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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 Article has an altmetric score of 7

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

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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 5

Androgen effects on gut motility are mediated by signaling in neurons, rather than smooth muscle.

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Androgen effects on gut motility are mediated by signaling in neurons, r...
(A and B) Cross-sections of colons from SHAM and ORCH mice immunostained for α-smooth muscle actin (SMA) show that the muscularis externa (ME) and muscularis mucosa (MM) are grossly normal in ORCH mice. Cell nuclei marked with DAPI. Scale bars = 20 μm. Tissues for analyses in A–E were isolated from mice 5 to 7 weeks after surgery. (C) There is no difference in colonic smooth muscle thickness between SHAM and ORCH mice (n = 5 mice/group; P = 0.7824). (D) Maximum contractile force exerted by colonic segments from SHAM (n = 15 segments from 5 mice) and ORCH mice (n = 19 segments from 6 mice) is no different (P = 0.9503). Force measurements in D and E were normalized to tissue mass. (E) The dose-dependent contractile force generated by colonic segments upon exposure to the acetylcholine receptor agonist carbachol is no different between segments isolated from SHAM and ORCH mice (n = 15–19, as in D). (F and G) AR immunoreactivity is undetectable in the muscularis externa of a colon from a 3-week-old wildtype male mouse (F). By the postpubertal age of 10 weeks, robust AR expression is observed both within a subset of enteric neurons and in the smooth muscle surrounding the myenteric plexus (G). Enteric neuronal soma are marked by ANNA-1 immunoreactivity. Scale bar = 50 μm. (H) GI transit time was no different in prepubertal (3-week-old) CTRL and cKO mice. When reassessed at a postpubertal age (10 weeks), GI transit time in cKO mice was prolonged (n = 8–10 mice/group; P = 0.0027). **P < 0.005. Unpaired t tests were used to compare pairs of group means in C, D and H. Error bars reflect standard error of the mean. Images in A, B, F, and G are representative of observations made in a minimum of 3 mice per condition.

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