Diminished androgen levels are linked to irritable bowel syndrome and cause bowel dysfunction in mice
Daniella Rastelli, … , Judy Nee, Meenakshi Rao
Daniella Rastelli, … , Judy Nee, Meenakshi Rao
Published November 30, 2021
Citation Information: J Clin Invest. 2022;132(2):e150789. https://doi.org/10.1172/JCI150789.
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Research Article Gastroenterology Neuroscience

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% 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.

Authors

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

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Figure 3

Gonadal androgen deficiency selectively disrupts colonic motility.

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Gonadal androgen deficiency selectively disrupts colonic motility. (A) G...
(A) Gastric emptying of a nonabsorbable dye was no different between SHAM and ORCH mice (n = 7–8/group; P = 0.0967). (B) Small intestinal transit, measured as the distance traveled by a fluorescent dye along the small intestine 15 minutes after gavage, was no different between SHAM and ORCH mice. The x axis represents intestinal segment number (proximal → distal) (n = 7–8 mice/group; each animal’s small intestine was divided into 10 equal segments for measurement of fluorescence). (C) Number of fecal pellets spontaneously expelled over 1 hour, measured 4 weeks after surgery (10 weeks of age) and 20 weeks after surgery (26 weeks of age) in SHAM and ORCH mice (n = 6–8/group; 10 weeks, P = 0.0111; 26 weeks, P = 0.0456). *P < 0.05. (D) Ex vivo imaging showed that colons from ORCH mice had fewer effective, colonic migrating motor contractions (defined as those starting proximally and propagating > 50% of the length of the bowel), than those from SHAM mice (*P = 0.0150). (E–H) Representative spatiotemporal maps illustrating contractile activity of colons from SHAM (E) and ORCH (G) mice ex vivo. Color reflects degree of gut contraction (measured as gut width). Vertical slice analysis at proximal (PS) and distal segments (DS) of the SHAM mouse colon (F) shows regular periodic contractions that start proximally and propagate distally (each green drop in gut width is followed by a pink drop). Similar analysis of ORCH mouse colon (H) shows more disorganized contractions with less efficient propagation. See Supplemental Video 1 for representative videos. Unpaired t tests were used to compare pairs of group means in A, C, and D. Error bars reflect standard error of the mean.