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Intestinal Fungal Dysbiosis Is Associated With Visceral Hypersensitivity in Patients With Irritable Bowel Syndrome and Rats
Open accessAbstract
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.
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“Also neglected to date is the gut mycobiome, and there are indications that our intestinal fungi are an important component of host-microbe interactions of relevance to immune homeostasis and inflammatory disorders (Leonardi et al., 2018) and stress-related disorders such as irritable bowel syndrome (Botschuijver et al., 2017).”
From Gut reactions: Breaking down xenobiotic–microbiome interactions (2019) · cites this paper as Botschuijver et al., 2017
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Metadata
- Authors
- 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.
- Affiliations
- Amsterdam UMC Location University of Amsterdam (NL)
- Netherlands Organisation for Applied Scientific Research (NL)
- Maastricht University Medical Centre (NL)
- Westerdijk Fungal Biodiversity Institute (NL)
- University of Pisa (IT)
- ORCID
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2017-10
- Volume
- 153
- Issue
- 4
- Pages
- 1026-1039
- ISSN
- 0016-5085 (ISSN-L)
- OpenAlex
- W2624678362
- Cited by
- 202
- References
- 50
- Citations by year
- 2026: 12 · 2025: 12 · 2024: 23 · 2023: 19 · 2022: 23 · 2021: 32 · 2020: 31 · 2019: 29 · 2018: 16 · 2017: 5
- FWCI
- 23.23
- Type
- journal article
- Language
- en
- Open access
- green
- pure.amsterdamumc.nl
- Licence
- Locations
- Gastroenterology (publishedVersion)
- PubMed (publishedVersion)
- KNAW research portal (Royal Academy of Art and Sciences (KNAW)) (publishedVersion)
- Pure Amsterdam UMC (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion, cc-by-nc-nd)
- Research Publications (Maastricht University) (submittedVersion)
- UvA-DARE (University of Amsterdam) (submittedVersion)
- TNO Repository (submittedVersion)
- Repository hosted by TU Delft Library (TU Delft) (submittedVersion)
- Funders
- Danone
- Topics
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Gastroenterology › Inflammatory Bowel Disease
- Keywords
- irritable bowel syndrome, visceral hypersensitivity, fungal dysbiosis, gut fungi, mast cells, Dectin-1, Syk signaling, β-glucan, fungicides, fecal microbiota transplantation, water avoidance stress, maternal separation, nociception, gut-brain axis, rats, human gut microbiome, metabarcoding
- MeSH terms
- Gastrointestinal Microbiome, Fecal Microbiota Transplantation, Syk Kinase, Adult, Animals, Antifungal Agents, Anxiety, Separation, Behavior, Animal, Cell Line, Disease Models, Animal, Feces, Female, Fungi, Humans, Hyperalgesia, Intestinal Mucosa, Intestines, Male, Mast Cells, Maternal Deprivation, Middle Aged, Pain Measurement, Cell Degranulation, Abdominal Pain, Case-Control Studies, Pain Threshold, Rats, Long-Evans, Irritable Bowel Syndrome, beta-Glucans, Protein Kinase Inhibitors, Pain Perception, Dysbiosis
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