This review explains how the gut’s built‑in immune system spots and fights bacteria, highlighting the role of the peptide LL‑37 (the only human cathelicidin) as a broad‑spectrum antimicrobial that also helps regulate inflammation and blood vessel growth. It also covers other sensors like Toll‑like receptors and NOD proteins, and notes that problems with NOD2 are linked to Crohn’s disease.

Exciting progress has been made recently in identifying receptors and effector molecules of innate immunity. The review focuses on new insights and their applications to intestinal physiology in the areas of toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)-containing proteins as microbial sensors, and defensins and cathelicidins as antimicrobial effectors. Toll-like receptors recognize conserved bacterial structures including cell wall components and specific DNA motifs. Several TLRs are expressed constitutively or inducibly in the intestine, and contribute to immune defense against enteric pathogens such as Salmonella. NOD proteins are cytoplasmic sensors of bacterial components. NOD1 is expressed in intestinal epithelial cells and activates proinflammatory cytokine production in response to a peptidoglycan motif in gram-negative bacteria. NOD2 is present in macrophages, dendritic and Paneth cells, and can be induced in enterocytes. Its activation by bacterial muramyl dipeptide induces expression of proinflammatory mediators. Mutations in NOD2 are highly associated with the development of Crohn disease. The major groups of antimicrobial proteins in humans are defensins, with at least 8 alpha- and 10 beta-defensin genes, and cathelicidins, with only one known gene, LL-37/hCAP18. They all have broad-spectrum antimicrobial activity, but several also exhibit immunoregulatory and angiogenic functions. Their differential expression and regulation in the epithelium throughout the gastrointestinal tract suggests that the various antimicrobial peptides have distinct functional niches in mucosal innate defense. More than 50 human genes have been identified to date that can sense and destroy enteric microbes. Elucidation of their physiologic functions will aid in developing new treatment and prevention strategies for inflammatory and infectious diseases in the intestine.