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Neutralization of IL-1? ameliorates Crohn's disease-like ileitis by functional alterations of the gut microbiome.

ABSTRACT: Crohn's disease and ulcerative colitis are chronic and progressive inflammatory bowel diseases (IBDs) that are attributed to dysregulated interactions between the gut microbiome and the intestinal mucosa-associated immune system. There are limited studies investigating the role of either IL-1? or IL-1? in mouse models of colitis, and no clinical trials blocking either IL-1 have yet to be performed. In the present study, we show that neutralization of IL-1? by a specific monoclonal antibody against murine IL-1? was highly effective in reducing inflammation and damage in SAMP mice, mice that spontaneously develop a Crohn's-like ileitis. Anti-mouse IL-1? significantly ameliorated the established, chronic ileitis and also protected mice from developing acute DSS-induced colitis. Both were associated with taxonomic divergence of the fecal gut microbiome, which was treatment-specific and not dependent on inflammation. Anti-IL-1? administration led to a decreased ratio of Proteobacteria to Bacteroidetes, decreased presence of Helicobacter species, and elevated representation of Mucispirillum schaedleri and Lactobacillus salivarius Such modification in flora was functionally linked to the antiinflammatory effects of IL-1? neutralization, as blockade of IL-1? was not effective in germfree SAMP mice. Furthermore, preemptive dexamethasone treatment of DSS-challenged SAMP mice led to changes in flora composition without preventing the development of colitis. Thus, neutralization of IL-1? changes specific bacterial species of the intestinal microbiome, which is linked to its antiinflammatory effects. These functional findings may be of significant value for patients with IBD, who may benefit from targeted IL-1?-based therapies.

SUBMITTER: Menghini P

PROVIDER: S-EPMC6936591 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Neutralization of IL-1α ameliorates Crohn's disease-like ileitis by functional alterations of the gut microbiome.

Menghini Paola P Corridoni Daniele D Buttó Ludovica F LF Osme Abdullah A Shivaswamy Sushma S Lam Minh M Bamias Giorgos G Pizarro Theresa T TT Rodriguez-Palacios Alexander A Dinarello Charles A CA Cominelli Fabio F

Proceedings of the National Academy of Sciences of the United States of America 20191216 52

Crohn's disease and ulcerative colitis are chronic and progressive inflammatory bowel diseases (IBDs) that are attributed to dysregulated interactions between the gut microbiome and the intestinal mucosa-associated immune system. There are limited studies investigating the role of either IL-1α or IL-1β in mouse models of colitis, and no clinical trials blocking either IL-1 have yet to be performed. In the present study, we show that neutralization of IL-1α by a specific monoclonal antibody again ...[more]

PMID: 31843928

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Project description:BackgroundEpidemiological studies indicate that the use of artificial sweeteners doubles the risk for Crohn's disease (CD). Herein, we experimentally quantified the impact of 6-week supplementation with a commercial sweetener (Splenda; ingredients sucralose maltodextrin, 1:99, w/w) on both the severity of CD-like ileitis and the intestinal microbiome alterations using SAMP1/YitFc (SAMP) mice.MethodsMetagenomic shotgun DNA sequencing was first used to characterize the microbiome of ileitis-prone SAMP mice. Then, 16S rRNA microbiome sequencing, quantitative polymerase chain reaction, fluorescent in situ hybridization (FISH), bacterial culture, stereomicroscopy, histology, and myeloperoxidase (MPO) activity analyses were then implemented to compare the microbiome and ileitis phenotype in SAMP with that of control ileitis-free AKR/J mice after Splenda supplementation.ResultsMetagenomics indicated that SAMP mice have a gut microbial phenotype rich in Bacteroidetes, and experiments showed that Helicobacteraceae did not have an exacerbating effect on ileitis. Splenda did not increase the severity of (stereomicroscopic/histological) ileitis; however, biochemically, ileal MPO activity was increased in SAMP treated with Splenda compared with nonsupplemented mice (P < 0.022) and healthy AKR mice. Splenda promoted dysbiosis with expansion of Proteobacteria in all mice, and E. coli overgrowth with increased bacterial infiltration into the ileal lamina propria of SAMP mice. FISH showed increase malX gene-carrying bacterial clusters in the ilea of supplemented SAMP (but not AKR) mice.ConclusionsSplenda promoted gut Proteobacteria, dysbiosis, and biochemical MPO reactivity in a spontaneous model of (Bacteroidetes-rich) ileal CD. Our results indicate that although Splenda may promote parallel microbiome alterations in CD-prone and healthy hosts, this did not result in elevated MPO levels in healthy mice, only CD-prone mice. The consumption of sucralose/maltodextrin-containing foods might exacerbate MPO intestinal reactivity only in individuals with a pro-inflammatory predisposition, such as CD.

Dataset Information

Neutralization of IL-1? ameliorates Crohn's disease-like ileitis by functional alterations of the gut microbiome.

Publications

Neutralization of IL-1α ameliorates Crohn's disease-like ileitis by functional alterations of the gut microbiome.

Similar Datasets

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