Dietary tryptophan prevents sepsis

Recently, Professor Hu Bei’s team from Guangdong Provincial People’s Hospital made significant progress in the field of sepsis research.

Their research, published in the Chinese Medical Journal, shows that dietary tryptophan (Trp) can prevent sepsis by regulating the intestinal microbiota and its metabolic functions, generating the key metabolic product indole-3-pyruvic acid (IPyA), which then activates the GPR37 receptor on the surface of macrophages, enhancing the bacterial phagocytic ability of macrophages, and ultimately effectively preventing sepsis. This provides a new nutritional intervention strategy and molecular target for the prevention and treatment of sepsis.

Sepsis and macrophage activation

Sepsis is a life-threatening disease and one of the main causes of death among hospitalized patients. There are approximately 50 million cases worldwide each year. Currently, in addition to conventional hormone and antibiotic treatments, effectively regulating the host’s immune system is crucial for controlling sepsis-related infections.

Macrophages, as a key cell type of the host’s immune system, play a critical role in resisting infections through their phagocytic and bactericidal functions are of great significance in resisting infections, but during sepsis, the functions of macrophages are easily damaged, and there is a metabolic disorder in the plasma, with a reduction in protective metabolites and an increase in toxic metabolites. New anti-infection strategies needed to be explored urgently.

Background and core findings

Based on this, the research team obtained several key findings through animal experiments, cell experiments, and clinical sample analysis: Dietary tryptophan supplementation can significantly increase the survival rate of septic mice, alleviate multi-organ damage such as in the lungs, liver, and kidneys, reduce plasma levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and inflammatory factors (IL-6, IL-1β, TNF-α), and this protective effect depends on the intestinal microbiota.

When the intestinal microbiota was cleared, the protective effect of dietary tryptophan disappeared, while the feces of mice fed with dietary tryptophan reproduced the protective effect.

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It was also found that the average IPyA levels in sepsis patients and septic mouse models were significantly reduced, and the plasma IPyA level of patients was negatively correlated with the AST level; exogenous supplementation of IPyA can simulate the protective effect of dietary tryptophan, prolong the survival time of septic mice, alleviate organ damage, and reduce the bacterial load in blood and peritoneal lavage fluid (PLF).

The mechanism is that IPyA can directly bind to GPR37 on the surface of macrophages, activate small GTPase RAC1/CDC42, increase the expression of actin-related protein (Arp) 2/3, and ultimately enhance the phagocytic ability of macrophages against bacteria. It also enhances phagocytosis in patient-derived macrophages.

Research significance and outlook

Professor Hu Bei pointed out that this study is the first to clarify the “dietary tryptophan - intestinal microbiota - IPyA - GPR37 - macrophage phagocytosis” regulatory axis in the prevention of sepsis, not only enriching the understanding of the pathogenesis of sepsis, but also providing a new direction for the prevention and treatment of sepsis.

On one hand, dietary tryptophan is an essential amino acid for the human body, with widely available sources and high safety, and is expected to become a preventive nutritional supplement for high-risk populations of sepsis (such as patients undergoing major surgeries and those with compromised immune function); on the other hand, IPyA and its receptor GPR37 can be used as drug development targets, laying the foundation for the development of new drugs for sepsis treatment.

Currently, the team has begun the screening and optimization of IPyA analogues, and plans to conduct a prospective cohort study on the use of dietary tryptophan for the prevention of sepsis in clinical settings, to further verify its clinical application value.