Gut-liver axis and probiotics: their role in non-alcoholic fatty liver disease

Abstract

The incidence of obesity and its related conditions, including non-alcoholic fatty liver disease (NAFLD), has dramatically increased in all age groups worldwide. Given the health consequences of these conditions, and the subsequent economic burden on healthcare systems, their prevention and treatment have become major priorities. Because standard dietary and lifestyle changes and pathogenically-oriented therapies (e.g., antioxidants, oral hypoglycemic agents, and lipid-lowering agents) often fail due to poor compliance and/or lack of efficacy, novel approaches directed toward other pathomechanisms are needed. Here we present several lines of evidence indicating that, by increasing energy extraction in some dysbiosis conditions or small intestinal bacterial overgrowth, specific gut microbiota and/or a "low bacterial richness" may play a role in obesity, metabolic syndrome, and fatty liver. Under conditions involving a damaged intestinal barrier ("leaky gut"), the gut-liver axis may enhance the natural interactions between intestinal bacteria/bacterial products and hepatic receptors (e.g., toll-like receptors), thus promoting the following cascade of events: oxidative stress, insulin-resistance, hepatic inflammation, and fibrosis. We also discuss the possible modulation of gut microbiota by probiotics, as attempted in NAFLD animal model studies and in several pilot pediatric and adult human studies. Globally, this approach appears to be a promising and innovative add-on therapeutic tool for NAFLD in the context of multi-target therapy.

Keywords: Bacterial translocation; Barrier function; Gut-liver axis; Intestinal microbiota; Non-alcoholic fatty liver disease; Probiotics; Small intestinal bacterial overgrowth.

Figures

Figure 1

Intestinal barrier and liver. The intestinal microbiota plays an important role in the development of gut-associated lymphoid tissue (GALT), IgA secretion, and the production of antimicrobial peptides. Environmental factors (injury, infection, or high fat diet) may induce small intestinal bacterial overgrowth (SIBO)/intestinal dysbiosis and increased intestinal permeability that promote the translocation of bacteria and bacterial products, pathogen-associated molecular patterns (PAMPs), and damage-associated molecular patterns (DAMPs). Malfunction of tight junctions (TJ), composed of occludin, claudin, and tricellulin proteins, and under the influence of proteins involved in the cascade of the signal-transduction pathways (G protein and protein kinase C), probably play a critical role in gut “leakiness”. Activation of toll-like receptors (TLRs) induces hepatic inflammation, lipogenesis, fibrogenesis, oxidative stress, and insulin sensitivity. In particular, activation of TLRs on stellate cells determines hepatic fibrosis and activation of TRLs on Kupffer cells promotes hepatic inflammation. In some dysbiosis conditions an high proportion of ethanol producing bacteria (E. Coli) may lead to high levels of endogenous alcohol, whose effects further reflect on intestinal permeability and hepatic damage. HFD: High fat diet; LPS: Lipopolysaccharide; PKC: Protein kinase C; SCFA: Short chain fatty acids.

Figure 2

Mechanisms of the interplay between the intestinal microbiota and non-alcoholic fatty liver disease. Intestinal dysbiosis promotes the translocation of bacterial products [e.g., damage associated molecular patterns (DAMP) and pathogen-associated molecular patterns (PAMPs)] from the intestinal lumen into the lamina propria and to the bloodstream. This event is associated with the activation of toll-like receptor 4 (TLR-4), which causes hepatic fibrogenesis and systemic inflammation. Furthermore, the intestinal microbiota reduces fasting-induced adipose factor (FIAF) expression, lipogenesis, and free fatty acids (FFA) uptake. The gut microbiota have an increased capacity to harvest energy from non-digestible indigestible complex polysaccharides into monosaccharides and short chain fatty acids (SCFAs), which are substrates for hepatic lipogenesis and gluconeogenesis. Endogenous ethanol production by some bacteria is another mechanism damaging the liver. The properties of bile acids, which exert bacteriostatic activity, are also altered. The conversion of choline into methylamines leads to insulin resistance, fat accumulation, and ROS production (modified from refs 4 and 91). LPL: Lipoprotein lipase.