Dysrupted microbial tryptophan metabolism associates with SARS-CoV-2 acute inflammatory responses and long COVID, 2024, Yao et al.

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Dysrupted microbial tryptophan metabolism associates with SARS-CoV-2 acute inflammatory responses and long COVID
Lu Yao; Hannah Devotta; Junhui Li; Nonhlanhla Lunjani; Corinna Sadlier; Aonghus Lavelle; Werner C. Albrich; Jens Walter; Paul W. O’Toole; Liam O’Mahony

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.

Link | PDF (Gut Microbes) [Open Access]

 

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the long COVID population described here had been hospitalized during their acute disease and many long COVID patients develop disease after a mild course of SARS CoV2 infection. We do not yet know if our findings are also relevant for long COVID patients that were not hospitalized during acute infection.

 

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APC research discovers novel role for microbial metabolism in COVID-19 severity and long COVID | University College Cork

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20 June 2025

APC research discovers novel role for microbial metabolism in COVID-19 severity and long COVID​

27 Nov 2024

New research shows that people with lower levels of tryptophan production and tryptophan metabolism may suffer increased risk of severe and chronic outcomes from COVID 19, according to new research published in Gut Microbes from APC Microbiome Ireland, a Research Ireland centre based at University College Cork.

PAPER HIGHLIGHTS

• Bacterial metabolism of tryptophan in the gut is shown to influence immune responses to SARS-CoV-2 infection
• People with poor immune response to infection have lower levels of tryptophan and its bacterial metabolites
• Supplementation with bacterial tryptophan metabolites may protect against the damaging effects of COVID-19 and long COVID
• This is further evidence that the relationship between nutrition and microbes has a profound effect on immune health.

Our gut microbiome, an ecosystem of microbes that live in our digestive tract, plays an important role in human health. Tryptophan is an essential amino acid, meaning that the human body cannot produce tryptophan and must obtain it from other sources. The study published in Gut Microbes is the first to comprehensively explore the links between microbial metabolism of tryptophan in the gut, with systemic immune responses to virus infection. It revealed significant differences in the capacity to generate tryptophan and its derivatives in patients with severe SARS-CoV-2 infection. Circulating levels of these metabolites also correlated with severity of infection and remained altered in some patients with long COVID. Using laboratory models, the anti-viral responses of human immune cells were significantly altered by these bacterial-derived metabolites.

The findings highlight the importance of gut microbes and microbial metabolism to human immune health. Microbial immune regulatory metabolites are expected and evolutionarily hardwired into immune system decision making processes. When these metabolites are missing, the immune system will become hyper-responsive and will not respond correctly to infections. This new study represents a novel strategy for targeted approaches to prevent inflammatory or damaging immune responses to infection and promote healing and resolution of inflammation following clearance of the virus.

Professor Liam O’Mahony, Principal Investigator at APC and Professor of Immunology, at UCC, who is senior author of the study, commented on the research’s implications: “From our previous studies, we hypothesised that microbial production of tryptophan and its downstream metabolites might restrain the devastating overproduction of inflammatory mediators, which leads to multiorgan failure during SARS-CoV-2 infection or risk of long COVID. Our new data suggests that screening people for lower-level microbiome capacity for tryptophan metabolism may help identify at risk individuals, while supplementing with tryptophan metabolizing probiotics may benefit those with low levels of these microbes.”

Dysrupted Microbial Tryptophan Metabolism Associates with SARS-CoV-2 Acute Inflammatory Responses and Long COVID’ was carried out in collaboration with University College Cork, Cork University Hospital and Cantonal Hospital St. Gallen. The paper is available to read on Online at Gut Microbes: Full article: Dysrupted microbial tryptophan metabolism associates with SARS-CoV-2 acute inflammatory responses and long COVID

This study was supported by funding from Research Ireland Frontiers for the Future