Microbiota metabolite butyrate constrains neutrophil functions and ameliorates mucosal inflammation in inflammatory bowel disease

Host-microbial cross-talk plays a crucial role in maintenance of gut homeostasis. However, how microbiota-derived metabolites, e.g., butyrate, regulate functions of neutrophils in the pathogenesis of inflammatory bowel disease (IBD) remains elusive. We sought to investigate the effects of butyrate on IBD neutrophils and elucidate the therapeutic potential in regulating mucosal inflammation. Peripheral neutrophils were isolated from IBD patients and healthy donors, and profiles of proinflammatory cytokines and chemokines were determined by qRT-PCR and ELISA, respectively. The migration and release of neutrophil extracellular traps (NETs) were studied by a Transwell model and immunofluorescence, respectively. The in vivo role of butyrate in regulating IBD neutrophils was evaluated in a DSS-induced colitis model in mice. We found that butyrate significantly inhibited IBD neutrophils to produce proinflammatory cytokines, chemokines, and calprotectins. Blockade of GPCR signaling with pertussis toxin (PTX) did not interfere the effects whereas pan-histone deacetylase (HDAC) inhibitor, trichostatin A (TSA) effectively mimicked the role of butyrate. Furthermore, in vitro studies confirmed that butyrate suppressed neutrophil migration and formation of NETs from both CD and UC patients. RNA sequencing analysis revealed that the immunomodulatory effects of butyrate on IBD neutrophils were involved in leukocyte activation, regulation of innate immune response and response to oxidative stress. Consistently, oral administration of butyrate markedly ameliorated mucosal inflammation in DSS-induced murine colitis through inhibition of neutrophil-associated immune responses such as proinflammatory mediators and NET formation. Our data thus reveal that butyrate constrains neutrophil functions and may serve as a novel therapeutic potential in the treatment of IBD.

Automated summary

Host-microbial cross-talk is important for gut homeostasis. Butyrate was found to inhibit proinflammatory responses of neutrophils in IBD and may have therapeutic potential. The mechanism of action involves HDAC inhibition and modulation of neutrophil functions.