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Summary Commensal microbes are necessary for a healthy gut immune system. However, the mechanism involving these microbes that establish and maintain gut immune responses is largely unknown. Here, we have found that the gut immune receptor leucine-rich repeat (LRR) C19 is involved in host-microbiota interactions. LRRC19 deficiency not only impairs the gut immune system but also reduces inflammatory responses in gut tissues. We demonstrate that the LRRC19-associated chemokines CCL6, CCL9, CXCL9, and CXCL10 play a critical role in immune cell recruitment and intestinal inflammation. The expression of these chemokines is associated with regenerating islet-derived (REG) protein-mediated microbiotas. We also found that the expression of REGs may be regulated by gut Lactobacillus through LRRC19-mediated activation of NF-κB. Therefore, our study establishes a regulatory axis of LRRC19, REGs, altered microbiotas, and chemokines for the recruitment of immune cells and the regulation of intestinal inflammation., Graphical Abstract, Highlights • The gut immune receptor LRRC19 is involved in host-microbiota interactions • LRRC19-associated chemokines control immune cell recruitment and gut inflammation • Chemokines are regulated by REG protein-mediated gut microbiotas • Lactobacillus may modulate the expression of REG proteins through LRRC19, Cao et al. found that the gut epithelial receptor LRRC19 is involved in gut host-microbiota interactions and that it plays a critical role in promoting the recruitment of immune cells and intestinal inflammation.