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

Significance Here we demonstrate that IL-1α neutralization reduces the severity of disease in a mouse model of Crohn’s disease. Unexpectedly, IL-1α neutralization exerts its antiinflammatory effects by modulating the gut microbial ecosystem, and corrected the mucosal dysbiosis. Although studies report that the gut microbiome affects cytokine production, few have shown that specific neutralization of a pivotal cytokine such as IL-1α alters the composition and function of the gut microbiome. The study demonstrates a predictive relationship between IL-1α neutralization and abundance of specific bacterial species. The findings have translational significance, since IL-1α treatment prevented DSS-induced mucosal dysbiosis and preserved immunological homeostasis. These preclinical findings support the therapeutic potential of IL-1α neutralization in patients with IBD. 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 against murine IL-1α was highly effective in reducing inflammation and damage in SAMP mice, mice that spontaneously develop a Crohn’s-like ileitis. Anti-mouse IL-1α 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-1α 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-1α neutralization, as blockade of IL-1α 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-1α 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-1α–based therapies.