Gut microbial trimethylamine is elevated in alcohol-associated hepatitis and contributes to ethanol-induced liver injury in mice

Abstract

There is mounting evidence that microbes resident in the human intestine contribute to diverse alcohol-associated liver diseases (ALD) including the most deadly form known as alcohol-associated hepatitis (AH). However, mechanisms by which gut microbes synergize with excessive alcohol intake to promote liver injury are poorly understood. Furthermore, whether drugs that selectively target gut microbial metabolism can improve ALD has never been tested. We used liquid chromatography tandem mass spectrometry to quantify the levels of microbe and host choline co-metabolites in healthy controls and AH patients, finding elevated levels of the microbial metabolite trimethylamine (TMA) in AH. In subsequent studies, we treated mice with non-lethal bacterial choline TMA lyase (CutC/D) inhibitors to blunt gut microbe-dependent production of TMA in the context of chronic ethanol administration. Indices of liver injury were quantified by complementary RNA sequencing, biochemical, and histological approaches. In addition, we examined the impact of ethanol consumption and TMA lyase inhibition on gut microbiome structure via 16S rRNA sequencing. We show the gut microbial choline metabolite trimethylamine (TMA) is elevated in AH patients and correlates with reduced hepatic expression of the TMA oxygenase flavin-containing monooxygenase 3 (FMO3). Provocatively, we find that small molecule inhibition of gut microbial CutC/D activity protects mice from ethanol-induced liver injury. CutC/D inhibitor-driven improvement in ethanol-induced liver injury is associated with distinct reorganization of the gut microbiome and host liver transcriptome. The microbial metabolite TMA is elevated in patients with AH, and inhibition of TMA production from gut microbes can protect mice from ethanol-induced liver injury.

Gut microbiota–mitochondrial inter-talk in non-alcoholic fatty liver disease

“…gut microbiota are closely related to environmental influences such as sex, diet, and drugs administered during treatment (25).…”

“…Indeed, the composition of the gut microbiota shows marked dynamic changes from birth to adulthood and old age ( 24 ). However, most alterations in the gut microbiota are closely related to environmental influences such as sex, diet, and drugs administered during treatment ( 25 ).…”

Why Does Doxycycline Pose a Relatively Low Risk for Promotion of Clostridioides difficile Infection?

“…DNA Extraction and 16S rRNA amplicon sequencing DNA Extraction and 16S sRNA amplicon sequencing were performed as described previously [16]. Briefly, DNA was isolated from stool samples using the QIAamp DNA Microbiome kit (Qiagen).…”

Altered gut microbiota and metabolites profile are associated with reduced bone metabolism in ethanol‐induced osteoporosis

“…Although accumulating evidence shows that ethanol is an important risk factor for osteoporosis, 5,6 it remains largely unknown how bone loss and osteopenia occur as parts of many unwanted consequences of ethanol consumption. It is recently reported that chronic heavy ethanol consumption directly impairs gut microbiota (GM) composition, which might be a pivotal pathogenic factor or aggravate pre‐existing illnesses 7 . Notably, studies have repeatedly shown that a gut‐bone regulatory axis exists, by which GM composition could indirectly regulate bone metabolism 8 .…”

“…It is recently reported that chronic heavy ethanol consumption directly impairs gut microbiota (GM) composition, which might be a pivotal pathogenic factor or aggravate pre‐existing illnesses. 7 Notably, studies have repeatedly shown that a gut‐bone regulatory axis exists, by which GM composition could indirectly regulate bone metabolism. 8 However, it remains largely unknown whether the osteoporosis caused by chronic heavy ethanol consumption is related to the impairments of GM composition.…”