Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 115, Issue 25, Pages 6458-6463Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1720017115
Keywords
microbiota; enteric nervous system; serotonin; 5-HT4R
Categories
Funding
- Swedish Research Council
- Novo Nordisk Foundation
- Torsten Soderberg Foundation
- Swedish Heart Lung Foundation
- Goran Gustafsson Foundation
- IngaBritt och Arne Lundberg Foundation
- Knut and Alice Wallenberg Foundation
- European Molecular Biology Organization Long-Term Fellowship [ALTF 1305-2014, GA-2013-609409]
- La Ligue Contre Le Cancer postdoctoral fellowship
- Wenner-Gren foundations
- NIH [2P01 AG032959-06A1]
- Columbia Aging Center
- European Research Council [615362-METABASE]
- NATIONAL INSTITUTE ON AGING [P01AG032959] Funding Source: NIH RePORTER
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The enteric nervous system (ENS) is crucial for essential gastrointestinal physiologic functions such as motility, fluid secretion, and blood flow. The gut is colonized by trillions of bacteria that regulate host production of several signaling molecules including serotonin (5-HT) and other hormones and neurotransmitters. Approximately 90% of 5-HT originates from the intestine, and activation of the 5-HT4 receptor in the ENS has been linked to adult neurogenesis and neuroprotection. Here, we tested the hypothesis that the gut micro-biota could induce maturation of the adult ENS through release of 5-HT and activation of 5-HT4 receptors. Colonization of germ-free mice with a microbiota from conventionally raised mice modified the neuroanatomy of the ENS and increased intestinal transit rates, which was associated with neuronal and mucosal 5-HT production and the proliferation of enteric neuronal progenitors in the adult intestine. Pharmacological modulation of the 5-HT4 receptor, as well as depletion of endogenous 5-HT, identified a mechanistic link between the gut microbiota and maturation of the adult ENS through the release of 5-HT and activation of the 5-HT4 receptor. Taken together, these findings show that the microbiota modulates the anatomy of the adult ENS in a 5-HT-dependent fashion with concomitant changes in intestinal transit.
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