“Leaky Gut”: A Potential Contributor to the Brain-Gut-Microbiota Axis

BY: Stephanie Thomas, PhD

DATE: 3 April 2017

In my previous blog, I introduced the rapidly expanding research of the gut microbiota and its potential influence in mood and behavior.1  This complex microbial community influences cognition (how we think) as well as depression and anxiety (how we feel) in relation to eating disorders.2-6 The most perplexing question is how the trillions of individual micro-organisms living in the gut communicate with our brains (the brain-gut-microbiota axis) and how disruption of this microbial community (also referred to as a dysbiosis) negatively affects brain function. Understanding how this communication happens is the one of the next steps toward developing treatments that help promote recovery from eating disorders.

To investigate the brain-gut-microbiota axis we must first understand that what we eat matters not only to our brains, but also to the micro-organisms in our guts. Here we will focus on the fascinating relationship between diet and gut microbiota. When we feed ourselves, we are also feeding our gut microbiota. What we eat, they eat!  The micro-organisms in our intestines utilize the foods we consume—but they do not all utilize the same nutrients in the same ways. It is entirely possible that we are selecting for specific microbial species based on the type of nutrients we consume. Let’s consider the typical Western diet which tends to be high in fat and sugar. If one regularly partakes in a high fat/sugar diet, the microbes that are best at utilizing fats and sugars will be at an advantage and will be selected for (natural selection). Over time, this will lead to a microbial imbalance in the gut. Similarly, the guts of individuals who restrict food intake (like people with anorexia nervosa) will select for organisms that can survive on scarce nutrients or nutrients that are difficult for the host to digest and adsorb. Different diets result in different phylogenetic profiles (or ratios of bacterial families),2,7,8  with unhealthy diets, such as the Western diet resulting in unhealthy microbial communities that promote intestinal disease, metabolic disease, opportunistic pathogens, or altered cognitive and social functioning.5,9-11 The evidence suggests that diet shapes the intestinal microbiota, which then alters the interactions and cross-talk between the microbiota, the intestine, and the brain.

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One possible answer to the question of “How?” communication across the brain-gut-microbiota occurs is via increased intestinal permeability. The gut barrier is a semi-permeable layer of epithelial cells that separate the intestinal luminal contents from the underlying host cells. Transport of molecules across this layer occurs transcellularly (through the cells) or paracellularly (between the cells). Paracellular transport is regulated through a network of proteins that bind epithelial cells to one another. These tight junction proteins are highly regulated, where disruption results in altered paracellular transport.12

Dysbiosis of the gut microorganisms occurs in many intestinal diseases, such as inflammatory bowel disease (IBD), ulcerative colitis (UC), and irritable bowel syndrome (IBS).13-15 Hallmarks of these diseases are intestinal inflammation and a “leaky” gut, (increased intestinal permeability), and is often the result of changes in the tight junction regulation. A leaky gut is just what it sounds like, the intestinal barrier leaks things, like molecules, nutrients, microbes and other microbially produced products, where passage from the inside of the gut to the inside of our bodies occurs more freely. The increased passage of microbes and their byproducts harms intestinal integrity by triggering an inflammatory response leading to even greater permeability and disease severity.

Given the extreme diets (restricting, binge eating) and shifts in microbial communities seen in people with eating disorders, it is likely that any leaky gut is a consequence rather than a cause of the disorders. In fact, obesity and consumption of a Western diet are associated with increased intestinal permeability and it is tempting to speculate that this physiological abnormality in the intestine may be a consequence of an imbalanced gut microbiota.11  Unlike obesity, gut permeability in people with anorexia nervosa has not been well studied. One study reported no abnormalities in the intestinal permeability in anorexia nervosa; however, they only looked at the small intestine, not the colon.16 A more recent study of a mouse model of anorexia showed increased permeability in the colon, but not in the small intestine.17 Clearly, more research is needed in this area.

Understanding how intestinal micro-organisms might cause elevated permeability is an enormous task given that 300-1000 different species make a home in our guts. One possible mechanism is through bacterial proteins called proteases that actively bind to the cells of the gut. The binding then triggers the redistribution of the tight junction proteins of the cells and increases permeability.

Similar to bacterial proteases, other bacterial products (most notably, lipopolysaccharide, LPS) can bind to the intestinal cells and lead to changes in tight junction distribution. LPS also triggers the release of inflammatory signals into the gut and blood stream. Some of these inflammatory signals can travel through the blood to the brain where they can affect appetite regulation.

Certainly, intestinal permeability is only one mechanism of the numerous avenues that the microbiota can communicate with the brain (see reviews by Noble et al. and Cryan et al. 11,14). Nevertheless, if correcting a “leaky” gut will alleviate gastrointestinal discomfort, and maybe even improve mood, then we should continue studying this phenomenon in individuals with eating disorders. Humans have co-evolved with our gut microbiota and the interactions between them are complicated. As research progresses, we gain a better understanding of the relationship between what we eat, our microbial community, and our intestinal and mental well-being.

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