Dysrupted microbial tryptophan metabolism associates with SARS-CoV-2 acute inflammatory responses and long COVID

Abstract

Protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and risk of long COVID has been associated with the depletion or over-abundance of specific taxa within the gut microbiome. However, the microbial mechanisms mediating these effects are not yet known. We hypothesized that altered microbial production of tryptophan and its downstream derivatives might contribute to inappropriate immune responses to viral infection. In patients hospitalized with COVID-19 (n = 172), serum levels of tryptophan and indole-3-propionate (IPA) negatively correlated with serum levels of many proinflammatory mediators (including C-reactive protein and Serum amyloid A), while C-glycosyltryptophan (C-Trp), indole-3-lactic acid (ILA) and indole-3-acetic acid (IAA) levels were positively correlated with levels of acute phase proteins, proinflammatory cytokines, alarmins and chemokines. A similar pattern was observed in long COVID patients (n = 20) where tryptophan and IPA were negatively associated with a large number of serum cytokines, while C-Trp and IAA were positively associated with circulating cytokine levels. Metagenomic analysis of the fecal microbiota showed the relative abundance of genes encoding the microbial enzymes required for tryptophan production (e.g. anthranilate synthase) and microbial tryptophan metabolism was significantly lower in patients hospitalized with COVID-19 (n = 380) compared to healthy controls (n = 270). Microbial tryptophan metabolites reduced innate cell proinflammatory responses to cytosolic DNA sensor Stimulator of interferon genes (STING), toll-like receptor (TLR)-3 and TLR-4 stimulation in vitro, while IL-10 secretion was enhanced. Microbial tryptophan metabolites also modified ex vivo human lymphocyte responses by limiting the production of TH1 and TH17 associated cytokines, while enhancing secretion of IL-22. These data suggest that lower levels of tryptophan production and tryptophan metabolism by gut microbes may increase the risk of severe and chronic outcomes to SARS-CoV-2 infection due to impaired innate and adaptive responses to infection. Screening patients for lower-level microbiome capacity for tryptophan metabolism may help identify at-risk individuals.

Keywords: COVID-19; Microbiota; indoles; long COVID; tryptophan.

Figure 1.

Tryptophan metabolites correlate with cytokine levels.

Figure 2.

Microbial tryptophan metabolism genes.

Figure 3.

Microbial genes for tryptophan biosynthesis.

Figure 4.

Microbial genes for tryptophan metabolism.

Figure 5.

Microbial tryptophan metabolites influence immune cell responses.

Figure 6.

Circulating levels of microbial tryptophan metabolites correlated with inflammatory markers and COVID-19 severity. Similarly, the relative abundance of bacterial genes encoding tryptophan synthesis and metabolism enzymes were underepresented in hospitalised COVID-19 patients. Bacterial-derived indoles modified activated immune cell responses by enhancing secretion of IL-10 and IL-22, while reducing IRF3 mediated transcription and reduced secretion of IP-10, interferons and IL-17.