key: cord-1028675-3af0alih
authors: Zhang, Yu-Hang; Cui, Yi-Min
title: Gut microbiome metabolism drives the resolution of patients with COVID-19
date: 2021-12-23
journal: Gastroenterology
DOI: 10.1053/j.gastro.2021.12.261
sha: bdaacf1e3136ecc8ce272d4aafbeb3ba4bf2aded
doc_id: 1028675
cord_uid: 3af0alih

nan

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Following the outbreak of COVID-19, its long-term sequelae after recovery has become the wide-ranging concern. Sequelae symptoms and complications, including but not limited to chronic fatigue, lung fibrosis, anxiety, depression, cognitive impairment and venous thromboembolism, have emerged in some patients after hospital stay 1-2 . However, little is currently known on the underlying mechanisms of these chronic health sequelae. In this issue of Gastroenterology, Zhang F et al. has reported that severe or critical COVID-19 patients are characterized by impaired capacity of gut microbiome for short chain fatty acid (SCFA), L-isoleucine biosynthesis and enhanced capacity for urea production for their gut microbiome 3 . To our knowledge, this is the first longitudinal cohort study of hospital survivors with COVID-19 so far to describe the dynamic gut microbiome functionality within 30 days after discharge. By metagenomic analysis, they found Bray-Curtis dissimilarity of microbial pathways in COVID-19 patients with severe/critical illness was significantly higher than non-COVID-19 controls. In particular, SCFA biosynthesis of commensal bacteria is served as the energy sources of host cells. Its impairment thus could contribute to the symptoms of fatigue and muscle weakness. Besides, they were also conscious of dietary factors of patients over the course of hospitalization, which were substantiated to be excluded. This study has comprehensively clarified how gut microbiome functionality modulates the outcome of SARS-CoV-2-infected patients during hospitalization and beyond one month after discharge.

Even though Zhang F et al. claimed the limitations of their dietary records before disease onset and mechanistic studies between SARS-CoV-2 infection and the gut immune system, this study is also lacking in plasma measurements to solidate its conclusion. All levels of plasma multi-omics profiles were previously determined in 139 COVID-19 patients, from their serial blood draws collected during the first week of infection following diagnosis 4 . They identified the upregulation of CCL7, IL-10, and IL-6 (that barely misses significance between moderate and severe disease with p = 0.056). Keratin-19 (KRT19) involved in the organization of muscle fibers is upregulated in all comparisons and may be a marker of tissue damage between moderate and severe COVID-19 cases. Several inflammation-associated proteins, including CCL7 and IL-6, are anti-correlated with many plasma lipids. For healthy donors or mildly infected patients, these lipid levels drop precipitously. Therefore, the mentioned plasma measurements were insufficient for the perspective of inflammatory reaction. More pro-inflammatory cytokines (e.g., CXCL6) and proteins associated with immune cell activation (e.g., CD244 and CD40) as high contributing factors should be determined in COVID-19 cases and their controls. In addition, relationships between plasma analytes, clinical measures, and disease severity are also deserved to be explored. For example, blood urea nitrogen (BUN) (in hospitalized patients) has many connections with amino acid metabolism, suggesting amino acid catabolism in advanced COVID-19 4 .

The discoveries reported by Zhang F et al. highlight the effects that gut microbial metabolism can have on COVID-19 severity, and demonstrate that microbiota functional capabilities are critical for the long-term SARS-CoV-2 infections recovery. A highly diverse microbial community has an intrinsic capacity to act as a protective barrier against virus invasion and pathobiont expansion in the circulatory system. Gut metabolites or signaling molecules, such as SCFA, L-isoleucine and urea production, play an important role in these inherent protective functions of the microbiota. The functional properties of native microbiota and its molecules mediating virus colonization should be the focus of further work, with the potential to harness them for new and improved therapies.

The long-term sequelae of COVID-19: an international consensus on research priorities for patients with pre-existing and newonset airways disease

Gastrointestinal sequelae 90 days after discharge for COVID-19

Prolonged Impairment of Short-Chain Fatty Acid and L-Isoleucine Biosynthesis in Gut Microbiome in Patients With COVID-19

Multi-Omics Resolves a Sharp Disease-State Shift between Mild and Moderate COVID-19