Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2019 Mar 21;7(1):45.
doi: 10.1186/s40168-019-0656-z.

Evidence for an association of gut microbial Clostridia with brain functional connectivity and gastrointestinal sensorimotor function in patients with irritable bowel syndrome, based on tripartite network analysis

Jennifer S Labus  1 , Vadim Osadchiy  1 , Elaine Y Hsiao  1   2 , Julien Tap  3 , Muriel Derrien  3 , Arpana Gupta  1 , Kirsten Tillisch  1 , Boris Le Nevé  3 , Cecilia Grinsvall  4 , Maria Ljungberg  5 , Lena Öhman  4   6 , Hans Törnblom  4 , Magnus Simren  4   7 , Emeran A Mayer  8
Affiliations

Evidence for an association of gut microbial Clostridia with brain functional connectivity and gastrointestinal sensorimotor function in patients with irritable bowel syndrome, based on tripartite network analysis

Jennifer S Labus et al. Microbiome. .

Abstract

Background and aims: Evidence from preclinical and clinical studies suggests that interactions among the brain, gut, and microbiota may affect the pathophysiology of irritable bowel syndrome (IBS). As disruptions in central and peripheral serotonergic signaling pathways have been found in patients with IBS, we explored the hypothesis that the abundance of serotonin-modulating microbes of the order Clostridiales is associated with functional connectivity of somatosensory brain regions and gastrointestinal (GI) sensorimotor function.

Methods: We performed a prospective study of 65 patients with IBS and 21 healthy individuals (controls) recruited from 2011 through 2013 at a secondary/tertiary care outpatient clinic in Sweden. Study participants underwent functional brain imaging, rectal balloon distension, a nutrient and lactulose challenge test, and assessment of oroanal transit time within a month. They also submitted stool samples, which were analyzed by 16S ribosomal RNA gene sequencing. A tripartite network analysis based on graph theory was used to investigate the interactions among bacteria in the order Clostridiales, connectivity of brain regions in the somatosensory network, and GI sensorimotor function.

Results: We found associations between GI sensorimotor function and gut microbes in stool samples from controls, but not in samples from IBS patients. The largest differences between controls and patients with IBS were observed in the Lachnospiraceae incertae sedis, Clostridium XIVa, and Coprococcus subnetworks. We found connectivity of subcortical (thalamus, caudate, and putamen) and cortical (primary and secondary somatosensory cortices) regions to be involved in mediating interactions among these networks.

Conclusions: In a comparison of patients with IBS and controls, we observed disruptions in the interactions between the brain, gut, and gut microbial metabolites in patients with IBS-these involve mainly subcortical but also cortical regions of brain. These disruptions may contribute to altered perception of pain in patients with IBS and may be mediated by microbial modulation of the gut serotonergic system.

Keywords: Bacteria; Brain imaging; Brain–gut axis; Central nervous system; Microbiome.

PubMed Disclaimer

Conflict of interest statement

Ethics approval and consent to participate

All subjects were given verbal and written information about the study prior to providing written informed consent to participate. The Regional Ethical Review Board in Gothenburg approved the study before the start of subject inclusion.

Consent for publication

Not applicable.

Competing interests

JSL, VO, EYH, AG, KT, CG, ML, LO, and HT have nothing to declare. BLN, MD, and JT are employees of Danone Nutricia Research. MS received unrestricted research grants from Danone Nutricia Research and Ferring Pharmaceuticals, and served as a Consultant/Advisory Board member for AstraZeneca, Danone, Nestlé, Almirall, Allergan, Albireo, Glycom, and Shire, and as a speaker for Tillotts, Menarini, Takeda, Shire, Allergan, and Almirall. EAM is a scientific advisory board member of Dannon, Danone, DanoneWave, Axial Biotherapeutics, Viome, Amare, and Pharmavite.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Global tripartite microbial genus-brain connectivity-evoked symptom network. a Demonstrates the global tripartite healthy controls network. b Demonstrates the global tripartite IBS network. c Demonstrates the global tripartite difference network. For clarity, labels related to brain connectivity measures have been omitted from these global networks. 1st Sens first sensation threshold during balloon distension, Disc Thresh discomfort threshold during balloon distension, IBS-SS irritable bowel syndrome–scoring system scores, IV Clostridium IV, LC Disc discomfort during lactulose challenge test, LC Pain pain during lactulose challenge test, OATT oroanal transit time, Pain Thresh pain threshold during balloon distension, Disc Intensity visual analogue scale rating of discomfort during 24 mmHg distension, Pain Intensity visual analogue scale rating of pain during 24 mmHg distension, IBS-SSS IBS Severity Scoring System, XIVa Clostridium XIVa, XIVb Clostridium XIVb, Lachnospiraceae Lachnospiraceae incertae sedis
Fig. 2
Fig. 2
Tripartite Lachnospiraceae incertae sedis subnetwork. a Demonstrates the Lachnospiracea incertae sedis healthy controls subnetwork. b Demonstrates the Lachnospiracea incertae sedis IBS subnetwork. c Demonstrates the Lachnospiracea incertae sedis difference network. Functional brain connectivity of regions of interest is presented with the region of interest noted in a larger font, with the connectivity measure and lateralization indicated below in the form X_Y, where X indicates a connectivity measure (B betweenness centrality, E eigenvector centrality, S degree strength) and Y indicates lateralization (L left, R right). Pain Thresh pain threshold during balloon distension, XIVa Clostridium XIVa, Lachnospiraceae Lachnospiraceae incertae sedis
Fig. 3
Fig. 3
Tripartite Coprococcus Subnetwork. a Demonstrates the Coprococcus healthy controls subnetwork. b Demonstrates the Coprococcus IBS subnetwork. c Demonstrates the Coprococcus difference network. Functional brain connectivity of regions of interest is presented with the region of interest noted in a larger font, with the connectivity measure and lateralization indicated below in the form X_Y, where X indicates a connectivity measure (B betweenness centrality, E eigenvector centrality, S degree strength) and Y indicates lateralization (L left, R right). IV Clostridium IV, LC Disc discomfort during lactulose challenge test, LC Pain pain during nutrient and lactulose challenge test, XIVa Clostridium XIVa
Fig. 4
Fig. 4
Tripartite Clostridium XIVa subnetwork. a Demonstrates the Clostridium XIVa healthy controls subnetwork. b Demonstrates the Clostridium XIVa IBS subnetwork. c Demonstrates the Clostridium XIVa difference network. Functional brain connectivity of regions of interest is presented with the region of interest noted in a larger font, with the connectivity measure and lateralization indicated below in the form X_Y, where X indicates a connectivity measure (B betweenness centrality, E eigenvector centrality, S degree strength) and Y indicates lateralization (L left, R right). Disc Thresh discomfort threshold during balloon distension, LC Pain pain during lactulose challenge test, OATT oroanal transit time, Pain Thresh pain threshold during balloon distension, Disc Intensity visual analogue scale rating of discomfort during 24 mmHg distension, XIVa Clostridium XIVa, Lachnospiraceae Lachnospiraceae incertae sedis
Fig. 5
Fig. 5
Tripartite Clostridium XIVb subnetwork. a Demonstrates the Clostridium XIVb healthy controls subnetwork. b Demonstrates the Clostridium XIVb IBS subnetwork. c Demonstrates the Clostridium XIVb difference network. Functional brain connectivity of regions of interest is presented with the region of interest noted in a larger font, with the connectivity measure and lateralization indicated below in the form X_Y, where X indicates a connectivity measure (B betweenness centrality, E eigenvector centrality, S degree strength) and Y indicates lateralization (L left, R right). IBS-SSS IBS severity scoring system, IV Clostridium IV, XIVb Clostridium XIVb
See this image and copyright information in PMC

References

    1. Mayer EA, Savidge T, Shulman RJ. Brain-gut microbiome interactions and functional bowel disorders. Gastroenterology. 2014;146:1500–1512. doi: 10.1053/j.gastro.2014.02.037. - DOI - PMC - PubMed
    1. Mayer EA, Gupta A, Kilpatrick LA, Hong JY. Imaging brain mechanisms in chronic visceral pain. Pain. 2015;156(Suppl 1):S50–S63. doi: 10.1097/j.pain.0000000000000106. - DOI - PMC - PubMed
    1. Labus JS, Van Horn JD, Gupta A, Alaverdyan M, Torgerson C, Ashe-McNalley C, Irimia A, Hong JY, Naliboff B, Tillisch K, Mayer EA. Multivariate morphological brain signatures predict patients with chronic abdominal pain from healthy control subjects. Pain. 2015;156:1545–1554. doi: 10.1097/j.pain.0000000000000196. - DOI - PMC - PubMed
    1. Tillisch K, Mayer EA, Labus JS. Quantitative meta-analysis identifies brain regions activated during rectal distension in irritable bowel syndrome. Gastroenterology. 2011;140:91–100. doi: 10.1053/j.gastro.2010.07.053. - DOI - PMC - PubMed
    1. Simren M, Tornblom H, Palsson OS, van Tilburg MAL, Van Oudenhove L, Tack J, Whitehead WE. Visceral hypersensitivity is associated with GI symptom severity in functional GI disorders: consistent findings from five different patient cohorts. Gut. 2018;67:255–262. doi: 10.1136/gutjnl-2016-312361. - DOI - PubMed

Publication types

Substances