Characterization of intestinal perturbations after Citrobacter rodentium infection. Consequences on host’s well-being

Le syndrome de l’intestin irritable (SII) est le trouble fonctionnel gastro-intestinal le plus fréquent. Il se caractérise par des douleurs abdominales, dont le mécanisme physiopathologique sous-jacent est l’hypersensibilité viscérale d’origine colique (HSVC), et est souvent associé à des troubles de l’humeur. Un SII peut survenir à la suite d’une infection intestinale d’origine bactérienne. Il s’agit alors d’un SII post-infectieux. A ce jour, il n’est pas compris pourquoi un sous-groupe de patients développe ce trouble alors que la plupart des patients se remet de l’infection. Il est donc nécessaire de mieux caractériser la physiopathologie de ce trouble, notamment grâce à la mise en place d’un modèle animal post-infectieux pertinent. Le modèle murin d’infection à Citrobacter rodentium est couramment utilisé pour modéliser les infections aux Escherichia coli pathogènes humaines, agents infectieux impliqués dans le développement du SII post-infectieux. L’objectif de ce travail a été de caractériser les perturbations de l’homéostasie intestinale associées au développement d’une HSVC et de troubles du comportement via l’utilisation du modèle d’infection à C. rodentium. L’étude des comorbidités associées à l’infection à C. rodentium a révélé le développement d’une HSVC et d’un comportement anxieux à distance de l’infection. L’analyse des paramètres coliques nous a permis de mettre en évidence le développement et le maintien d’une inflammation colique à bas bruit. Grâce à la caractérisation de la composition du microbiote associé à la muqueuse colique nous avons pu montrer la présence d’une dysbiose semblable à celle décrite dans le SII. De manière intéressante, l’abondance relative en Burkholderiales a été corrélée au comportement anxieux. L’analyse des métabolites bactériens a révélé une augmentation de la concentration fécale en acide acétique chez les animaux infectés. Enfin, nous avons montré que l’HSVC et les troubles anxieux peuvent être améliorés par l’induction de la voie de l’interleukine-22 (IL-22), au niveau des entérocytes, par un mécanisme indépendant de l’inflammation. Grâce à l’utilisation du modèle d’infection à C. rodentium, notre étude a permis de mieux caractériser les mécanismes périphériques associés au développement du SII post infectieux. Ces résultats permettront à terme de proposer de nouvelles stratégies thérapeutiques ciblant le microbiote intestinal et/ou la voie de l’IL-22 pour une meilleure prise en charge des patients voire pour prévenir l’apparition de ce trouble.Irritable bowel syndrome (IBS) is the most common functional gastrointestinal disorder. It is characterized by abdominal pain, whose underlying mechanisms is colonic hypersensitivity (CHS), and is often associated with mood disorders. IBS can occur following bacterial infectious enteritis and is referred as to post-infectious IBS. Nowadays, it is not known why only a subgroup of patients develop this disorder while others recover from the infection. Hence, it is necessary to develop a relevant post-infectious animal model in order to better characterize the pathogenesis of IBS. The mouse model of Citrobacter rodentium infection is widely use to mimic human pathogenic Escherichia coli infection, causative infectious agents in the development of post-infectious IBS. Thus, the aim of this study was to characterize disturbances of intestinal homeostasis associated with CHS and mood disorders development by using the mouse model of C. rodentium infection.Study of C. rodentium-induced comorbidities revealed development of CHS and anxiety-like behavior in post-infectious period. Assessment of colonic parameters indicated the development of long-lasting colonic low-grade inflammation. Assessment of the composition of colonic mucosa-associated microbiota highlighted gut dysbiosis similar to that observed in IBS patients. Interestingly, we found a correlation between relative abundance of Burkholderiales and anxiety-like behavior. Analysis of bacterial metabolites revealed an increase of fecal concentration of acetic acid in infected mice. Finally, we observed improvement of CHS and anxiety-like behavior by inducing interleukin-22 (IL-22) expression in enterocytes, through an inflammation independent mechanism.Thanks to the use of the mouse model of C. rodentium infection, our study allowed to better characterize peripheral mechanisms associated with post-infectious IBS. These results offer the opportunity to develop new therapeutic strategies targeting intestinal microbiota and/or IL-22 signaling pathway for a better care of patients or prevent post-infectious IBS

Etude des perturbations de l'homéostasie intestinale en cas d'infection par citrobacter rodentium. Conséquences sur le bien-être de l'hôte

Irritable bowel syndrome (IBS) is the most common functional gastrointestinal disorder. It is characterized by abdominal pain, whose underlying mechanisms is colonic hypersensitivity (CHS), and is often associated with mood disorders. IBS can occur following bacterial infectious enteritis and is referred as to post-infectious IBS. Nowadays, it is not known why only a subgroup of patients develop this disorder while others recover from the infection. Hence, it is necessary to develop a relevant post-infectious animal model in order to better characterize the pathogenesis of IBS. The mouse model of Citrobacter rodentium infection is widely use to mimic human pathogenic Escherichia coli infection, causative infectious agents in the development of post-infectious IBS. Thus, the aim of this study was to characterize disturbances of intestinal homeostasis associated with CHS and mood disorders development by using the mouse model of C. rodentium infection.Study of C. rodentium-induced comorbidities revealed development of CHS and anxiety-like behavior in post-infectious period. Assessment of colonic parameters indicated the development of long-lasting colonic low-grade inflammation. Assessment of the composition of colonic mucosa-associated microbiota highlighted gut dysbiosis similar to that observed in IBS patients. Interestingly, we found a correlation between relative abundance of Burkholderiales and anxiety-like behavior. Analysis of bacterial metabolites revealed an increase of fecal concentration of acetic acid in infected mice. Finally, we observed improvement of CHS and anxiety-like behavior by inducing interleukin-22 (IL-22) expression in enterocytes, through an inflammation independent mechanism.Thanks to the use of the mouse model of C. rodentium infection, our study allowed to better characterize peripheral mechanisms associated with post-infectious IBS. These results offer the opportunity to develop new therapeutic strategies targeting intestinal microbiota and/or IL-22 signaling pathway for a better care of patients or prevent post-infectious IBS.Le syndrome de l’intestin irritable (SII) est le trouble fonctionnel gastro-intestinal le plus fréquent. Il se caractérise par des douleurs abdominales, dont le mécanisme physiopathologique sous-jacent est l’hypersensibilité viscérale d’origine colique (HSVC), et est souvent associé à des troubles de l’humeur. Un SII peut survenir à la suite d’une infection intestinale d’origine bactérienne. Il s’agit alors d’un SII post-infectieux. A ce jour, il n’est pas compris pourquoi un sous-groupe de patients développe ce trouble alors que la plupart des patients se remet de l’infection. Il est donc nécessaire de mieux caractériser la physiopathologie de ce trouble, notamment grâce à la mise en place d’un modèle animal post-infectieux pertinent. Le modèle murin d’infection à Citrobacter rodentium est couramment utilisé pour modéliser les infections aux Escherichia coli pathogènes humaines, agents infectieux impliqués dans le développement du SII post-infectieux. L’objectif de ce travail a été de caractériser les perturbations de l’homéostasie intestinale associées au développement d’une HSVC et de troubles du comportement via l’utilisation du modèle d’infection à C. rodentium. L’étude des comorbidités associées à l’infection à C. rodentium a révélé le développement d’une HSVC et d’un comportement anxieux à distance de l’infection. L’analyse des paramètres coliques nous a permis de mettre en évidence le développement et le maintien d’une inflammation colique à bas bruit. Grâce à la caractérisation de la composition du microbiote associé à la muqueuse colique nous avons pu montrer la présence d’une dysbiose semblable à celle décrite dans le SII. De manière intéressante, l’abondance relative en Burkholderiales a été corrélée au comportement anxieux. L’analyse des métabolites bactériens a révélé une augmentation de la concentration fécale en acide acétique chez les animaux infectés. Enfin, nous avons montré que l’HSVC et les troubles anxieux peuvent être améliorés par l’induction de la voie de l’interleukine-22 (IL-22), au niveau des entérocytes, par un mécanisme indépendant de l’inflammation. Grâce à l’utilisation du modèle d’infection à C. rodentium, notre étude a permis de mieux caractériser les mécanismes périphériques associés au développement du SII post infectieux. Ces résultats permettront à terme de proposer de nouvelles stratégies thérapeutiques ciblant le microbiote intestinal et/ou la voie de l’IL-22 pour une meilleure prise en charge des patients voire pour prévenir l’apparition de ce trouble

Effects of tryptophan derivatives via the AHR/Il22 signaling pathway modulation on host disturbances in post citrobacter rodentium infection model mimicking irritable bowel syndrome

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Tryptophan derivatives effects via the AhR signaling pathway modulation on host disturbances after a Citrobacter rodentium infection

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Efficient and reproducible experimental infections of rats with Blastocystis spp.

Although Blastocystis spp. infect probably more than 1 billion people worldwide, their clinical significance is still controversial and their pathophysiology remains poorly understood. In this study, we describe a protocol for an efficient and reproducible model of chronic infection in rats, laying the groundwork for future work to evaluate the pathogenic potential of this parasite. In our experimental conditions, we were unable to infect rats using vacuolar forms of an axenically cultivated ST4 isolate, but we successfully established chronic infections of 4 week-old rats after oral administration of both ST3 and ST4 purified cysts isolated from human stool samples. The infection protocol was also applied to 4 week-old C57BL/9, BALB/C and C3H mice, but any mouse was found to be infected by Blastocystis. Minimal cyst inoculum required for rat infection was higher with ST3 (105) than with ST4 (102). These results were confirmed by co-housing experiments highlighting a higher contagious potential of ST4 in rats compared to ST3. Finally, experiments mimicking fecal microbiota transfer from infected to healthy animals showed that Blastocystis spp. could easily infect a new host, even though its intestinal microbiota is not disturbed. In conclusion, our results provide a well-documented and robust rat model of Blastocystis chronic infection, reproducing "natural" infection. This model will be of great interest to study host parasite interactions and to better evaluate clinical significance of Blastocystis

The IL-22 pathway as target to relieve visceral pain and animal well-being

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Preclinical and clinical evidence of the association of colibactin-producing Escherichia coli with anxiety and depression in colon cancer

International audienceBACKGROUND The association between the intestinal microbiota and psychiatric disorders is becoming increasingly apparent. The gut microbiota contributes to colorectal carcinogenesis (CRC), as demonstrated with colibactin-producing Escherichia coli (CoPEC). AIM To evaluate the association between CoPEC prevalence and anxiety- and depressive-like behaviors with both preclinical and clinical approaches. METHODS Patients followed after a CRC surgery and for whom the prevalence of CoPEC has been investigated underwent a psychiatric interview. Results were compared according to the CoPEC colonization. In parallel C57BL6/J wild type mice and mice with a CRC susceptibility were chronically infected with a CoPEC strain. Their behavior was assessed using the Elevated Plus Maze test, the Forced Swimming Test and the Behavior recognition system PhenoTyper®. RESULTS In a limited cohort, all patients with CoPEC colonization presented with psychiatric disorders several years before cancer diagnosis, whereas only one patient (17%) without CoPEC did. This result was confirmed in C57BL6/J wild-type mice and in a CRC susceptibility mouse model (adenomatous polyposis colimultiple intestinal neoplasia/+). Mice exhibited a significant increase in anxiety- and depressive-like behaviors after chronic infection with a CoPEC strain. CONCLUSION This finding provides the first evidence that CoPEC infection can induce microbiota-gut-brain axis disturbances in addition to its procarcinogenic properties

Fecal dysbiosis associated with colonic hypersensitivity and behavioral alterations in chronically Blastocystis-infected rats

International audienceBackground: Infectious gastroenteritis is a risk factor for the development of post-infectious Irritable Bowel Syndrome (PI-IBS). Recent clinical studies reported a higher prevalence of the intestinal parasite Blastocystis in IBS patients. Using a rat model, we investigated the possible association between Blastocystis infection, colonic hypersensitivity (CHS), behavioral disturbances and gut microbiota changes.Methods: Rats were orally infected with Blastocystis subtype 4 (ST4) cysts, isolated from human stool samples. Colonic sensitivity was assessed by colorectal distension and animal behavior with an automatic behavior recognition system (PhenoTyper), the Elevated Plus Maze test and the Forced Swimming tests. Feces were collected at different time points after infection to study microbiota composition by 16 S rRNA amplicon sequencing and for short-chain fatty acid (SFCA) analysis.Results: Blastocystis-infected animals had non-inflammatory CHS with increased serine protease activity. Infection was also associated with anxiety- and depressive-like behaviors. Analysis of fecal microbiota composition showed an increase in bacterial richness associated with altered microbiota composition. These changes included an increase in the relative abundance of Oscillospira and a decrease in Clostridium, which seem to be associated with lower levels of SCFAs in the feces from infected rats.Conclusions: Our findings suggest that experimental infection of rats with Blastocystis mimics IBS symptoms with the establishment of CHS related to microbiota and metabolic shifts