This topic is central to gene-environment interactions, i.e. the environment is “excessive alcohol drinking”, and the genes are those that attempt to protect the liver against this onslaught (the environmental signal), but the patient winds up developing alcohol-related liver disease (ARLD) — also called alcohol use disorder (AUD). ARLD leads to alcoholic hepatitis, with mortality ranging from 20% to 40% at 6 months; as many as 75% of patients die within 90 days of diagnosis of severe alcoholic hepatitis. Corticosteroid therapy is only marginally effective. Early liver transplantation is the only curative therapy, but is offered only at select centers and to a limited group of patients (i.e. those with a promise for not becoming addicted in the future).
It is now realized that ARLD can be transmitted via fecal microbiota (i.e. the gut microbiome). Authors [see attached article & editorial] investigated the microorganisms and microbial factors responsible for this transmissible phenotype. Authors performed 16S ribosomal RNA (rRNA) gene sequencing; they showed that altered composition of fecal microbiota existed in patients with AUD and alcoholic hepatitis, compared to subjects without AUD (i.e. the control group). One substantial difference was an increased proportion of Enterococcus species in patients with alcoholic hepatitis: in these patients, 5.6% of fecal bacteria were Enterococcus species, compared with almost none (0.023%) in controls. About 80% of patients with alcoholic hepatitis were positive for
E. faecalis in fecal samples.
Authors [see attached article & editorial] studied fecal samples from both mice and humans. Previous experiments in mice (exposed to high rates of alcohol intake) had hinted that the gut microbiome, and specifically Enterococcus faecalis, might be involved. However,
E. faecalis is usually thought of as “an old friend” (i.e. commensal bacteria) that inhabits the intestine of many animals across the evolutionary tree “in a beneficial relationship” — from nematode worms to humans. Enterococcus faecalis usually represents less than 0.1% of all bacteria in fecal samples from healthy people; however, after antibiotic treatment, bacteria within the Enterococcus genus increase in prevalence — to become one of the most common types of gut microbiota. In fact, Enterococcus faecalis can infect the blood, heart, urinary bladder, brain, and teeth — that have undergone root-canal surgery.
Authors identified E. faecalis in fecal samples from ~80% of people with alcoholic hepatitis, including ~30% of these strains that secreted a toxin called cytolysin. Furthermore, ARLD patients had ~2,700 times more E. faecalis in their stool samples than did controls not having ARLD. Moreover, the presence of cytolysin in fecal samples was highly correlated with mortality within 180 days of hospitalization, compared with only 3.8% mortality of ARLD people whose samples lacked cytolysin. In “humanized mice, authors then treated the animals with bacteriophages that kill the E. faecalis-secreting cytolysin, and were able to abolish ARLD. A clinical trial is now recommended — to validate in humans the relevance of these findings — and to test whether this therapeutic approach might be effective for ARLD patients…!! 😊
Nature 21 Nov 2019; 575: 505-511 & editorial, pp 451-453