Diminished androgen levels are linked to irritable bowel syndrome and cause bowel dysfunction in mice.

Daniella Rastelli,Kathryn Hall,Liang Sun,Meenakshi Rao,Kristina Perez,Rafla Hassan,Lynley T Matthews,Amy Shepherd,Valentina N Lagomarsino,Madison Mixer,Aleksandra Prochera,Peter D Yim,Anthony Lembo,Sarah Ballou,William Dan,Ariel Robinson,Judy Nee

doi:10.1172/jci150789

Abstract

Functional gastrointestinal disorders (FGIDs) have prominent sex differences in incidence, symptoms, and treatment response that are not well understood. Androgens are steroid hormones present at much higher levels in males than females and could be involved in these differences. In adults with irritable bowel syndrome (IBS), a FGID that affects 5% to 10% of the population worldwide, we found that free testosterone levels were lower than those in healthy controls and inversely correlated with symptom severity. To determine how this diminished androgen signaling could contribute to bowel dysfunction, we depleted gonadal androgens in adult mice and found that this caused a profound deficit in gastrointestinal transit. Restoring a single androgen hormone was sufficient to rescue this deficit, suggesting that circulating androgens are essential for normal bowel motility in vivo. To determine the site of action, we probed androgen receptor expression in the intestine and discovered, unexpectedly, that a large subset of enteric neurons became androgen-responsive upon puberty. Androgen signaling to these neurons was required for normal colonic motility in adult mice. Taken together, these observations establish a role for gonadal androgens in the neural regulation of bowel function and link altered androgen levels with a common digestive disorder.

Highlights

Almost all disorders of the gut-brain axis, from inflammatory bowel disease to neurological disorders with GI comorbidities, exhibit sex differences [1,2,3]
We found that both males and females with Irritable bowel syndrome (IBS) had lower levels of circulating free testosterone than healthy controls, with no difference in DHT levels (Figure 1, A and B and Supplemental Table 2), suggesting that IBS was associated with selective androgen deficits
To ascertain whether androgen levels were linked to the degree of symptoms that patients with IBS experienced, we examined the association between free testosterone and IBS symptom severity score (IBS-SSS), a commonly used composite measure of IBS severity [14]

Summary

Introduction

Almost all disorders of the gut-brain axis, from inflammatory bowel disease to neurological disorders with GI comorbidities, exhibit sex differences [1,2,3]. Irritable bowel syndrome (IBS) is one of the most common of these disorders and is characterized by abdominal pain and altered stool patterns (diarrhea, constipation, or both). Much less attention has been paid to androgens, such as testosterone, which circulate at higher levels in postpubertal males than females. They could be involved, possibly with protective effects. Isolated studies have probed this possibility in small cohorts of patients with IBS or a related functional gastrointestinal disorder (FGID) and found conflicting associations between testosterone levels and symptoms [6,7,8]. The role of androgens in these disorders remains unclear

Methods

Results

Conclusion