Mechanisms underlying gut dysfunction in a murine model of chronic parasitic infection.
Irritable bowel syndrome (IBS) is common in countries where chronic parasitic infestations are endemic. However, the relationship between parasitic infection and IBS is not clear. The aim of this study was to examine whether chronic parasitic infection is accompanied by gut dysfunction and whether the continued presence of the parasite is required for the maintenance of the dysfunction. We used chronic Trichuris muris infection in Th1-biased susceptible AKR mice to evaluate this relationship. AKR mice were infected with T. muris and were euthanized on various days postinfection (pi) to examine worm burden, muscle function, and immune and inflammatory responses. Mice were treated with the anthelmintic oxantel pamoate to assess the effect of eradication of infection on muscle function. Infection resulted in persistence of the parasite, elevated IFN-γ, and increased MPO activity evident at 45 days pi. This was accompanied by a reduction in muscle contractility and excitatory innervation. Whereas parasite eradication at 7 days pi normalized IFN-γ and muscle contractility, eradication at 28 days pi failed to normalize muscle contractility. Administration of dexamethasone after parasite eradication normalized all parameters. Anthelmintic treatment improved histology except for eosinophils, which were normalized by subsequent dexamethasone therapy. Persistent gut dysfunction is independent of the continued presence of the parasite and is maintained by inflammatory process that includes eosinophils. Thus data in this preclinical model suggest that parasitic infection could be a cause of IBS, and the lack of symptomatic improvement following eradication is insufficient evidence to refute a causal relationship between the infection and IBS.
Motomura
Yasuaki
Y
Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Canada. yasumm@gmail.com
Khan
Waliul I
WI
El-Sharkawy
Rami T
RT
Verma-Gandhu
Monica
M
Grencis
Richard K
RK
Collins
Stephen M
SM
D000305:Adrenal Cortex Hormones / Q000494:pharmacology; D000818:Animals; D000871:Anthelmintics / Q000627:therapeutic use; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002908:Chronic Disease; D003106:Colon / Q000469:parasitology / Q000502:physiology; D003907:Dexamethasone / Q000494:pharmacology; D005767:Gastrointestinal Diseases / Q000469:parasitology* / Q000503:physiopathology; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008806:Mice, Inbred AKR; D009119:Muscle Contraction; D009130:Muscle, Smooth / Q000469:parasitology / Q000502:physiology; D009195:Peroxidase / Q000235:genetics / Q000378:metabolism; D011716:Pyrantel Pamoate / Q000031:analogs & derivatives / Q000627:therapeutic use; D014257:Trichuriasis / Q000503:physiopathology*; D014258:Trichuris
D000305:Adrenal Cortex Hormones; D000871:Anthelmintics; D000893:Anti-Inflammatory Agents; D003907:Dexamethasone; D011716:Pyrantel Pamoate; D007371:Interferon-gamma; D009195:Peroxidase; C037225:oxantel pamoate