Dataset Information

Enterotoxigenic Bacteroides fragilis Exacerbates Alcoholic Liver Disease by Driving Host Metabolic Reprogramming via the Tryptophan-Kynurenine-Retinol Pathway

ABSTRACT:

Background & Aims: Alcoholic liver disease (ALD) is a major public health concern. Gut dysbiosis plays a critical role in its pathogenesis, yet the specific microbial and functional shifts driving ALD progression require further elucidation. This study aims to characterize these alterations and their mechanisms.

Methods: We recruited 28 male patients with alcoholic fatty liver (AFL), 22 with alcoholic cirrhosis (ALC), and 25 healthy male controls. Fecal samples were analyzed via shotgun metagenomic sequencing and targeted short-chain fatty acid (SCFA) metabolomics. Serum samples underwent untargeted metabolomics. Key findings were validated in mouse models through fecal microbiota transplantation (FMT), bacterial gavage, and integrated transcriptomic and metabolomic analyses.

Results: Metagenomic analysis revealed a depletion of SCFA-producing bacteria (e.g., Faecalibacterium prausnitzii, Fusicatenibacter saccharivorans) and an enrichment of enterotoxigenic Bacteroides fragilis (ETBF) in ALD patients. Fecal concentrations of acetate, propionate, and butyrate were significantly decreased and negatively correlated with serum ALT, AST, and GGT levels. Serum metabolomics identified a distinct profile in ALD, featuring elevated levels of metabolites such as 9,10-DHOME and reduced levels of specific lysophosphatidylcholines. Multi-omics integration suggested microbial regulation of ALD via bile acid and SCFA pathways. FMT from ALD patients exacerbated alcohol-induced liver injury in mice. Gavage with ETBF significantly worsened ALD phenotypes in mice, likely mediated by Bacteroides fragilis toxin (BFT)-induced gut barrier damage and inflammation. Mouse multi-omics further demonstrated that ETBF perturbation enhanced the tryptophan-kynurenine metabolic pathway and upregulated hepatic retinol metabolism, contributing to increased liver injury, inflammation, and fibrosis.

Conclusion: Gut dysbiosis characterized by the loss of beneficial SCFA producers and the rise of pathogenic ETBF is pivotal in ALD progression. ETBF exacerbates disease via toxin-driven barrier dysfunction and the dysregulation of tryptophan and retinol metabolic pathways, revealing novel mechanistic insights and potential therapeutic targets.

INSTRUMENT(S): Liquid Chromatography MS - positive - hilic, Liquid Chromatography MS - negative - hilic

PROVIDER: MTBLS13649 | MetaboLights | 2026-01-10

REPOSITORIES: MetaboLights

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			Action	DRS
	a_MTBLS13649_LC-MS_negative_hilic_metabolite_profiling.txt	Txt
	a_MTBLS13649_LC-MS_positive_hilic_metabolite_profiling.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS13649_LC-MS_negative_hilic_metabolite_profiling_v2_maf.tsv	Tabular
	m_MTBLS13649_LC-MS_positive_hilic_metabolite_profiling_v2_maf.tsv	Tabular

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Project description:Background & Aims: Alcoholic liver disease (ALD) is a major public health concern. Gut dysbiosis plays a critical role in its pathogenesis, yet the specific microbial and functional shifts driving ALD progression require further elucidation. This study aims to characterize these alterations and their mechanisms.Methods: We recruited 28 male patients with alcoholic fatty liver (AFL), 22 with alcoholic cirrhosis (ALC), and 25 healthy male controls. Fecal samples were analyzed via shotgun metagenomic sequencing and targeted short-chain fatty acid (SCFA) metabolomics. Serum samples underwent untargeted metabolomics. Key findings were validated in mouse models through fecal microbiota transplantation (FMT), bacterial gavage, and integrated transcriptomic and metabolomic analyses.Results: Metagenomic analysis revealed a depletion of SCFA-producing bacteria (e.g., Faecalibacterium prausnitzii, Fusicatenibacter saccharivorans) and an enrichment of enterotoxigenic Bacteroides fragilis (ETBF) in ALD patients. Fecal concentrations of acetate, propionate, and butyrate were significantly decreased and negatively correlated with serum ALT, AST, and GGT levels. Serum metabolomics identified a distinct profile in ALD, featuring elevated levels of metabolites such as 9,10-DHOME and reduced levels of specific lysophosphatidylcholines. Multi-omics integration suggested microbial regulation of ALD via bile acid and SCFA pathways. FMT from ALD patients exacerbated alcohol-induced liver injury in mice. Gavage with ETBF significantly worsened ALD phenotypes in mice, likely mediated by Bacteroides fragilis toxin (BFT)-induced gut barrier damage and inflammation. Mouse multi-omics further demonstrated that ETBF perturbation enhanced the tryptophan-kynurenine metabolic pathway and upregulated hepatic retinol metabolism, contributing to increased liver injury, inflammation, and fibrosis.Conclusion: Gut dysbiosis characterized by the loss of beneficial SCFA producers and the rise of pathogenic ETBF is pivotal in ALD progression. ETBF exacerbates disease via toxin-driven barrier dysfunction and the dysregulation of tryptophan and retinol metabolic pathways, revealing novel mechanistic insights and potential therapeutic targets.

Project description:Purpose: To determine whether previously observed behavioral differences in alcoholic human patients after fecal microbiota transplantation (FMT) could be transferred to mice. Methods: Fecal microbiota samples from a previously published phase 1, double-blind, randomized clinical trial of AUD-related cirrhosis patients were used to colonize germ-free mice. Fecal material was transferred to 10-15-week-old GF C57BL/6 male mice by daily gavage for 3 day. The mice were housed in sterile individually filtered cages for 15 days after which stool was collected and then they underwent the alcohol preference experiment using 2-bottle choice drinking (water and 20% ethanol v/v). Microbial DNA was isolated from stool samples by sequencing the V1 and V2 variable regions of the bacterial 16S rRNA gene were sequenced using Multitag fusion primers and sequenced on an Ion Torrent PGM next-generation sequencer. Intestinal mucosa, liver, and prefrontal cortex tissue was collected from mice at time of sacrifice. RNAseq was used to measure gene expression in pre-FMT and post-FMT samples. RNAseq data were aligned to the mouse genome (GRCm39) using STAR (version 2.7.9a) and counts were generated with HTSeq (version 0.13.5). Genes with very low counts across the study (defined as fewer than 10 counts in more than 2 samples) were eliminated before differential expression analysis. Low count genes were determined separately for each tissue type. The DESeq2 package for R was then used to measure differential expression between pre-FMT and post-FMT mice in the intestine, liver, and PFC. Benjamini and Hochberg False Discovery Rate (FDR) was used to correct for multiple testing with FDR ≤ 0.2 considered significant. Results: Mice colonized with post-FMT stool significantly reduced ethanol acceptance, intake and preference versus pre-FMT colonized mice. Microbial taxa that were higher in post-FMT humans were also associated with lower alcohol intake and preference in mice. RNAseq further showed that differential gene expression, post-FMT, occurred in the intestine rather than the liver and prefrontal cortex. Conclusions: FMT leads to significant change in gut microbiome population, which in turn alters gene expression in the intestine. FMT also significantly affects alcohol consumption. The microbiotal-intestinal interface may alter gut-liver-brain axis and reduce alcohol consumption in humans.

Dataset Information

Enterotoxigenic Bacteroides fragilis Exacerbates Alcoholic Liver Disease by Driving Host Metabolic Reprogramming via the Tryptophan-Kynurenine-Retinol Pathway

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