Dietary emulsifier carboxymethylcellulose-induced gut dysbiosis and SCFA reduction aggravate acute pancreatitis through classical monocyte activation.

Abstract

Objective: Carboxymethylcellulose (CMC), one of the most common emulsifiers used in the food industry, has been reported to promote chronic inflammatory diseases, but its impact on acute inflammatory diseases, e.g., acute pancreatitis (AP), remains unclear. This study investigates the detrimental effects of CMC on AP and the potential for mitigation through Akkermansia muciniphila or butyrate supplementation.

Design: C57BL/6 mice were given pure water or CMC solution (1%) for 4 weeks and then subjected to caerulein-induced AP. The pancreas, colon, and blood were sampled for molecular and immune parameters associated with AP severity. Gut microbiota composition was assessed using 16S rRNA gene amplicon sequencing. Fecal microbiota transplantation (FMT) was used to illustrate gut microbiota's role in mediating the effects of CMC on host mice. Additional investigations included single-cell RNA sequencing, monocytes-specific C/EBPδ knockdown, LPS blocking, fecal short-chain fatty acids (SCFAs) quantification, and Akkermansia muciniphila or butyrate supplementation. Finally, the gut microbiota of AP patients with different severity was analyzed.

Results: CMC exacerbated AP with gut dysbiosis. FMT from CMC-fed mice transferred such adverse effects to recipient mice, while single-cell analysis showed an increase in classical monocytes in blood. LPS-stimulated C/EBPδ, caused by an impaired gut barrier, drives monocytes towards classical phenotype. LPS antagonist (eritoran), Akkermansia muciniphila or butyrate supplementation ameliorates CMC-induced AP exacerbation. Fecal Akkermansia muciniphila abundance was negatively correlated with AP severity in patients.

Conclusions: This study reveals the detrimental impact of CMC on AP due to gut dysbiosis, with Akkermansia muciniphila or butyrate offering potential therapeutic avenues for counteracting CMC-induced AP exacerbation. Video Abstract.