Giardia duodenalis induces paracellular bacterial translocation and causes postinfectious visceral hypersensitivity.

Irritable bowel syndrome (IBS) is the most frequent functional gastrointestinal disorder. It is characterized by abdominal hypersensitivity, leading to discomfort and pain, as well as altered bowel habits. While it is common for IBS to develop following the resolution of infectious gastroenteritis [then termed postinfectious IBS (PI-IBS)], the mechanisms remain incompletely understood. Giardia duodenalis is a cosmopolitan water-borne enteropathogen that causes intestinal malabsorption, diarrhea, and postinfectious complications. Cause-and-effect studies using a human enteropathogen to help investigate the mechanisms of PI-IBS are sorely lacking. In an attempt to establish causality between giardiasis and postinfectious visceral hypersensitivity, this study describes a new model of PI-IBS in neonatal rats infected with G. duodenalis At 50 days postinfection with G. duodenalis (assemblage A or B), long after the parasite was cleared, rats developed visceral hypersensitivity to luminal balloon distension in the jejunum and rectum, activation of the nociceptive signaling pathway (increased c-fos expression), histological modifications (villus atrophy and crypt hyperplasia), and proliferation of mucosal intraepithelial lymphocytes and mast cells in the jejunum, but not in the rectum. G. duodenalis infection also disrupted the intestinal barrier, in vivo and in vitro, which in turn promoted the translocation of commensal bacteria. Giardia-induced bacterial paracellular translocation in vitro correlated with degradation of the tight junction proteins occludin and claudin-4. The extensive observations associated with gut hypersensitivity described here demonstrate that, indeed, in this new model of postgiardiasis IBS, alterations to the gut mucosa and c-fos are consistent with those associated with PI-IBS and, hence, offer avenues for new mechanistic research in the field.

Halliez MC ，Motta JP ，Feener TD ，Guérin G ，LeGoff L ，François A ，Colasse E ，Favennec L ，Gargala G ，Lapointe TK ，Altier C ，Buret AG ... -  《-》

Giardia duodenalis induces pathogenic dysbiosis of human intestinal microbiota biofilms.

Giardia duodenalis is a prevalent cause of acute diarrheal disease worldwide. However, recent outbreaks in Italy and Norway have revealed a link between giardiasis and the subsequent development of chronic post-infectious irritable bowel syndrome. While the mechanisms underlying the causation of post-infectious irritable bowel syndrome remain obscure, recent findings suggest that alterations in gut microbiota communities are linked to the pathophysiology of irritable bowel syndrome. In the present study, we use a laboratory biofilm system to culture and enrich mucosal microbiota from human intestinal biopsies. Subsequently, we show that co-culture with Giardia induces disturbances in biofilm species composition and biofilm structure resulting in microbiota communities that are intrinsically dysbiotic - even after the clearance of Giardia. These microbiota abnormalities were mediated in part by secretory-excretory Giardia cysteine proteases. Using in vitro cell culture and germ-free murine infection models, we show that Giardia-induced disruptions of microbiota promote bacterial invasion, resulting in epithelial apoptosis, tight junctional disruption, and bacterial translocation across an intestinal epithelial barrier. Additionally, these dysbiotic microbiota communities resulted in increased activation of the Toll-like receptor 4 signalling pathway, and overproduction of the pro-inflammatory cytokine IL-1beta in humanized germ-free mice. Previous studies that have sought explanations and risk factors for the development of post-infectious irritable bowel syndrome have focused on features of enteropathogens and attributes of the infected host. We propose that polymicrobial interactions involving Giardia and gut microbiota may cause persistent dysbiosis, offering a new interpretation of the reasons why those afflicted with giardiasis are predisposed to gastrointestinal disorders post-infection.

Beatty JK ，Akierman SV ，Motta JP ，Muise S ，Workentine ML ，Harrison JJ ，Bhargava A ，Beck PL ，Rioux KP ，McKnight GW ，Wallace JL ，Buret AG ... -  《-》

Effects of octreotide on jejunal hypersensitivity triggered by Cryptosporidium parvum intestinal infection in an immunocompetent suckling rat model.

Similar to other bacterial or protozoan infections, human cryptosporidiosis may trigger postinfectious irritable bowel syndrome (IBS)-like symptoms, a condition in which enhanced visceral perception of pain during intestinal distension plays a pivotal role. In an immunocompetent suckling rat model which mimicks features of postinfectious IBS, Cryptosporidium parvum infection induces long-lasting jejunal hypersensitivity to distension in association with intestinal activated mast cell accumulation. The aim of the present study was to explore in this model whether octreotide, a somatostatin agonist analog, could prevent the development of jejunal hypersensitivity and intestinal mast cell/nerve fiber accumulation. Five-day-old Sprague-Dawley rats were infected with C. parvum and treated 10 days later with octreotide (50 g kg(-1) day(-1), i.p.) for 7 days. Compared with untreated infected rats, octreotide treatment of infected rats resulted in increased weight gain [day 23 postinfection (PI)], decreased food intake (day 16 PI), and a reduction in jejunal villus alterations (day 14 PI), CD3(+) IEL (day 37 PI) and mast cell (days 37 and 50 PI) accumulations, nerve fiber densities (day 50 PI), and hypersensitivity to distension (day 120 PI). In uninfected rats, the effects of octreotide treatment were limited to higher weight gain (days 16 and 23 PI) and decreased food intake (day 23 PI) compared with uninfected-untreated rats. Data confirms the relevance of the present rat model to postinfectious IBS studies and prompt further investigation of somatostatin-dependent regulatory interactions in cryptosporidiosis.

Bai J ，Khaldi S ，Gargala G ，Baishanbo A ，François A ，Ballet JJ ，Ducrotté P ，Fioramonti J ，Favennec L ，Le Goff L ... -  《-》

Diarrhoea-predominant irritable bowel syndrome: an organic disorder with structural abnormalities in the jejunal epithelial barrier.

Martínez C ，Lobo B ，Pigrau M ，Ramos L ，González-Castro AM ，Alonso C ，Guilarte M ，Guilá M ，de Torres I ，Azpiroz F ，Santos J ，Vicario M ... -  《-》

On the fiftieth anniversary. Postinfectious irritable bowel syndrome: mechanisms related to pathogens.

Gastrointestinal (GI) infections resulting from bacterial, viral, and parasitic pathogens predispose to postinfectious irritable bowel syndrome (PI-IBS) and other functional GI disorders. Existing literature supports the role of enterochromaffin cell hyperplasia, serotonin synthesis and reuptake, impaired barrier function, altered immune activation, and potentially mast cell activation in the pathophysiology of PI-IBS. The objective of this review was to summarize from the literature the characteristics of the pathogens commonly implicated in PI-IBS, their acute enteritis phases, and the changes seen in the postinfectious phase that may contribute toward development of IBS. A limitation of our current understanding is that the postinfectious GI sequelae reported in prior studies followed epidemic diarrheal outbreaks often involving more than one pathogen, or the studies focused on highly selected, tertiary referral patients. Understanding the mechanisms, natural history, and optimized management of individuals suffering PI-IBS following the more typical sporadic infection requires larger studies of PI-IBS following GI infections encountered in community settings. These studies should include genetic, physiological, and molecular studies to provide more generalizable information that can ultimately be used to diagnose, manage, and potentially prevent the development of PI-IBS.

Grover M ，Camilleri M ，Smith K ，Linden DR ，Farrugia G ... -  《-》