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Infusion of donor feces affects the gut-brain axis in humans with metabolic syndrome.

ABSTRACT: OBJECTIVES:There is increasing evidence that intestinal microbiota play a role in diverse metabolic processes via intestinal butyrate production. Based on bariatric surgery data in humans it has been suggested that the gut-brain axis is also involved in this process, however the underlying mechanisms are still unknown. DESIGN:We therefore compared the effect of fecal microbiota transfer (FMT) from post-Roux-en-Y gastric bypass (RYGB) donors versus oral butyrate supplementation on (123I-FP-CIT determined) brain dopamine transporter (DAT) and serotonin transporter (SERT) binding as well as stable isotope determined insulin sensitivity at baseline and after 4 weeks in 24 male and female treatment-naïve metabolic syndrome subjects. Also, plasma metabolites and fecal microbiota were determined at these timepoints. RESULTS:We observed an increase in brain DAT upon donor FMT compared to oral butyrate that reduced this binding. However, no effect on body weight and insulin sensitivity was seen upon post-RYGB donor feces transfer in either humans with metabolic syndrome. In line, increases in fecal levels of Bacteroides uniformis were significantly associated with an increase in DAT whereas increases in Prevotella spp. showed an inverse association. Furthermore, changes in the plasma metabolites glycine, betaine, methionine and lysine (associated with the S-adenosylmethionine cycle) were also associated with altered striatal DAT expression. CONCLUSION:Although more and larger studies are needed, our data suggest a potential gut microbiota-driven modulation of brain dopamine and serotonin transporters in human obese metabolic syndrome subjects. Moreover, these data suggest the presence of a gut-brain axis in humans,that can be modulated. NTR registration: 4488.

SUBMITTER: Hartstra AV

PROVIDER: S-EPMC7536740 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Infusion of donor feces affects the gut-brain axis in humans with metabolic syndrome.

Hartstra Annick V AV Schüppel Valentina V Imangaliyev Sultan S Schrantee Anouk A Prodan Andrei A Collard Didier D Levin Evgeni E Dallinga-Thie Geesje G Ackermans Mariette T MT Winkelmeijer Maaike M Havik Stefan R SR Metwaly Amira A Lagkouvardos Ilias I Nier Anika A Bergheim Ina I Heikenwalder Mathias M Dunkel Andreas A Nederveen Aart J AJ Liebisch Gerhard G Mancano Giulia G Claus Sandrine P SP Benítez-Páez Alfonso A la Fleur Susanne E SE Bergman Jacques J JJ Gerdes Victor V Sanz Yolanda Y Booij Jan J Kemper Elles E Groen Albert K AK Serlie Mireille J MJ Haller Dirk D Nieuwdorp Max M

Molecular metabolism 20200908

<h4>Objective</h4>Increasing evidence indicates that intestinal microbiota play a role in diverse metabolic processes via intestinal butyrate production. Human bariatric surgery data suggest that the gut-brain axis is also involved in this process, but the underlying mechanisms remain unknown.<h4>Methods</h4>We compared the effect of fecal microbiota transfer (FMT) from post-Roux-en-Y gastric bypass (RYGB) donors vs oral butyrate supplementation on (<sup>123</sup>I-FP-CIT-determined) brain dopam ...[more]

PMID: 32916306

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Project description:Emerging evidence suggests that the gut microbiota may interact with the host brain and play pivotal roles in the pathogenesis of neuropsychiatric disorders. However, the mechanism underlying reciprocal interactions along the microbiota-gut-brain axis in depression remains unclear. In this study, a murine model of chronic restraint stress (CRS) was established to investigate the metabolic signaling of tryptophan (Trp) neurotransmission at the intestinal and central levels in depression. The results showed that CRS mice displayed depression- and anxiety-like behaviors. Additionally, kynurenine (Kyn) and its metabolites, an important Trp metabolic pathway, were strongly activated in the brain. Intriguingly, the Kyn toxic signaling was exacerbated in the gut, especially in the colon. Indoleamine 2,3-dioxygenase (IDO), a rate-limiting enzyme responsible for Kyn metabolic pathway initiation, was significantly upregulated in the brain and gut in CRS mice compared with control mice, promoting transfer of Trp metabolic pathway to Kyn signaling. Additionally, administration of IDO inhibitor, 1-methyl-tryptophan (1-MT), partially rescued CRS-induced depression- and anxiety-like changes. Moreover, the enhanced intestinal permeability mediated by CRS allowed toxic metabolites to "leak" into the bloodstream. The microbiome profiles of CRS mice displayed obviously altered taxonomic composition and negative correlations were observed between Enterorhabdus, Parabacteroides and Kyn levels in the brain. Reciprocal crosstalk between the brain and gut was further validated by citalopram treatment, IDO inhibitor and microbiota intervention, which counteracted depression-like behavior, Kyn metabolic signaling and microbiota composition in CRS mice. Meanwhile, Parabacteroides treatment affected Trp metabolism in mouse hippocampus, manifesting as elevated concentration of 5-HT as well as ratio of 5-HT to Trp. These results suggest that long-term stress disrupts Kyn metabolism and endocrine function along the gut-brain axis, accompanied by the disrupted homeostasis of certain microbiota, which collectively contribute to the development of depression-like behavior.

Dataset Information

Infusion of donor feces affects the gut-brain axis in humans with metabolic syndrome.

Publications

Infusion of donor feces affects the gut-brain axis in humans with metabolic syndrome.

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