Intestinal Fungal Dysbiosis Is Associated With Visceral Hypersensitivity in Patients With Irritable Bowel Syndrome and Rats
| Autor: | Botschuijver, S., Roeselers, G., Levin, E., Jonkers, D.M., Welting, O., Heinsbroek, S.E.M., Weerd, H.H. de, Boekhout, T., Fornai, M., Masclee, A.A., Schuren, F.H.J., Jonge, W.J. de, Seppen, J., Wijngaard, R.M. van den |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
Adult
Male Pain Threshold Abdominal pain Antifungal Agents Separation anxiety Biomedical Innovation Cell Degranulation Cell Line Irritable Bowel Syndrome Feces Life Mycobiota Anxiety Separation Beta-Glucans Animals Humans Syk Kinase Rats Long-Evans Mast Cells Biology Immune Response Protein Kinase Inhibitors Pain Measurement Behavior Animal Maternal Deprivation Protein kinase Syk Fungi Pain Perception Fecal Microbiota Transplantation Middle Aged Yeast Gastrointestinal Microbiome Intestines Disease Models Animal MSB - Microbiology and Systems Biology Hyperalgesia Case-Control Studies Protein kinase inhibitor Dysbiosis Syk protein rat Female ELSS - Earth Life and Social Sciences Healthy Living Dectin-1 |
| Zdroj: | Gastroenterology, 4, 153, 1026-1039 |
| Popis: | 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 |
| Databáze: | OpenAIRE |
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