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

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 5-10% 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.

RET Signaling Persists in the Adult Intestine and Stimulates Motility by Limiting PYY Release from Enteroendocrine Cells

“…The sex-dependent effects of disrupting epithelial RET were striking and resembled the sex-dependent penetrance of RET mutations, a major factor in the disproportionate incidence of HSCR in males. The role of epithelial RET in motility may similarly be established during fetal development or acquired later, such as upon puberty, when gonadal steroids surge and influence gut motility 22 . To distinguish between these possibilities, we assessed GI motility in 3-week-old, pre-pubertal RET EpiKO mice.…”

“…GI motility was intact in juvenile RET EpiKO males, suggesting that puberty alters male EECs and/or their cell circuits. Gonadal androgen signaling to the ENS regulates colonic motility in post-pubertal males 22 . Although there is no evidence for androgen effects on EECs, estrogen has been shown to stimulate endocrine cell secretion 42 .…”

“…For CMMC measurements, two colons were studied in tandem in the organ bath: one from a vehicle-treated animal and one from a drug-treated animal. All parameters were obtained as averages from three 15-minute videos analyzed by Scribble and Matlab scripts 22 . CMMCs were defined as beginning in the proximal colon and propagating > 50% of the colon length.…”

Genotypes of Pain and Analgesia in a Randomized Trial of Irritable Bowel Syndrome

“…Several studies have reported on these sex differences in the context of IBS, however, the mechanisms mediating their presentation are not well defined. In recent years, increased focus has been placed on the role of hormones in modulating sex differences in the presentation of functional gastrointestinal disorders ( 27 , 29 ). Together with our findings, these studies indicate the potential for identification of the cause of sex-linked symptom profiles, particularly in conditions associated with chronic pain.…”