Dataset Information

Microbiota-Regulated IL-25 Increases Eosinophil Number to Provide Protection during Clostridium difficile Infection.

ABSTRACT: Clostridium difficile infection (CDI) is the most common cause of hospital-acquired infection in the United States. Host susceptibility and the severity of infection are influenced by disruption of the microbiota and the immune response. However, how the microbiota regulate immune responses to mediate CDI outcome remains unclear. Here, we have investigated the role of the microbiota-linked cytokine IL-25 during infection. Intestinal IL-25 was suppressed during CDI in humans and mice. Restoration of IL-25 reduced CDI-associated mortality and tissue pathology even though equivalent levels of C. difficile bacteria and toxin remained in the gut. IL-25 protection was mediated by gut eosinophils, as demonstrated by an increase in intestinal eosinophils and a loss of IL-25 protection upon eosinophil depletion. These findings support a mechanism whereby the induction of IL-25-mediated eosinophilia can reduce host mortality during active CDI. This work may provide targets for future development of microbial or immune-based therapies.

SUBMITTER: Buonomo EL

PROVIDER: S-EPMC4945404 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Microbiota-Regulated IL-25 Increases Eosinophil Number to Provide Protection during Clostridium difficile Infection.

Buonomo Erica L EL Cowardin Carrie A CA Wilson Madeline G MG Saleh Mahmoud M MM Pramoonjago Patcharin P Petri William A WA

Cell reports 20160623 2

Clostridium difficile infection (CDI) is the most common cause of hospital-acquired infection in the United States. Host susceptibility and the severity of infection are influenced by disruption of the microbiota and the immune response. However, how the microbiota regulate immune responses to mediate CDI outcome remains unclear. Here, we have investigated the role of the microbiota-linked cytokine IL-25 during infection. Intestinal IL-25 was suppressed during CDI in humans and mice. Restoration ...[more]

PMID: 27346351

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Project description:Clostridioides difficile infection (CDI) is the most common hospital-acquired infection in the United States. Antibiotic-induced dysbiosis is the primary cause of susceptibility, and fecal microbiota transplantation (FMT) has emerged as an effective therapy for recurrence. We previously demonstrated in the mouse model of CDI that antibiotic-induced dysbiosis reduced colonic expression of interleukin 25 (IL-25) and that FMT protected in part by restoring IL-25 signaling. Here, we conducted a prospective study in humans to test if FMT induced IL-25 expression in the colons of patients with recurrent CDI (rCDI). Colonic biopsy specimens and blood were collected at the time of FMT and 60 days later. Colon biopsy specimens were analyzed for IL-25 protein levels, total tissue transcriptome, and epithelium-associated microbiota before and after FMT, and peripheral immune cells were immunophenotyped. FMT increased alpha diversity of the colonic microbiota and levels of IL-25 in colonic tissue. In addition, FMT increased expression of homeostatic genes and repressed inflammatory genes. Finally, circulating Th17 cells were decreased post-FMT. The increase in levels of the cytokine IL-25 accompanied by decreased inflammation is consistent with FMT acting in part to protect from recurrent CDI via restoration of commensal activation of type 2 immunity. IMPORTANCE Fecal microbiota transplantation (FMT) is an effective treatment for C. difficile infection for most patients; however, introducing a complex mixture of microbes also has had unintended consequences for some patients. Attempts to create a standardized probiotic therapeutic that recapitulates the efficacy of FMT have been unsuccessful to date. We sought to understand what immune markers are changed in patients undergoing FMT to treat recurrent C. difficile infection and identified an immune signaling molecule, IL-25, that was restored by FMT. This finding indicates that adjunctive therapy with IL-25 could be useful in treating C. difficile infection.

Project description:UNLABELLED:Clostridium difficile infection (CDI) is dramatically increasing as a cause of antibiotic- and hospital-associated diarrhea worldwide. C. difficile, a multidrug-resistant pathogen, flourishes in the colon after the gut microbiota has been altered by antibiotic therapy. Consequently, it produces toxins A and B that directly cause disease. Despite the enormous public health problem posed by this pathogen, the molecular mechanisms that regulate production of the toxins, which are directly responsible for disease, remained largely unknown until now. Here, we show that C. difficile toxin synthesis is regulated by an accessory gene regulator quorum-signaling system, which is mediated through a small (<1,000-Da) thiolactone that can be detected directly in stools of CDI patients. These findings provide direct evidence of the mechanism of regulation of C. difficile toxin synthesis and offer exciting new avenues both for rapid detection of C. difficile infection and development of quorum-signaling-based non-antibiotic therapies to combat this life-threatening emerging pathogen. IMPORTANCE:Clostridium difficile infection (CDI) is the most common definable cause of hospital-acquired and antibiotic-associated diarrhea in the United States, with the total cost of treatment estimated between 1 and 4.8 billion U.S. dollars annually. C. difficile, a Gram-positive, spore-forming anaerobe, flourishes in the colon after the gut microbiota has been altered by antibiotic therapy. As a result, there is an urgent need for non-antibiotic CDI treatments that preserve the colonic microbiota. C. difficile produces toxins A and B, which are directly responsible for disease. Here, we report that C. difficile regulates its toxin synthesis by quorum signaling, in which a novel signaling peptide activates transcription of the disease-causing toxin genes. This finding provides new therapeutic targets to be harnessed for novel nonantibiotic therapy for C. difficile infections.

Dataset Information

Microbiota-Regulated IL-25 Increases Eosinophil Number to Provide Protection during Clostridium difficile Infection.

Publications

Microbiota-Regulated IL-25 Increases Eosinophil Number to Provide Protection during Clostridium difficile Infection.

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