Estrous cycle and ovariectomy-induced changes in visceral pain are microbiota-dependent

Mónica Tramullas,James M Collins,Patrick Fitzgerald,Timothy G Dinan,Siobhain M O’ Mahony,John F Cryan

doi:10.1016/j.isci.2021.102850

Abstract

SummaryVisceral hypersensitivity (VH) is a hallmark of many functional gastrointestinal disorders including irritable bowel syndrome and is categorized by a dull, diffuse sensation of abdominal pain. Recently, the gut microbiota has been implicated in VH in male mice, but the effects in females have yet to be explored fully. To this end, we now show that somewhat surprisingly, female germ-free mice have similar visceral pain responses to colorectal distension (CRD) as their conventional controls. However, we show that although sensitivity to CRD is estrous cycle stage-dependent in conventional mice, it is not in germ-free mice. Further, ovariectomy (OVX) induced VH in conventional but not germ-free mice, and induced weight gain regardless of microbiota status. Finally, we show that estrogen-replacement ameliorated OVX-induced VH. Taken together, this study provides evidence for a major role of female sex hormones and the gut microbiota in sensation of visceral pain in females.

Highlights

Visceral pain is a common and complex occurrence categorized by a diffuse, often dull sensation of pain centered around the midline and upper abdomen originating from some, but not all internal organs (Cervero and Laird, 1999; Sikandar and Dickenson, 2012)
We show that somewhat surprisingly, female germ-free mice have similar visceral pain responses to colorectal distension (CRD) as their conventional controls
Absence of microbiota does not affect the visceral pain response to colorectal distension in female mice To assess the role of the microbiota in the visceral pain response, the response to CRD in GF and conventionally colonized (CC) animals was investigated

Summary

Introduction

Visceral pain is a common and complex occurrence categorized by a diffuse, often dull sensation of pain centered around the midline and upper abdomen originating from some, but not all internal organs (Cervero and Laird, 1999; Sikandar and Dickenson, 2012). Visceral pain-associated disorders such as irritable bowel syndrome (IBS) are more commonly presented in women; to date the majority of preclinical studies on visceral pain are carried out exclusively in males, with their results being generalized to include females in terms of treatment of these disorders (Lee et al, 2018). The estrous cycle is the term used to describe the female reproductive cycle in rodents and is similar to the menstrual cycle in humans In rodents, this cycle has four phases: (i) proestrus, (ii) estrus, (iii) metestrus, and (iv) diestrus, and lasts between 4 and 5 days (Byers et al, 2012). Not all studies agree on the specific changes in visceral pain perception across the estrous cycle, with some reporting heightened visceral sensation when in proestrus versus metestrus/diestrus, or the converse (Ji et al, 2008; Giamberardino et al, 1997)

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