Gut microbiota modulates visceral sensitivity through calcitonin gene-related peptide (CGRP) production

ABSTRACT

Abdominal pain is common in patients with gastrointestinal disorders, but its pathophysiology is unclear, in part due to poor understanding of basic mechanisms underlying visceral sensitivity. Accumulating evidence suggests that gut microbiota is an important determinant of visceral sensitivity. Clinical and basic research studies also show that sex plays a role in pain perception, although the precise pathways are not elucidated. We investigated pain responses in germ-free and conventionally raised mice of both sexes, and assessed visceral sensitivity to colorectal distension, neuronal excitability of dorsal root ganglia (DRG) neurons and the production of substance P and calcitonin gene-related peptide (CGRP) in response to capsaicin or a mixture of G-protein coupled receptor (GPCR) agonists. Germ-free mice displayed greater in vivo responses to colonic distention than conventional mice, with no differences between males and females. Pretreatment with intracolonic capsaicin or GPCR agonists increased responses in conventional, but not in germ-free mice. In DRG neurons, gut microbiota and sex had no effect on neuronal activation by capsaicin or GPCR agonists. While stimulated production of substance P by DRG neurons was similar in germ-free and conventional mice, with no additional effect of sex, the CGRP production was higher in germ-free mice, mainly in females. Absence of gut microbiota increases visceral sensitivity to colorectal distention in both male and female mice. This is, at least in part, due to increased production of CGRP by DRG neurons, which is mainly evident in female mice. However, central mechanisms are also likely involved in this process.

KEYWORDS:

• Visceral pain
• bacteria
• germ-free
• dorsal root ganglia (DRG)
• substance P (SP)
• calcitonin-gene-related peptide (CGRP)

Acknowledgments

The authors thank the McMaster Axenic Gnotobiotic Unit staff for their support with axenic experiments and Dr. Michael G. Surette for the use of the inverted microscope for calcium flux experiments.

Disclosure statement

No potential conflict of interest was reported by the authors.

Data availability statement

The main and supplementary data that support the findings of this study are available in figshare at https://doi.org/10.6084/m9.figshare.21430500

Supplemental material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2023.2188874

Additional information

Funding

 The work was supported by the Canadian Institutes of Health Research.