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Intestinal Mucosal Mitochondrial Oxidative Phosphorylation worsens with Cirrhosis Progression and is ameliorated with FMT

ABSTRACT: Intestinal barrier dysfunction, driven by increased oxidative phosphorylation (OXPHOS) activity that leads to tissue hypoxia, contributes to the progression of cirrhosis, particularly impacting the upper intestine. This study explores the interplay between intestinal OXPHOS, gut microbiota changes, and the effects of fecal microbiota transplant (FMT) in cirrhotic patients. We investigated 32 age-matched men across three groups: healthy controls, compensated cirrhosis, and decompensated cirrhosis. Each underwent endoscopy with duodenal and ascending colon biopsies. Subsequently, in a follow-up study, nine patients with hepatic encephalopathy, previously enrolled in a randomized controlled trial for FMT capsules, underwent repeat pre and post-FMT upper endoscopy. Our bioinformatics analysis highlighted a significant upregulation of nuclear-encoded OXPHOS genes in both intestinal regions of cirrhosis patients compared to controls, with further dysregulation in the decompensated group. We also observed a strong correlation between shifts in gut microbiota composition, Model for End-Stage Liver Disease (MELD) scores, and OXPHOS activity. Following FMT, patients displayed a significant reduction in OXPHOS gene expression in the duodenum, suggesting that FMT may restore intestinal barrier function and offer a therapeutic avenue to mitigate liver disease progression. The findings indicate that managing intestinal OXPHOS and microbiota through FMT could be relevant in modulating microbially-based therapies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE285291 | GEO | 2024/12/26

REPOSITORIES: GEO

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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.

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Intestinal Mucosal Mitochondrial Oxidative Phosphorylation worsens with Cirrhosis Progression and is ameliorated with FMT

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