Analysis of brain networks and fecal metabolites reveals brain-gut alterations in premenopausal females with irritable bowel syndrome

Vadim Osadchiy^{1

2

3}, Emeran A Mayer^{1

2

4

5}, Kan Gao¹, Jennifer S Labus^{1

2

4}, Bruce Naliboff^{1

2

4}, Kirsten Tillisch^{1

2

4

5}, Lin Chang^{1

2

4}, Jonathan P Jacobs^{1

2

4

5

6}, Elaine Y Hsiao^{1

3

7}, Arpana Gupta^{8

9

10}

Affiliations

¹ G. Oppenheimer Center for Neurobiology of Stress and Resilience, University of California, Los Angeles, Los Angeles, CA, USA.
² David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
³ Department of Urology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
⁴ Vatche and Tamar Manoukian Division of Digestive Diseases, VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA.
⁵ UCLA Microbiome Center, VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA.
⁶ Division of Gastroenterology, Hepatology and Parenteral Nutrition, VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA.
⁷ Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, USA.
⁸ G. Oppenheimer Center for Neurobiology of Stress and Resilience, University of California, Los Angeles, Los Angeles, CA, USA. AGupta@mednet.ucla.edu.
⁹ David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. AGupta@mednet.ucla.edu.
¹⁰ Vatche and Tamar Manoukian Division of Digestive Diseases, VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA. AGupta@mednet.ucla.edu.

PMID: 33139708
PMCID: PMC7608552
DOI: 10.1038/s41398-020-01071-2

Analysis of brain networks and fecal metabolites reveals brain-gut alterations in premenopausal females with irritable bowel syndrome

Vadim Osadchiy et al. Transl Psychiatry. 2020.

. 2020 Nov 2;10(1):367.

doi: 10.1038/s41398-020-01071-2.

Authors

Affiliations

¹ G. Oppenheimer Center for Neurobiology of Stress and Resilience, University of California, Los Angeles, Los Angeles, CA, USA.
² David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
³ Department of Urology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
⁴ Vatche and Tamar Manoukian Division of Digestive Diseases, VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA.
⁵ UCLA Microbiome Center, VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA.
⁶ Division of Gastroenterology, Hepatology and Parenteral Nutrition, VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA.
⁷ Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, USA.
⁸ G. Oppenheimer Center for Neurobiology of Stress and Resilience, University of California, Los Angeles, Los Angeles, CA, USA. AGupta@mednet.ucla.edu.
⁹ David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. AGupta@mednet.ucla.edu.
¹⁰ Vatche and Tamar Manoukian Division of Digestive Diseases, VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA. AGupta@mednet.ucla.edu.

PMID: 33139708
PMCID: PMC7608552
DOI: 10.1038/s41398-020-01071-2

Abstract

Alterations in brain-gut-microbiome (BGM) interactions have been implicated in the pathogenesis of irritable bowel syndrome (IBS). Here, we apply a systems biology approach, leveraging neuroimaging and fecal metabolite data, to characterize BGM interactions that are driving IBS pathophysiology. Fecal samples and resting state fMRI images were obtained from 138 female subjects (99 IBS, 39 healthy controls (HCs)). Partial least-squares discriminant analysis (PLS-DA) was conducted to explore group differences, and partial correlation analysis explored significantly changed metabolites and neuroimaging data. All correlational tests were performed controlling for age, body mass index, and diet; results are reported after FDR correction, with q < 0.05 as significant. Compared to HCs, IBS showed increased connectivity of the putamen with regions of the default mode and somatosensory networks. Metabolite pathways involved in nucleic acid and amino acid metabolism differentiated the two groups. Only a subset of metabolites, primarily amino acids, were associated with IBS-specific brain changes, including tryptophan, glutamate, and histidine. Histidine was the only metabolite positively associated with both IBS-specific alterations in brain connectivity. Our findings suggest a role for several amino acid metabolites in modulating brain function in IBS. These metabolites may alter brain connectivity directly, by crossing the blood-brain-barrier, or indirectly through peripheral mechanisms. This is the first study to integrate both neuroimaging and fecal metabolite data supporting the BGM model of IBS, building the foundation for future mechanistic studies on the influence of gut microbial metabolites on brain function in IBS.

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Conflict of interest statement

E.A.M. is a scientific advisory board member of Danone, Axial Biotherapeutics, Viome, Amare, Mahana Therapeutics, UBiome, Pendulum, Bloom Biosciences, APC Microbiome Ireland. V.O., K.G., J.S.L., B.N., K.T., L.C., J.P.J., E.Y.H., and A.G. have nothing to disclose.

Figures

**Fig. 1. Multivariate analysis in the fecal samples for human subjects.**
The PLS-DA score map in the fecal samples between HC and IBS females.

**Fig. 2. The partial correlation of significantly changed metabolites and resting-state connectivity controlling for age, BMI, and diet between IBS and HC females.**
L_PosDCgG dorsal part of the left posterior cingulate gyrus, L_Pu left putamen, R_Pu right putamen, R_SupFG right superior frontal gyrus.

See this image and copyright information in PMC

References

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Analysis of brain networks and fecal metabolites reveals brain-gut alterations in premenopausal females with irritable bowel syndrome

Affiliations

Analysis of brain networks and fecal metabolites reveals brain-gut alterations in premenopausal females with irritable bowel syndrome

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

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