Brain-Gut-Microbiome Differences between Constipation-Predominant IBS Vs. Non-Constipation-Predominant IBS
Rachel Sarnoff, MD2,4; Emeran A. Mayer, MD1,2,4; Vadim Osadchiy3,4, MD; Zixi Chen1,2,4; Vishvak Subramanyam1,2,4; Priten Vora, BS1,2,4; Cathy Liu, BA1,2,4; Jean Stains, BS1,2,4; Jennifer Labus, PhD1,2,4; Bruce Naliboff, PhD1,2,4; Lin Chang, MD1,2,4; Arpana Gupta, PhD1,2,4
1Vatche and Tamar Manoukian Division of Digestive Diseases, 2Department of Medicine; 3Department of Urology; 4David Geffen School of Medicine at UCLA
Background and Objectives: The brain-gut-microbiome (BGM) axis has been implicated in irritable bowel syndrome (IBS), a female-predominant disorder of gut-brain interaction. Alterations in tryptophan and serotonin signaling are thought to play a role in BGM interactions in IBS and other functional bowel disorders. However, BGM interactions within IBS bowel habit subtypes, particularly in constipation-predominant IBS (IBS-C), have not yet been elucidated. We present a systems biology approach to characterize BGM interactions in IBS-C. Methods: Fecal samples and resting state fMRI imaging were obtained from 138 premenopausal women (36 Rome+ IBS-C, 28 diarrhea-predominant IBS (IBS-D), 26 mixed bowel habits IBS (IBS-M), 9 IBS-unspecified (IBS-U), and 39 healthy controls (HCs)). IBS-D, IBS-M, and IBS-U comprised the non-constipation-predominant IBS group (IBS-NC). Partial least squares discriminant analysis (PLS-DA) was conducted to explore group differences. Fecal metabolites and brain regions with values of the first principle component of variable importance projection in PLS-DA greater than 1.0 were assessed by Student’s t-test. We then performed partial correlation analysis between significantly changed metabolites and neuroimaging data. Analyses were performed controlling for age, body mass index, and diet; results are reported after FDR correction, with q<.05 as significant. Results: IBS-C, IBS-NC, and HCs could be distinguished from each other by their alterations in neuroanatomical and functional links on MRI (“brain connectivity,” Figure 1). Compared to HCs, IBS-C patients had greater functional connectivity within the somatosensory, emotional regulation, default mode, and central-executive networks. Metabolite pathways involved in nucleic and amino acid metabolism differentiated IBS-C, IBS-NC, and HCs. In an integrated analysis, IBS-C showed tryptophan-related metabolites that were positively correlated with sensorimotor network regions (2-oxindole-3-acetate: r=.33, p=.02; indole-3-carboxylic acid: r=.34, p=.02; r=.39, p=.008). Conclusion: This study is the first to integrate neuroimaging and microbiome data to characterize subtypes of IBS. IBS-C subjects had greater alterations in brain regions involved in the processing and perception of sensory signals and in networks related to salience assessment, emotional arousal, and attention. These brain patterns may enhance centrally-mediated visceral perception in IBS-C. The distinct gut microbiome patterns in IBS subtypes, including the relationship between tryptophan-related metabolites and sensorimotor connectivity, may highlight the role of serotonin in the pathophysiology of IBS-C in premenopausal women.
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Figure 1. sPLS-DA Analysis of Brain Connectivity among IBS-C, IBS-NC, and HC. |
Breakout Room: Sarnoff, Rachel
View Poster: https://uclacns.org/symposium2021/19-Sarnoff-Rachel.pdf