Microbial Metabolite 3-Indolepropionic Acid Mediates Immunosuppression

Abstract

The microbial-derived metabolite, 3-indolepropionic acid (3-IPA), has been intensely studied since its origins were discovered in 2009; however, 3-IPA’s role in immunosuppression has had limited attention. Untargeted metabolomic analyses of T-cell exhaustion and immunosuppression, represented by dysfunctional under-responsive CD8+ T cells, reveal a potential role of 3-IPA in these responses. T-cell exhaustion was examined via infection of two genetically related mouse strains, DBA/1J and DBA/2J, with lymphocytic choriomeningitis virus (LCMV) Clone 13 (Cl13). The different mouse strains produced disparate outcomes driven by their T-cell responses. Infected DBA/2J presented with exhausted T cells and persistent infection, and DBA/1J mice died one week after infection from cytotoxic T lymphocytes (CTLs)-mediated pulmonary failure. Metabolomics revealed over 70 metabolites were altered between the DBA/1J and DBA/2J models over the course of the infection, most of them in mice with a fatal outcome. Cognitive-driven prioritization combined with statistical significance and fold change were used to prioritize the metabolites. 3-IPA, a tryptophan-derived metabolite, was identified as a high-priority candidate for testing. To test its activity 3-IPA was added to the drinking water of the mouse models during LCMV Cl13 infection, with the results showing that 3-IPA allowed the mice to survive longer. This negative immune-modulation effect might be of interest for the modulation of CTL responses in events such as autoimmune diseases, type I diabetes or even COVID-19. Moreover, 3-IPA’s bacterial origin raises the possibility of targeting the microbiome to enhance CTL responses in diseases such as cancer and chronic infection.

Shotgun metagenomics and systemic targeted metabolomics highlight indole-3-propionic acid as a protective gut microbial metabolite against influenza infection

“…In a recent study, it was shown to abrogate the pathogenic effect of virus-specific cytotoxic T lymphocytes in certain strains of mice infected with lymphocytic choriomeningitis virus clone 13. 65 The potential role of IPA in other viral infections, notably respiratory infections, remains unclear. This is a relevant question regarding the drop in IPA in HIV-infected people, a phenomenon usually associated with a change in the functional status of the gut microbiome.…”

Perturbed pediatric serum metabolome in mild and severe dengue disease

“…Tryptophan can be metabolized into bioactive molecules that function in inflammation and ageing, gut-brain homeostasis, immune regulation, cardiovascular diseases, and endothelial dysfunction (33)(34)(35)(36)(37)(38)(39). It is also implicated in infectious diseases (40,41), including dengue virus infection and disease (10)(11)(12)42).…”

“…IPA was reported to have immunomodulatory, anti-inflammatory and antioxidant effects, and various protective functions in mammals (37,54). IPA abundance has a positive correlation with factors that promote cardiovascular health, and IPA levels decrease in scenarios where cardiovascular health is diminished (55).…”

Understanding emerging bioactive metabolites with putative roles in cancer biology

“…Indeed, 3-IPA has been shown to decrease cell proliferation in breast cancer ( 42 ) and protects against radiation toxicity ( 43 ). The metabolite may also suppress cancer immunity since recent untargeted metabolomic analyses revealed that 3-IPA is elevated in exhausted T cells and was shown to suppress T-cell responses when supplied exogenously ( 44 ). The effects of 3-IPA are proposed to be exerted through pregnane X receptor (PXR) and the aryl hydrocarbon receptor (AHR) ( 42 , 43 ) but the full mechanisms of action remain to be elucidated.…”