Roseburia spp. Abundance Associates with Alcohol Consumption in Humans and Its Administration Ameliorates Alcoholic Fatty Liver in Mice

• The depletion of Roseburia is associated with alcohol consumption in human cohorts
• R. intestinalis ameliorates the experimental ALD in mice regardless of viability
• Flagellin from R. intestinalis protects on ethanol-disrupted gut barrier functions
• The ethanol-induced gut microbiota dysbiosis is restored by R. intestinalis

Long-term excessive alcohol consumption is the most important risk factor for the development of alcohol-related liver diseases (ALDs), including alcoholic fatty liver disease (AFLD), alcoholic hepatitis, and cirrhosis (Bode and Bode, 1997, Savolainen et al., 1993). The incidence rates of ALDs are strongly affected by several risk factors such as the quantity and pattern of alcohol consumption, gender, ethnicity, diet, and host genetic factors (O`Shea et al., 2010, Stickel and Hampe, 2012). Dysbiosis of the gut microbiota has been reported to accelerate progression of ALDs via the gut-liver axis (Gao and Bataller, 2011, Szabo, 2015). The importance of the gut microbiota in ALDs was strongly suggested because antibiotic treatment that reduced gram-negative bacteria and their lipopolysaccharides (LPSs) led to the remission of ALDs in an ethanol-exposed rodent model (Adachi et al., 1995). Moreover, recent studies have increasingly demonstrated the important role of the gut microbiota in exacerbating ALDs by comparing the consequences of ethanol consumption between germ-free and conventional mice (Canesso et al., 2014, Llopis et al., 2016). Germ-free mice are much more resistant to ALDs under the equal ethanol consumption conditions, indicating that ethanol alone is not sufficient for the development of ALD and that dysbiosis of the gut microbiota is a critical factor in ALD pathogenesis.

Many studies have indicated that gut leakiness is a consequence of high-level alcohol consumption and that translocation of gut-derived LPS is the key risk factor for the development of ALDs (Keshavarzian et al., 2009, Leclercq et al., 2014, Yan et al., 2011). One of the proposed mechanisms for the progression of ALDs is binding of LPS to Toll-like receptor 4 (TLR4) in both Kupffer cells and hepatic stellate cells in the liver, which results in increased hepatic pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) (Louvet and Mathurin, 2015, Paik et al., 2003, Uesugi et al., 2001).

Data from animal studies have suggested that modulation of the gut microbiota has preventive effects on susceptibility to ALDs (Ferrere et al., 2017, Grander et al., 2018). For instance, ethanol-fed mice showed a decreased relative abundance of Bacteroides, and fecal microbiota transplantation (FMT) from healthy control mice significantly improved ALDs (Ferrere et al., 2017). Recently, administration of Akkermansia muciniphila, which is an anaerobic mucin-degrading gut commensal, ameliorated hepatic inflammation by enhancing gut barrier integrity (Grander et al., 2018). Also, supplementation with genetically engineered IL-22-producing Lactobacillus reuteri (L. reuteri) protected against ethanol-induced liver injury via the production of REG3γ, whereas the wild-type (WT) L. reuteri did not protect from the ALD (Hendrikx et al., 2018). Additionally, modulation of metabolites produced by the gut microbiota is important. For example, supplementation of saturated long-chain fatty acids (LCFAs) increased Lactobacillus growth, resulting in protection against ALDs (Chen et al., 2015). Moreover, supplementation with butyrate, which is a major short-chain fatty acid (SCFA), protected the tight junction proteins and improved ALDs (Cresci et al., 2014).

Tsuruya et al., (2016) also found that, in humans, dominant obligate anaerobes, such as the genera Bacteroides and Ruminococcus, were diminished, whereas genus Streptococcus was elevated in alcoholic subjects. However, the limitations of studies on human subjects include a very small sample size and a disregard for other important risk factors, such as gender and host genetic effects. Susceptibility to ALDs is higher in women than in men, and monozygotic (MZ) twins have a higher prevalence of ALDs than dizygotic (DZ) twins, highlighting the importance of the genetic background in ALDs (Stickel and Hampe, 2012). Thus, compensating for several risk factors, including gender and host genetics, is necessary for multivariate analysis of the gut microbiota associated with ALDs.