Sex-Bias in Irritable Bowel Syndrome: Linking Steroids to the Gut-Brain Axis

Abstract

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder that is more common in females. Despite its high global incidence, the disease mechanism is still unclear and therapeutic options remain limited. The sexual dimorphism in IBS incidence suggests that sex steroids play a role in disease onset and symptoms severity. This review considers sex steroids and their involvement in IBS symptoms and the underlying disease mechanisms. Estrogens and androgens play important regulatory roles in IBS symptomology, including visceral sensitivity, gut motility and psychological conditions, possibly through modulating the gut-brain axis. Steroids are regulators of hypothalamic-pituitary-adrenal activity and autonomic nervous system function. They also modulate gut microbiota and enteric nervous systems, impacting serotonin and mast cell signaling. Sex steroids also facilitate bidirectional cross-talk between the microbiota and host following bacterial transformation and recycling of steroids by the intestine. The sex-specific interplay between sex steroids and the host provides neuroendocrinology insight into the pathophysiology, epigenetics and treatment of IBS patients.

Gut feelings: the microbiota-gut-brain axis on steroids

“…As some neurological disorders including IBS and autism demonstrate sex bias in incidence and severity (222) (261), sexually dimorphic effects of steroids (particularly sex hormones) has been suggested as a possible etiology. Neuroactive hormone abundance under normal physiological conditions is different in females and males.…”

“…This could be due to estrogen potentiating TRPV1 channel activity (270), which contributes to pain sensation and is upregulated in IBS (4). Furthermore, sex steroids regulate the serotonergic system (222), which could also explain why sex dependence is evident in alterations of the serotonergic system in IBS, which is another signal associated with pain (168). Despite the lack of consistency in IBSassociated microbiome signatures, the gut microbiota could mediate the effect of steroids in IBS pathogenesis.…”

“…Considerable evidence over recent years also connects the gut microbiota to this signaling conduit, extending the commonly used terminology to the "microbiota-gut-brain axis" (144). Different signaling molecules, including steroids are involved in these complex communications (222). Steroids are lipid-derived molecules that generally contain four fused rings of carbon atoms with a chemical structure that plays an important role in a wide range of biological functions, including reproduction, metabolism and immune responses.…”

Obesity Exacerbates Irritable Bowel Syndrome-Related Sleep and Psychiatric Disorders in Women With Polycystic Ovary Syndrome

“…Clinical observations have found that women tend to have slower gastrointestinal (GI) transit and are more prone to constipation than men. However, previous studies have obtained contradictory findings regarding the effect of the various sex hormones on GI motility (25)(26)(27). A recent study based on female dihydrotestosterone (DHT)-treated PCOS rats found lower maximal colon muscle contractility in response to acetylcholine stimulation in DHT-treated rats than in untreated rats (28).…”

The intestinal microbiota and improving the efficacy of COVID-19 vaccinations

“…These immune responses could also underpin differences in COVID-19 vaccine efficacy. Sex steroids are known to regulate the gut microbiota ( Manosso et al, 2021 , So and Savidge, 2021 ) and thus could mediate vaccine efficacy through the gut microbiota. As such studies are warranted that would investigate the role of the gut microbiota in gender differences in COVID-19 vaccine efficacy.…”