• INFLAMMATION
• ALCOHOLIC LIVER DISEASE

Alcoholic hepatitis (AH) covers a spectrum of disease severities from subclinical liver inflammation to acute liver failure. Among the histological features of alcoholic liver disease (ALD), AH is associated with the highest risk of fibrosis progression, leading to development of cirrhosis in 40% of cases. Patients hospitalised for severe forms of AH show 1-month mortality rates of 40–50%.1 Patients with AH form a heterogeneous population, in severity, and probably in disease pathogenesis. This diverse clinical picture might be caused by various factors including host factors, immunity and as recently suggested, intestinal microbiota (IM).2

Patients with ALD present with an altered IM, a condition that is commonly called ‘dysbiosis’, and an increased intestinal permeability, even at an early stage of alcoholic liver injury; this leads to elevated endotoxin levels, with the highest levels in patients with cirrhosis.3 It has been shown that gut microbiota play an important role in experimental ALD. Mice treated with certain antibiotics are resistant to experimental ALD4 and alcohol-induced liver injury was largely blocked in mice lacking CD14 or TLR4 receptors.5 Administration of certain probiotics such as Lactobacillus rhamnosus GG to alcohol-fed mice improves the GI barrier and liver disease.6 Mutlu et al investigated the mucosa-associated colonic microbiome in subjects with and without ALD and in healthy controls.7 A subgroup of patients with ALD exhibited dysbiosis with lower median abundances of Bacteroidetes and higher ones of Proteobacteria. Interestingly, these changes correlated with endotoxaemia. Intestinal permeability and gut-bacterial dysbiosis-might play a role in other alcohol-related aspects such as alcohol-dependence severity.8 Therefore, it has been increasingly recognised that IM could be crucial in various aspects of alcohol-induced-disease, beyond liver disease.

In this issue of Gut, Llopis et al advance the concept that IM plays a crucial role in AH demonstrating that disease severity of human AH can be transferred to germ-free and conventionalised mice.9 First, AH-related dysbiosis was characterised by an increase of certain Bifidobacteria, Streptococci and Enterobacteria in stool samples whereas certain species such as Clostridium leptum or Faecalibacterium prausnitzii, both well established anti-inflammatory strains, were decreased.10 These protective strains were also negatively correlated with biological parameters of disease severity such as bilirubin level. In the following part of the study, the authors performed faecal microbiota transfer (FMT) from patients with or without AH into humanised germ-free mice and also into conventional mice. In these studies, the authors used generally accepted experimental strategies such as induction of mild ethanol-induced liver injury by continuous ethanol administration.11 Liver injury in these animals was dramatically aggravated after FMT from a patient with severe AH compared with FMT from a human donor without severe AH. To guarantee successful FMT, the authors could show that more than two-thirds of genera were indeed successfully transferred from human to mouse. Importantly, disease severity could also be transferred to conventional mice and a second subsequent FMT from an alcoholic patient without AH even improved liver disease after having received FMT from a donor with severe AH. These experiments therefore clearly tell us, that IM from patients with severe AH contain proinflammatory signals which are transferable from humans to mice. Currently we can only speculate that such signals may be derived from certain intestinal bacteria, that is, pathobionts which drive overwhelmingly inflammatory processes.

Several members of IM, however, might exert protective functions for the host including establishment of an intact intestinal barrier, as complete absence of microbiota increased the inflammatory response in the liver as well as degree of hepatic steatosis in acute alcohol-induced liver injury.12 Disease transfer via FMT has been demonstrated in the past by many investigators, initially mainly from mouse to mouse and recently also from human to mouse. Elegant examples included the demonstration that FMT from several discordant twin pairs with severe kwashiorkor into gnotobiotic mice resulted in successful disease transfer.13 Furthermore, Koren et al 14 showed that an FMT from mothers with gestational diabetes resulted in greater adiposity and impaired insulin sensitivity in recipient mice. Llopis et al have now introduced a similar concept in AH research, namely transferability of this disease from human to mouse which could allow in the future to further and to better characterise the potential role of various microbiota members in this disease.

One of the major challenges in diseases where IM might be involved in disease modification and severity is to identify which members of IM act as a potential protective strain and which members are causing or worsening disease by acting as a pathobiont. Several members of IM, such as F. prausnitzii in human IBDs10 or Akkermanisa muciniphila in metabolic inflammation, have been identified in the last years which might exert protective functions.15 Clostridium difficile is an elegant example of such a pathobiont which can rapidly turn into a disease-promoting member of IM. FMT has been convincingly demonstrated to be highly effective in the treatment of refractory C. difficile infection.16 Whereas initial studies mainly involved patients with less severe disease, FMT can even be used successfully in patients with severe C. difficle-associated disease.17 In this study, Camarotta et al showed that FMT has the potential to eliminate surgery/colectomy in this patient population. This is very promising for other severe diseases such as AH where IM is increasingly recognised as a major factor in disease progression. Whereas FMT using the duodenal or colonic mode of administration is one option, the use of FMT capsules could be another attractive treatment modality as demonstrated in patients with C. difficile infection.18 Therefore, one might assume that phase I studies could now be initiated to investigate the role of FMT in severe liver diseases such as AH.

In summary, IM has evolved as a major player in ALD. Alcohol disrupts the intestinal microbiome, alters the intestinal barrier and might affect various other intestinal functions such as mucosal immunity. Agents including various forms of diet might have the potential to influence and correct these disturbances, and appear as potential therapy of these diseases in the future. More importantly manipulation of IM by various steps including FMT, prebiotics or probiotics, selectively targeting key pathobionts, might constitute an even more promising treatment strategy. Therefore, a new treatment era might soon begin for this devastating and highly fatal disorder.