The Gut-Liver Axis and NAFLD: Clarifying the Link

William F. Balistreri, MD


December 11, 2013

In This Article

The Gut Microbiome

Emerging evidence indicates that the human intestinal microbiota is involved in the development of obesity and related complications, including obesity-related nonalcoholic fatty liver disease (NAFLD). What is the evidence?

The Human Microbiome Project has highlighted variations in our "microbial selves" -- the endogenous bacteria residing in the human gut[1] -- with the bottom line being that our health and our risk for disease are clearly influenced by our genome, but perhaps even more so by our microbiome.

Between 500 and 1000 microbial species inhabit the human gastrointestinal tract; the concentration and type are influenced by the host genotype and nutrient composition and availability.[2] This symbiotic relationship has clear functional implications.

Studies in both mice and humans have shown that the gut microbiota significantly affects host metabolism, specifically by enhancing yield from food and modulating dietary or host-derived compounds that alter host metabolic pathways. The community of bacterial species residing in the gut harvest otherwise inaccessible nutrients and energy from the diet, serving as a de facto "caloric gatekeeper" and a "metabolite control tower."

Altered Microbiota and Disease

Conversely, a "dysbiotic relationship" may emerge -- namely, an altered microbiota composition that is associated with disease. The link between the microbes in the human gut and the development of obesity; cardiovascular disease; and metabolic syndromes, such as type 2 diabetes, is now clear.

Henao-Mejia and colleagues[3] reported that the configuration of the gut microbiota was clearly associated with exacerbated hepatic steatosis and inflammation through the influx of TLR4 and TLR9 agonists into the portal circulation. This leads to enhanced hepatic tumor necrosis factor (TNF)-alpha expression, which drives the progression of liver injury. These observations highlight the central role of the microbiota in the pathogenesis of heretofore seemingly unrelated systemic autoinflammatory and metabolic disorders.

There appears to be an interrelated cycle that links nutrition; the composition of the gut microbiota; intestinal permeability; metabolic and immune responses, including insulin resistance; and liver injury.[3,4] The microbiota participates in host functions that affect the development and maintenance of the obese state, including host ingestive behavior, energy harvest, energy expenditure, and fat storage.[5] The intestinal bacterial composition of obese individuals differs significantly from that found in lean individuals and is involved in the regulation of body weight.[5,6] Differences in community composition, functional genes, and metabolic activities of the gut microbiota ("gut dysbiosis") distinguish lean vs obese individuals.


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