A high-risk gut microbiota configuration associates with fatal hyperinflammatory immune and metabolic responses to SARS-CoV-2

Abstract

Protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and associated clinical sequelae requires well-coordinated metabolic and immune responses that limit viral spread and promote recovery of damaged systems. However, the role of the gut microbiota in regulating these responses has not been thoroughly investigated. In order to identify mechanisms underpinning microbiota interactions with host immune and metabolic systems that influence coronavirus disease 2019 (COVID-19) outcomes, we performed a multi-omics analysis on hospitalized COVID-19 patients and compared those with the most severe outcome (i.e. death, n = 41) to those with severe non-fatal disease (n = 89), or mild/moderate disease (n = 42), that recovered. A distinct subset of 8 cytokines (e.g. TSLP) and 140 metabolites (e.g. quinolinate) in sera identified those with a fatal outcome to infection. In addition, elevated levels of multiple pathobionts and lower levels of protective or anti-inflammatory microbes were observed in the fecal microbiome of those with the poorest clinical outcomes. Weighted gene correlation network analysis (WGCNA) identified modules that associated severity-associated cytokines with tryptophan metabolism, coagulation-linked fibrinopeptides, and bile acids with multiple pathobionts, such as Enterococcus . In contrast, less severe clinical outcomes are associated with clusters of anti-inflammatory microbes such as Bifidobacterium or Ruminococcus , short chain fatty acids (SCFAs) and IL-17A. Our study uncovered distinct mechanistic modules that link host and microbiome processes with fatal outcomes to SARS-CoV-2 infection. These features may be useful to identify at risk individuals, but also highlight a role for the microbiome in modifying hyperinflammatory responses to SARS-CoV-2 and other infectious agents.

The central and biodynamic role of gut microbiota in critically ill patients

“…This last study also suggested that the Bacteroidetes/Firmicutes ratio could be a predictor of mortality [7]. Intestinal dysbiosis has been shown to be associated with patient susceptibility to nosocomial infections, sepsis, organ failure and even COVID-19 disease severity [32][33][34][35][36][37].…”

Multi-omics personalized network analyses highlight progressive disruption of central metabolism associated with COVID-19 severity

“…Further, metabolite essentiality analysis identified butyrate, a microbiome-derived four-carbon short-chain fatty acid, as an essential metabolite in severe COVID-19, which plays an essential role in energy metabolism and intestinal homeostasis (Liu et al, 2018). Recently our integrative analysis of cytokines, metabolites, and microbiome features suggested a potential role of microbial-derived immunoregulatory processes in fatal outcomes in COVID-19 due to the failure of the negative feedback mechanism that should confine the cytokine storm (Albrich et al, 2022). Interestingly, MCTs are also involved in the butyrate transportation (Chang et al, 2014).…”

Metabolic rewiring and serotonin depletion in patients with postacute sequelae of COVID‐19

“…We have previously shown that tryptophan metabolism was heavily disrupted in COVID‐19 patients during the acute phase of the infection, especially in those with the poorest outcomes. 4 Quinolinate is an excitotoxin that hinders neuronal function through multiple mechanisms including acting as an NMDA receptor agonist, and it indirectly drives accumulation of glutamate. In contrast, serotonin has essential modulatory effects on mood, anxiety, sleep, cognition, and memory.…”