Abstract
The composition of the intestinal microbiota influences the development of inflammatory disorders. However, associating inflammatory diseases with specific microbial members of the microbiota is challenging, because clinically detectable inflammation and its treatment can alter the microbiota's composition. Immunologic checkpoint blockade with ipilimumab, a monoclonal antibody that blocks cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) signalling, is associated with new-onset, immune-mediated colitis. Here we conduct a prospective study of patients with metastatic melanoma undergoing ipilimumab treatment and correlate the pre-inflammation faecal microbiota and microbiome composition with subsequent colitis development. We demonstrate that increased representation of bacteria belonging to the Bacteroidetes phylum is correlated with resistance to the development of checkpoint-blockade-induced colitis. Furthermore, a paucity of genetic pathways involved in polyamine transport and B vitamin biosynthesis is associated with an increased risk of colitis. Identification of these biomarkers may enable interventions to reduce the risk of inflammatory complications following cancer immunotherapy.
Highlights
The composition of the intestinal microbiota influences the development of inflammatory disorders
Faecal samples were obtained from patients before the first dose of ipilimumab (30/34), in two patients who subsequently developed inflammation and two patients who remained inflammation free, samples were obtained after initiation of ipilimumab, but before the onset of colitis
We found that the spermidine/putrescine polyamine transport system and three modules involved in the biosynthesis of B vitamins (riboflavin (B2), pantothenate (B5) and thiamine (B1)) were more abundant in colitis free (C-F) patients (Fig. 4b)
Summary
The composition of the intestinal microbiota influences the development of inflammatory disorders. Associating inflammatory diseases with specific microbial members of the microbiota is challenging, because clinically detectable inflammation and its treatment can alter the microbiota’s composition. Immunologic checkpoint blockade with ipilimumab, a monoclonal antibody that blocks cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) signalling, is associated with new-onset, immune-mediated colitis. Increased faecal abundance of the Bacteroidetes phylum and three of its families (Bacteroidaceae, Rikenellaceae and Barnesiellaceae), as well as microbial genetic pathways involved in polyamine transport and B vitamin biosynthesis, are correlated with resistance to the development of colitis following CTLA-4 blockade. This study provides a novel view of the intestinal microbiota before the development of colitis and offers insight into preventive treatments for patients at risk of adverse inflammatory events following immunologic checkpoint blockade
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