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

Abstract

ABSTRACTObiectiveBowel movement frequency (BMF) variation 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 (IBS) and inflammatory bowel disease (IBD). Slow intestinal transit times (constipation) are thought to 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, these phenomena have not been characterized in generally-healthy populations, and the connections between microbial metabolism and the early-stage development and progression of chronic disease remain underexplored.DesignHere, we examine the phenotypic impact of BMF variation across a cohort of over 2,000 generally-healthy, community dwelling adults with detailed clinical, lifestyle, and multi-omic data.ResultsWe show significant differences in key blood plasma metabolites, proteins, chemistries, gut bacterial genera, and lifestyle factors across BMF groups that have been linked, in particular, to inflammation and CKD severity and progression.DiscussionIn addition to dissecting BMF-related heterogeneity in blood metabolites, proteins, and the gut microbiome, we identify self-reported diet, lifestyle, and psychological factors associated with BMF variation, which suggest several potential strategies for mitigating constipation and diarrhea. Overall, this work highlights the potential for managing BMF to prevent disease.What is already known about this topicConstipation and diarrhea are linked to several chronic diseases, like IBD, CKD, and neurodegenerative disorders. Chronic constipation, in particular, is associated with the increased production of microbially-derived uremic toxins in the gut due to an ecosystem-wide switch from fiber fermentation to protein fermentation. A build-up of these gut-derived toxins in blood, like p-cresol, has been associated with CKD disease progression and severity.What this study addsWhile prior work has demonstrated associations between microbially-derived uremic toxins, constipation, and CKD severity/progression, here we show similar signatures in a generally-healthy cohort. Overall, we map out the molecular phenotypic effects of aberrant BMFs across individuals without any apparent disease, and show how these effects precede, and may contribute to, the development of chronic disease. We find that certain lifestyle and dietary patterns, like higher levels of exercise, reduced anxiety levels, a more plant-based diet, and drinking more water, are associated with a more optimal BMF range.How this study might affect research, policy, or practiceOverall, we suggest that even mild levels of chronic constipation may cause damage to organ systems over time and ultimately give rise to chronic diseases, like CKD or neurodegeneration. These findings pave the way for future research into early interventions for individuals at risk of developing chronic diseases related to BMF abnormalities. Managing BMF abnormalities prior to disease development may be an important disease prevention strategy, but this will require further evidence through longitudinal human intervention trials.