Intestinal Microbiome Shifts, Dysbiosis, Inflammation, and Non-alcoholic Fatty Liver Disease

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.

Keywords: NAFLD; dysbiosis; inflammation; intestinal epithelial cell dysbiosis; intestinal microbiome; macrophage; mucosal immunity.

Figure 1

Intestinal epithelial barrier and homeostasis. Several mechanisms, including a mucus layer, antimicrobial peptides and a tight junction protein network collaborate to ensure that the intestinal barrier is not compromised. Goblet cells secrete mucin to provide a protective coating, provide structural integrity and regulate macrophage and adaptive T cell responses during inflammation. Goblet cells also facilitate microbial translocation. The intestinal epithelia network of cells produce a range of soluble protein factors and also express the integrin ligand semaphorin 7A that modulates intestinal CX₃CR1 macrophage function. Localized CX3CR1 macrophages further release IL-10 to support the proliferation of induced Treg cells and B cell activating factor (BAFF) to further stimulate the production of migrating secretory IgA (sIgA) across the epithelium. Dendritic cells sample bacteria and present antigens to other cells including innate lymphoid cells (ILCs). Dietary starch is converted by intestinal bacteria into short chain fatty acids that serve as a source of energy for the epithelial cells but also act as signaling molecules. Signals from commensal bacteria help maintain tight junction via Toll-like receptor 2 (TLR-2) redistribution of ZO-1 proteins. (Kidd, ; Wahl, ; Hume, ; Ogino et al., ; Kayama et al., ; Abbas et al., ; Smith et al., ; Zheng, ; Ai et al., ; Guilliams et al., ; Peterson and Artis, ; Gottschalk and Kurts, ; Robinson et al., ; Nakahashi-Oda et al., 2016) Adapted from Peterson and Artis (2014).

Figure 2

Dysbiosis and the gut-liver axis. Increased intestinal permeability, small intestine bacterial overgrowth (SIBO) and elevated serum endotoxin like lipopolysaccharide (LPS) is found in patients with NAFLD. LPS, a hepatoxic component of gram-negative bacteria, is elevated in cases of SIBO. Increased intestinal permeability leads to increased bacterial translocation. Activated macrophages release inflammatory cytokines and dendritic cells stimulate the differentiation of naïve T cells to pro-inflammatory Th17 cells induced by TGF-β, IL-6, IL-23, and IL-1β. Th17 cells secrete neutrophil-activating IL-17. Lymphoid Th17 also migrate to the liver where IL-17 stimulates monocytes, Kupffer cells, biliary epithelial cells, and stellate cells, to secrete pro-inflammatory cytokines and chemokines—inducing liver inflammation. LPS, bacterial endotoxins, IL-17, pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) may reach the liver via the portal vein and induce inflammation via Toll-like receptor 4 (TLR-4) and interleukin-17 (IL-17) receptors. The gut-liver axis is underlined by the fact that at least 70% of the liver's blood supply is delivered directly from the intestinal tract via the portal vein outflow of the intestine. (Zheng, ; Carding et al., ; Robinson et al., ; Fukui, ; Kumar et al., 2016) Adapted from Peterson and Artis (2014).