Title
Intestinal Fungal Dysbiosis Is Associated With Visceral Hypersensitivity in Patients With Irritable Bowel Syndrome and Rats
Author
Botschuijver, S.
Roeselers, G.
Levin, E.
Jonkers, D.M.
Welting, O.
Heinsbroek, S.E.M.
de Weerd, H.H.
Boekhout, T.
Fornai, M.
Masclee, A.A.
Schuren, F.H.J.
de Jonge, W.J.
Seppen, J.
van den Wijngaard, R.M.
Publication year
2017
Abstract
Background & Aims Visceral hypersensitivity is one feature of irritable bowel syndrome (IBS). Bacterial dysbiosis might be involved in the activation of nociceptive sensory pathways, but there have been few studies of the role of the mycobiome (the fungal microbiome) in the development of IBS. We analyzed intestinal mycobiomes of patients with IBS and a rat model of visceral hypersensitivity. Methods We used internal transcribed spacer 1-based metabarcoding to compare fecal mycobiomes of 18 healthy volunteers with those of 39 patients with IBS (with visceral hypersensitivity or normal levels of sensitivity). We also compared the mycobiomes of Long-Evans rats separated from their mothers (hypersensitive) with non-handled (normally sensitive) rats. We investigated whether fungi can cause visceral hypersensitivity using rats exposed to fungicide (fluconazole and nystatin). The functional relevance of the gut mycobiome was confirmed in fecal transplantation experiments: adult maternally separated rats were subjected to water avoidance stress (to induce visceral hypersensitivity), then given fungicide and donor cecum content via oral gavage. Other rats subjected to water avoidance stress were given soluble β-glucans, which antagonize C-type lectin domain family 7 member A (CLEC7A or DECTIN1) signaling via spleen-associated tyrosine kinase (SYK), a SYK inhibitor to reduce visceral hypersensitivity, or vehicle (control). The sensitivity of mast cells to fungi was tested with mesenteric windows (ex vivo) and the human mast cell line HMC-1. Results α diversity (Shannon index) and mycobiome signature (stability selection) of both groups of IBS patients differed from healthy volunteers, and the mycobiome signature of hypersensitive patients differed from that of normally sensitive patients. We observed mycobiome dysbiosis in rats that had been separated from their mothers compared with non-handled rats. Administration of fungicide to hypersensitive rats reduced their visceral hypersensitivity to normal levels of sensitivity. Administration of cecal mycobiomes from rats that had been separated from their mothers (but not non-handled mycobiome) restored hypersensitivity to distension. Administration of soluble β-glucans or a SYK inhibitor reduced visceral hypersensitivity, compared with controls. Particulate β-glucan (a DECTIN-1 agonist) induced mast cell degranulation in mesenteric windows and HMC-1 cells responded to fungal antigens by release of histamine. Conclusions In an analysis of patients with IBS and controls, we associated fungal dysbiosis with IBS. In studies of rats, we found fungi to promote visceral hypersensitivity, which could be reduced by administration of fungicides, soluble β-glucans, or a SYK inhibitor. The intestinal fungi might therefore be manipulated for treatment of IBS-related visceral hypersensitivity. © 2017 AGA Institute. Chemicals/CAS: protein kinase Syk, 138674-26-7; Antifungal Agents; beta-Glucans; Protein Kinase Inhibitors; Syk Kinase; Syk protein, rat
Subject
Life
MSB - Microbiology and Systems Biology
ELSS - Earth, Life and Social Sciences
Biomedical Innovation
Biology
Healthy Living
Dectin-1
Immune Response
Mycobiota
Yeast
Protein kinase inhibitor
Protein kinase Syk
Syk protein, rat
Abdominal pain
Separation anxiety
Abdominal Pain
Adult
Animals
Antifungal Agents
Anxiety, Separation
Behavior, Animal
Beta-Glucans
Case-Control Studies
Cell Degranulation
Cell Line
Disease Models, Animal
Dysbiosis
Fecal Microbiota Transplantation
Feces
Female
Fungi
Gastrointestinal Microbiome
Humans
Hyperalgesia
Intestines
Irritable Bowel Syndrome
Male
Mast Cells
Maternal Deprivation
Middle Aged
Pain Measurement
Pain Perception
Pain Threshold
Protein Kinase Inhibitors
Rats, Long-Evans
Syk Kinase
To reference this document use:
http://resolver.tudelft.nl/uuid:c25bb7ce-4bc8-4998-bff0-388b02d7d6ac
DOI
https://doi.org/10.1053/j.gastro.2017.06.004
TNO identifier
781912
ISSN
0016-5085
Source
Gastroenterology, 153 (4), 1026-1039
Document type
article