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Published on: December 15, 2023
Gut microbes impact stroke severity via the trimethylamine N-oxide pathway
Weifei Zhu1, Kymberleigh A Romano1, Lin Li1
1Department of Cardiovascular & Metabolic Sciences, Cleveland Clinic, Cleveland, OH 44195, USA.
Abstract:
Clinical studies have demonstrated associations between circulating levels of the gut-microbiota-derived metabolite trimethylamine-N-oxide (TMAO) and stroke incident risk. However, a causal role of gut microbes in stroke has not yet been demonstrated. Herein we show that gut microbes, through dietary choline and TMAO generation, directly impact cerebral infarct size and adverse outcomes following stroke. Fecal microbial transplantation from low- versus high-TMAO-producing human subjects into germ-free mice shows that both TMAO generation and stroke severity are transmissible traits. Furthermore, employing multiple murine stroke models and transplantation of defined microbial communities with genetically engineered human commensals into germ-free mice, we demonstrate that the microbial cutC gene (an enzymatic source of choline-to-TMA transformation) is sufficient to transmit TMA/TMAO production, heighten cerebral infarct size, and lead to functional impairment. We thus reveal that gut microbiota in general, specifically the metaorganismal TMAO pathway, directly contributes to stroke severity.
Insights
Gut microbes impact stroke severity by producing trimethylamine-N-oxide (TMAO) from dietary choline. This study demonstrates TMAO generation and stroke severity are transmissible traits, highlighting the gut microbiota
Area of Science:
- Microbiology and Neuroscience
- Gut Microbiome and Cerebrovascular Health
Background:
- Clinical studies link circulating trimethylamine-N-oxide (TMAO) to stroke risk.
- A direct causal role for gut microbes in stroke pathogenesis remains unproven.
Purpose of the Study:
- To investigate the direct impact of gut microbiota, specifically TMAO production, on stroke outcomes.
- To determine if TMAO generation and stroke severity are heritable traits influenced by gut microbes.
Main Methods:
- Fecal microbial transplantation from human donors with varying TMAO levels into germ-free mice.
- Utilized murine stroke models and transplanted defined microbial communities, including genetically engineered commensals.
- Investigated the role of the microbial cutC gene in TMA/TMAO production and stroke severity.
Main Results:
- TMAO generation and stroke severity were shown to be transmissible traits via fecal microbial transplantation.
- The microbial cutC gene was sufficient to mediate TMA/TMAO production, increase cerebral infarct size, and cause functional impairment.
- Gut microbiota directly influences cerebral infarct size and stroke outcomes.
Conclusions:
- Gut microbiota, via the TMAO pathway involving dietary choline, directly contributes to stroke severity.
- Microbial TMAO production is a key factor influencing brain infarct size and functional recovery post-stroke.
- This study establishes a direct causal link between gut microbial metabolism and cerebrovascular disease.
