Supplementation of saturated long-chain fatty acids maintains intestinal eubiosis and reduces ethanol-induced liver injury in mice.

Alcoholic liver disease is a leading cause of mortality. Chronic alcohol consumption is accompanied by intestinal dysbiosis, and development of alcoholic liver disease requires gut-derived bacterial products. However, little is known about how alterations to the microbiome contribute to pathogenesis of alcoholic liver disease. We used the Tsukamoto-French mouse model, which involves continuous intragastric feeding of isocaloric diet or alcohol for 3 weeks. Bacterial DNA from the cecum was extracted for deep metagenomic sequencing. Targeted metabolomics assessed concentrations of saturated fatty acids in cecal contents. To maintain intestinal metabolic homeostasis, diets of ethanol-fed and control mice were supplemented with saturated long-chain fatty acids (LCFA). Bacterial genes involved in fatty acid biosynthesis, amounts of lactobacilli, and saturated LCFA were measured in fecal samples of nonalcoholic individuals and patients with active alcohol abuse. Analyses of intestinal contents from mice revealed alcohol-associated changes to the intestinal metagenome and metabolome, characterized by reduced synthesis of saturated LCFA. Maintaining intestinal levels of saturated fatty acids in mice resulted in eubiosis, stabilized the intestinal gut barrier, and reduced ethanol-induced liver injury. Saturated LCFA are metabolized by commensal Lactobacillus and promote their growth. Proportions of bacterial genes involved in fatty acid biosynthesis were lower in feces from patients with active alcohol abuse than controls. Total levels of LCFA correlated with those of lactobacilli in fecal samples from patients with active alcohol abuse but not in controls. In humans and mice, alcohol causes intestinal dysbiosis, reducing the capacity of the microbiome to synthesize saturated LCFA and the proportion of Lactobacillus species. Dietary approaches to restore levels of saturated fatty acids in the intestine might reduce ethanol-induced liver injury in patients with alcoholic liver disease.

Chen P ，Torralba M ，Tan J ，Embree M ，Zengler K ，Stärkel P ，van Pijkeren JP ，DePew J ，Loomba R ，Ho SB ，Bajaj JS ，Mutlu EA ，Keshavarzian A ，Tsukamoto H ，Nelson KE ，Fouts DE ，Schnabl B ... -  《-》

Metagenomic analyses of alcohol induced pathogenic alterations in the intestinal microbiome and the effect of Lactobacillus rhamnosus GG treatment.

Bull-Otterson L ，Feng W ，Kirpich I ，Wang Y ，Qin X ，Liu Y ，Gobejishvili L ，Joshi-Barve S ，Ayvaz T ，Petrosino J ，Kong M ，Barker D ，McClain C ，Barve S ... -  《PLoS One》

Intestinal HIF-1α deletion exacerbates alcoholic liver disease by inducing intestinal dysbiosis and barrier dysfunction.

Alcoholic liver disease (ALD) is characterized by gut dysbiosis and increased gut permeability. Hypoxia inducible factor 1α (HIF-1α) has been implicated in transcriptional regulation of intestinal barrier integrity and inflammation. We aimed to test the hypothesis that HIF-1α plays a critical role in gut microbiota homeostasis and the maintenance of intestinal barrier integrity in a mouse model of ALD. Wild-type (WT) and intestinal epithelial-specific Hif1a knockout mice (IEhif1α-/-) were pair-fed modified Lieber-DeCarli liquid diet containing 5% (w/v) alcohol or isocaloric maltose dextrin for 24 days. Serum levels of alanine aminotransferase and endotoxin were determined. Fecal microbiota were assessed. Liver steatosis and injury, and intestinal barrier integrity were evaluated. Alcohol feeding increased serum levels of alanine aminotransferase and lipopolysaccharide, hepatic triglyceride concentration, and liver injury in the WT mice. These deleterious effects were exaggerated in IEhif1α-/- mice. Alcohol exposure resulted in greater reduction of the expression of intestinal epithelial tight junction proteins, claudin-1 and occludin, in IEhif1α-/- mice. In addition, cathelicidin-related antimicrobial peptide and intestinal trefoil factor were further decreased by alcohol in IEhif1α-/- mice. Metagenomic analysis showed increased gut dysbiosis and significantly decreased Firmicutes/Bacteroidetes ratio in IEhif1α-/- mice compared to the WT mice exposed to alcohol. An increased abundance of Akkermansia and a decreased level of Lactobacillus in IEhif1α-/- mice were also observed. Non-absorbable antibiotic treatment reversed the liver steatosis in both WT and IEhif1α-/- mice. Intestinal HIF-1α is essential for the adaptative response to alcohol-induced changes in intestinal microbiota and barrier function associated with elevated endotoxemia and hepatic steatosis and injury. Alcohol consumption alters gut microbiota and multiple intestinal barrier protecting factors that are regulated by intestinal hypoxia-inducible factor 1α (HIF-1α). Absence of intestinal HIF-1α exacerbates gut leakiness leading to an increased translocation of bacteria and bacterial products to the liver, consequently causing alcoholic liver disease. Intestinal specific upregulation of HIF-1α could be developed as a novel approach for the treatment of alcoholic liver disease.

Shao T ，Zhao C ，Li F ，Gu Z ，Liu L ，Zhang L ，Wang Y ，He L ，Liu Y ，Liu Q ，Chen Y ，Donde H ，Wang R ，Jala VR ，Barve S ，Chen SY ，Zhang X ，Chen Y ，McClain CJ ，Feng W ... -  《-》

Solid-state fermented Chinese alcoholic beverage (baijiu) and ethanol resulted in distinct metabolic and microbiome responses.

Fang C ，Du H ，Zheng X ，Zhao A ，Jia W ，Xu Y ... -  《-》

Alcoholic liver disease: the gut microbiome and liver cross talk.

Alcoholic liver disease (ALD) is a leading cause of morbidity and mortality worldwide. Alcoholic fatty liver disease can progress to steatohepatitis, alcoholic hepatitis, fibrosis, and cirrhosis. Patients with alcohol abuse show quantitative and qualitative changes in the composition of the intestinal microbiome. Furthermore, patients with ALD have increased intestinal permeability and elevated systemic levels of gut-derived microbial products. Maintaining eubiosis, stabilizing the mucosal gut barrier, or preventing cellular responses to microbial products protect from experimental ALD. Therefore, intestinal dysbiosis and pathological bacterial translocation appear fundamental for the pathogenesis of ALD. This review highlights causes for intestinal dysbiosis and pathological bacterial translocation, their relationship, and consequences for ALD. We also discuss how the liver affects the intestinal microbiota.

Hartmann P ，Seebauer CT ，Schnabl B 《-》