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Intestinal β-galactosidase acts as a regulator of sepsis progression

ABSTRACT: This project investigates the role of intestinal β-galactosidase in sepsis using 16S rRNA sequencing, metabolomic, and proteomic analyses. Septic patients showed reduced intestinal β-galactosidase activity associated with depletion of putative β-galactosidase-producing bacteria, including Blautia, Faecalibacterium, and Ruminococcus. Metabolomic profiling identified hesperetin as a key microbiota-associated metabolite, and proteomic analysis identified CDK13 as a critical downstream target regulating NLRP3 inflammasome priming and macrophage pyroptosis. Restoration of intestinal β-galactosidase promoted dietary hesperetin liberation and improved survival in septic mice.

ORGANISM(S): Mus Musculus

SUBMITTER: Shenhai Gong

PROVIDER: PXD082250 | iProX | Wed Aug 05 00:00:00 GMT+01:00 2026

REPOSITORIES: iProX

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Project description:Background and aims: Gene mutations or variants leading to insufficient reactive oxygen species (ROS) production have been associated with inflammatory bowel disease (IBD). In particular, 40-50% of patients with chronic granulomatous disease have IBD (CGD-IBD). CGD is caused by inherited defects in any one of the 5 subunits forming the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex 2 (NOX2), leading to severely reduced or absent phagocyte-derived ROS production. While conventional IBD therapies can treat CGD-IBD, their benefits must be weighed against the risk of infection in this immune compromised population. Understanding the impact of NOX2 defects on the composition and function of the intestinal microbiota may lead to the identification of treatments for CGD-IBD. Methods: We evaluated GI symptom and quality of life scores, and clinical biomarkers of local (i.e. fecal occult blood and calprotectin) and systemic (i.e. CBC, CRP, ESR, and albumin) inflammation in a cohort of 79 patients with CGD, 8 mutation carriers and 17 healthy controls followed at the National Institutes of Health (NIH). We profiled the intestinal microbiome by 16S rRNA (V4 region) sequencing and the stool metabolome by mass spectrometry in all fecal samples, and further validated our findings by profiling the stool microbiome in a second cohort of 36 patients with CGD recruited from 11 centers across North-America through the Primary Immune Deficiency Treatment Consortium (PIDTC). Predictive functional profiling of the microbial communities based on 16S rRNA sequencing was also performed. Results: After controlling for significant variables, we show decreased alpha diversity and identified distinct intestinal microbiome and metabolomic profiles in patients with CGD compared to healthy individuals. In particular, we observed enrichment for Erysipelatoclostridium spp., Sellimonas spp. and Lachnoclostridium spp. in stool samples from patients with CGD. Despite differences in alpha and beta diversity in samples from the NIH compared to the PIDTC cohort, there were several bacterial taxa that correlated significantly between both cohorts. We further demonstrate that patients with active IBD and/or a history of IBD have a distinct microbiome and metabolomic profile compared to patients without CGD-IBD and identified bacterial taxa to be evaluated as potential markers of disease severity, as well as targets for future therapeutic interventions. Conclusions: Intestinal microbiome and metabolomic signatures distinguished patients with CGD and CGD-IBD and identified microbial and metabolomic candidates to be further evaluated as potential targets to improve the management of patients with CGD-IBD.

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Intestinal β-galactosidase acts as a regulator of sepsis progression

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