The role of brain-gut microbiome interactions in mediating IBS and constipation symptoms during menses and menopause

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ABSTRACT Irritable bowel syndrome (IBS) and chronic (functional) constipation have a worldwide prevalence of 11.2% and 14%, respectively and are more common in women than men. However, the pathophysiology of IBS and normal transit constipation (the largest subtype of chronic constipation) is incompletely understood and this likely contributes to the fact that treatments are only efficacious in a subset of patients. Significant sex-related differences include increased severity of gastrointestinal (GI) symptoms in women compared to men and during menopause and in the premenses and menses phase of the menstrual cycle which are states of depleted or declining estrogen. Based on previous studies and our preliminary data, our general hypotheses are: 1) IBS symptom severity in female IBS increases during times of low or declining estrogen states, namely in menopause and mid to late-luteal phase of the menstrual cycle, and is due to reduced estrogen-dependent corticolimbic inhibition of emotional arousal networks, resulting in enhanced visceral perception. Alterations in circulating gut microbial metabolites, in particular tryptophan, estrogen, and bile acids affecting brain stem nuclei may play an additional role, and 2) The increased prevalence and severity of normal transit constipation in women (in the absence of changes in transit or defecation), is due to altered perception of normal, non- noxious afferent signals from the colon resulting from altered central processing. This is due to widespread changes in sensorimotor, salience, and emotional arousal networks and is in part related to increased input from ascending arousal systems originating in brainstem nuclei. Changes in the activity of and ascending projections from these brainstem nuclei may be related in part to the influence of gut microbial metabolites and of estrogen. We will test these hypotheses in two specific aims in which we will measure the relative abundance of gut microbial taxa (16S rRNA), total microbial gene content (shotgun metagenomics), plasma and fecal metabolites (commercial metabolomic platform), and multimodal brain MRI (functional resting state connectivity and pain threat evoked responses) in female subjects: 1) Compare GI symptoms and BGM interactions in premenopausal and postmenopausal female IBS and healthy controls (HCs) and 2) Compare BGM interactions in premenopausal females with normal transit constipation with slow transit constipation and HCs. We anticipate that our findings will identify novel endophenotypes that can lead to the development of novel treatment approaches.