Generally-healthy individuals with aberrant bowel movement frequencies show enrichment for microbially-derived blood metabolites associated with reduced kidney function.

Autor:	Johnson-Martínez JP; Institute for Systems Biology, Seattle, WA 98109, USA.; Department of Bioengineering, University of Washington, Seattle, WA 98195, USA., Diener C; Institute for Systems Biology, Seattle, WA 98109, USA., Levine AE; Institute for Systems Biology, Seattle, WA 98109, USA.; Seattle Children's Hospital, Seattle, WA 98105, USA., Wilmanski T; Institute for Systems Biology, Seattle, WA 98109, USA., Suskind DL; Seattle Children's Hospital, Seattle, WA 98105, USA., Ralevski A; Institute for Systems Biology, Seattle, WA 98109, USA., Hadlock J; Institute for Systems Biology, Seattle, WA 98109, USA., Magis AT; Institute for Systems Biology, Seattle, WA 98109, USA., Hood L; Institute for Systems Biology, Seattle, WA 98109, USA.; Department of Bioengineering, University of Washington, Seattle, WA 98195, USA.; Phenome Health, Seattle, WA 98109.; Department of Immunology, University of Washington, Seattle, WA 98195, USA.; Paul G. Allen School of Computer Science & Engineering, University of Washington, Seattle, WA 98195, USA., Rappaport N; Institute for Systems Biology, Seattle, WA 98109, USA., Gibbons SM; Institute for Systems Biology, Seattle, WA 98109, USA.; Department of Bioengineering, University of Washington, Seattle, WA 98195, USA.; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.; eScience Institute, University of Washington, Seattle, WA 98195, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Mar 09. Date of Electronic Publication: 2024 Mar 09.
DOI:	10.1101/2023.03.04.531100
Abstrakt:	Bowel movement frequency (BMF) has been linked to changes in the composition of the human gut microbiome and to many chronic conditions, like metabolic disorders, neurodegenerative diseases, chronic kidney disease (CKD), and other intestinal pathologies like irritable bowel syndrome and inflammatory bowel disease. Lower BMF (constipation) can lead to compromised intestinal barrier integrity and a switch from saccharolytic to proteolytic fermentation within the microbiota, giving rise to microbially-derived toxins that may make their way into circulation and cause damage to organ systems. However, the connections between BMF, gut microbial metabolism, and the early-stage development and progression of chronic disease remain underexplored. Here, we examined the phenotypic impact of BMF variation in a cohort of generally-healthy, community dwelling adults with detailed clinical, lifestyle, and multi-omic data. We showed significant differences in microbially-derived blood plasma metabolites, gut bacterial genera, clinical chemistries, and lifestyle factors across BMF groups that have been linked to inflammation, cardiometabolic health, liver function, and CKD severity and progression. We found that the higher plasma levels of 3-indoxyl sulfate (3-IS), a microbially-derived metabolite associated with constipation, was in turn negatively associated with estimated glomerular filtration rate (eGFR), a measure of kidney function. Causal mediation analysis revealed that the effect of BMF on eGFR was significantly mediated by 3-IS. Finally, we identify self-reported diet, lifestyle, and psychological factors associated with BMF variation, which indicate several common-sense strategies for mitigating constipation and diarrhea. Overall, we suggest that aberrant BMF is an underappreciated risk factor in the development of chronic diseases, even in otherwise healthy populations. Competing Interests: DECLARATION OF INTERESTS L.H. is a former shareholder of Arivale. A.T.M. was a former employee of Arivale. Arivale is no longer a commercially operating company as of April 2019. The remaining authors report no competing interests.
Databáze:	MEDLINE
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