Abstract
Adverse fluctuations in the distribution of the intestinal microbiome cohort has been associated with the onset of intra- and extra-intestinal inflammatory conditions, like the metabolic syndrome (MetS) and it's hepatic manifestation, non-alcoholic fatty liver disease (NAFLD). The intestinal microbial community of obese compared to lean subjects has been shown to undergo configurational shifts in various genera, including but not limited to increased abundances of Prevotella, Escherichia, Peptoniphilus, and Parabacteroides and decreased levels of Bifidobacteria, Roseburia, and Eubacteria genera. At the phylum level, decreased Bacteroidetes and increased Firmicutes have been reported. The intestinal microbiota therefore presents an important target for designing novel therapeutic modalities that target extra-intestinal inflammatory disorders, such as NAFLD. This review hypothesizes that disruption of the intestinal–mucosal macrophage interface is a key factor in intestinal-liver axis disturbances. Intestinal immune responses implicated in the manifestation, maintenance and progression of NAFLD provide insights into the dialogue between the intestinal microbiome, the epithelia and mucosal immunity. The pro-inflammatory activity and immune imbalances implicated in NAFLD pathophysiology are reported to stem from dysbiosis of the intestinal epithelia which can serve as a source of hepatoxic effects. We posit that the hepatotoxic consequences of intestinal dysbiosis are compounded through intestinal microbiota-mediated inflammation of the local mucosa that encourages mucosal immune dysfunction, thus contributing important plausible insight in NAFLD pathogenesis. The administration of probiotics and prebiotics as a cure-all remedy for all chronic diseases is not advocated, instead, the incorporation of evidence based probiotic/prebiotic formulations as adjunctive modalities may enhance lifestyle modification management strategies for the amelioration of NAFLD.
Highlights
non-alcoholic fatty liver disease (NAFLD) is a growing public health concern, laying claim to both a steadily rising prevalence as well as an increasingly young age at diagnosis (Welsh et al, 2013; Nobili et al, 2014)
As a spectrum of diseases, NAFLD has been associated with significant morbidity and mortality, with advanced forms of the disease expressed as fibrosis, cirrhosis, and hepatocellular carcinoma (HCC).insulin resistance (IR) and obesity have been identified as NAFLD risk factors (Gaggini et al, 2013), with NAFLD reported to increase the risk of type 2 diabetes mellitus (T2DM) and cardiovascular disease, justly classifying NAFLD as the hepatic manifestation of the metabolic syndrome (MetS) (Adams et al, 2005; Targher et al, 2007, 2010; Dunn et al, 2008; Starley et al, 2010; Gregor and Hotamisligil, 2011; Lumeng and Saltiel, 2011; Dietrich and Hellerbrand, 2014; Paolella et al, 2014; Paquissi, 2016)
With the purported pathogenic mechanisms of NAFLD being intertwined with peripheral IR, increased liver lipolysis is reported to contribute to increased levels of hepatic free fatty acids (FFAs) (Paolella et al, 2014)
Summary
NAFLD is a growing public health concern, laying claim to both a steadily rising prevalence as well as an increasingly young age at diagnosis (Welsh et al, 2013; Nobili et al, 2014). With the first hit said to be the onset and maintenance of SS, and the additional hits of gut-derived endotoxins and pro-inflammatory cytokines from adipose tissue reported to provide the impetus for NASH development and subsequent progression (Day and James, 1998) This hypothesis is flagging the importance of aberrant innate immunity as a central pathway for NAFLD progression (Miele et al, 2009; Tilg and Moschen, 2010) along with stress signaling networks and circulating adipocytokines and pro-inflammatory cytokines (Miele et al, 2009; Tilg and Moschen, 2010). Disruption to intestinal epithelial homeostasis leads to hepatic exposure to exogenous and endogenous antigens that drives hepatoxic influences via the gut-liver axis interface (Glavan et al, 2016)
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