Gut microbiota‐derived tryptophan metabolites improve total parenteral nutrition‐associated infections by regulating Group 3 innate lymphoid cells

Abstract Clinical nutritional support is recognized by Klinefner's Surgery as one of the four pivotal advancements in surgical practice during the 20th century. Surgeons regard clinical nutrition as a “life‐saving” discipline, pivotal in preserving the lives of numerous critically ill patients and facilitating the success of many surgical procedures. Parenteral nutrition (PN) support serves as a crucial component of clinical nutritional therapy, while a range of complications associated with total parenteral nutrition (TPN) can significantly undermine the efficacy of patient treatment. Impaired intestinal homeostasis is strongly associated with the occurrence and progression of TPN‐related infections, yet the underlying mechanisms remain poorly understood. In this study, RNA sequencing and single‐cell RNA sequencing (scRNA‐Seq) revealed that reduced secretion of interleukin‐22 (IL‐22) by intestinal Group 3 innate lymphoid cells (ILC3s) is a significant factor contributing to the onset of TPN‐related infections. Additionally, through 16S ribosomal RNA (16S rRNA) gene sequencing of the gut microbiota from patients with chronic intestinal failure and metagenomic sequencing analysis of the gut microbiota from mice, we observed that TPN reduced the abundance of Lactobacillus murinus ( L. murinus ), while supplementation with L. murinus could promote IL‐22 secretion by ILC3s. Mechanistically, L. murinus upregulates indole‐3‐carboxylic acid, which activates the nuclear receptor Rorγt to stimulate IL‐22 secretion by ILC3s. This pathway strengthens gut barrier integrity and reduces infection susceptibility. Our findings enhance our understanding of the mechanisms driving the onset of TPN‐related infections, highlighting the critical role of gut microbiota in maintaining immune homeostasis and improving clinical outcomes.