic CID.

” Chronic inflammatory diseases associated with dysregulation of the zonulin pathway

  • Autoimmune disorders such as Celiac disease, Type 1 diabetes, inflammatory bowel disease, multiple sclerosis, and ankylosing spondylitis
  • Metabolic disorders such as obesity, insulin resistance, nonalcoholic fatty liver disease, gestational diabetes, hyperlipidemia, and Type 2 diabetes
  • Intestinal diseases such as irritable bowel syndrome, non-celiac gluten sensitivity, and
    environmental enteric dysfunction (a chronic disease affecting the proximal intestine)
  • Neuroinflammatory diseases such as autism spectrum disorder, schizophrenia, major
    depressive disorder, and chronic fatigue/myalgic encephalomyelitis
  • Brain and liver cancers

Gut Microbes Influence Genes, Can Alter Cancer Risk

While the inclusion of cancer on that list may seem odd at first glance, some researchers believe the gut microbiome may actually end up being a game-changer for cancer prevention and treatment.

Not only have gut bacteria been shown to influence gene expression, turning some genes on and others off, research published in 2018 found gut microbes actually control antitumor immune responses in your liver, and that antibiotics can alter the composition of immune cells in your liver, triggering tumor growth.

Certain gut bacteria also promote inflammation, which is an underlying factor in virtually all cancers, whereas other bacteria quell it. The presence of certain gut bacteria has even been shown to boost the patient’s response to anticancer drugs.

One way in which gut bacteria improve the effectiveness of cancer treatment is by activating your immune system and allowing it to function more efficiently. Researchers have actually found that when these specific microbes are absent, certain anticancer drugs may not work at all.

Gut Bacteria Are Part of Your Antiviral Defense

Gut bacteria are also involved in your antiviral defense, recent research shows. As reported by Harvard Medical School on Nov. 18, 2020:

“For the first time, Harvard Medical School researchers have … identified the specific the population of gut microbes that modulates both localized and systemic immune response to ward off viral invaders. The work … pinpoints a group of gut microbes and a specific species within it, that causes immune cells to release virus-repelling chemicals known as type 1 interferons.

“The researchers further identified the precise molecule—shared by many gut bacteria within that group—that unlocks the immune-protective cascade. That molecule, the researchers noted, is not difficult to isolate and could become the basis for drugs that boost antiviral immunity in humans.”

While the findings still need to be replicated and confirmed, they point to the possibility that you might be able to enhance your antiviral immunity by reseeding your gut with Bacteroides fragilis and other bacteria in the Bacteroides family.

These bacteria initiate a signaling cascade that induces the release of interferon-beta that protect against viral invasion by stimulating immune cells to attack the virus and causing virus-infected cells to self-destruct.

“Specifically, … a molecule that resides on the bacterium’s surface triggers the release of interferon-beta by activating the so-called TLR4-TRIF signaling pathway,” Harvard explains. “This bacterial molecule stimulates an immune-signaling pathway initiated by one of the nine toll-like receptors (TLR) that are part of the innate immune system.”

The Role of Vitamin D

Recent research also highlights the role of vitamin D in gut health and systemic autoimmunity. The review article, published Jan. 21, 2020, in Frontiers in Immunology, notes:

“Autoimmune diseases tend to share a predisposition for vitamin D deficiency, which alters the microbiome and integrity of the gut epithelial barrier.

“… Vitamin D deficiency may contribute to autoimmunity via its effects on the intestinal barrier function, microbiome composition, and/or direct effects on immune responses.”

As noted in this review, vitamin D has several direct and indirect regulatory effects on your immune system, including promoting regulatory T cells (Tregs), inhibiting differentiation of Th1 and Th17 cells, impairing the development and function of B cells, reducing monocyte activation, and stimulating antimicrobial peptides from immune cells.

That said, the relationship between vitamin D and autoimmunity is complicated. Aside from suppressing an immune response that could run amok, vitamin D also appears to improve autoimmune disorders by the way it affects your microbiota composition and gut barrier.

The review cites research showing that your vitamin D status alters the composition of your gut microbiome. Generally speaking, vitamin D deficiency tends to increase Bacteriodetes and Proteobacteria, while higher vitamin D intake tends to increase prevalence of Prevotella and reduce certain types of Proteobacteria and Firmicutes.

While research is still slim when it comes to vitamin D’s impact on gut bacteria, especially in patients with autoimmune disease, vitamin D deficiency and autoimmune diseases are known comorbidities and vitamin D supplementation is often recommended for these patients.

Vitamin D Required for Tight Junction Maintenance

Better known is how vitamin D supports intestinal and immune cell defenses in the gut. In fact, vitamin D is one of the crucial components required for maintaining tight junctions.

This is important for the health of the intestinal epithelium, the single cell layer that lines the interior of the small and large intestine (colon) of the gastrointestinal tract.

As explained in this review:

“The intestinal epithelium is in constant interaction with the external environment. Adequate barrier integrity and antimicrobial function at epithelial surfaces are critical in maintaining homeostasis and preventing invasion or overcolonization of particular microbial species.

“A healthy intestinal epithelium and intact mucus layer are critical to protect against invasion by pathogenic organisms, and vitamin D helps to maintain this barrier function …”

Vitamin D May Contribute to Autoimmune Disease

According to the authors, vitamin D deficiency may contribute to autoimmune disease by affecting the microbiome and the immune system in the following manner:

1. Vitamin D deficiency or supplementation changes the microbiome, and manipulation of bacterial abundance or composition impacts disease manifestation.

2. Lack of vitamin D signaling due to dietary deficiency can impair physical and functional barrier integrity of the gut, thereby allowing bacterial interactions to either stimulate or inhibit immune responses.

3. Your innate immunologic defenses may be compromised if you are deficient in vitamin D.

How to Optimize Your Gut Microbiome

All of this information should really drive home the point that optimizing your gut flora and vitamin D level is of crucial importance for good health. By reseeding your gut with beneficial bacteria, you can keep pathogenic microbes and fungi in check and prevent them from taking over, and optimizing your vitamin D will help avoid leaky gut.

Regularly eating traditionally fermented and cultured foods is the easiest, most effective, and least expensive way to make a significant impact on your gut microbiome. Healthy choices include lassi (an Indian yogurt drink), cultured grass-fed organic milk products such as kefir and yogurt, natto (fermented soy) and fermented vegetables of all kinds.

Although I’m not a major proponent of taking many supplements (as I believe the majority of your nutrients need to come from food), probiotics are an exception if you don’t eat fermented foods on a regular basis. Spore-based probiotics, or sporebiotics, can be particularly helpful when you’re taking antibiotics. They’re also an excellent
the complement to regular probiotics.

Sporebiotics, which consist of the cell wall of bacillus spores, will help boost your immune tolerance. And because they don’t contain any live bacillus strains, only its spores—the protective shell around the DNA and the working mechanism of that DNA—they are unaffected by antibiotics.

Antibiotics, as you may know, indiscriminately kill your gut bacteria, both good and bad. This is why secondary infections and lowered immune function are common side effects of taking antibiotics. Chronic low-dose exposure to antibiotics through your food also takes a toll on your gut microbiome, which can result in chronic ill health and increased risk of drug resistance. Last but not least, you also need to avoid things that disrupt or kill your microbiome, and this includes:

  • Antibiotics, unless absolutely necessary
  • Conventionally raised meats and other animal products, as these animals are routinely fed
  • low-dose antibiotics, plus genetically engineered and/or glyphosate-treated grains
  • Processed foods (as the excessive sugars feed pathogenic bacteria)
  • Chlorinated and/or fluoridated water
  • Antibacterial soap and products containing triclosan

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