Dear Editors:
After the outbreak of coronavirus disease 2019 (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. Zhang et al3 reported that severe or critical patients with COVID-19 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.
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 patients with COVID-19 with severe/critical illness was significantly higher than in individuals without COVID-19. In particular, SCFA biosynthesis of commensal bacteria 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 patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during hospitalization and beyond 1 month after discharge.
Even though Zhang et al3 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 solidify its conclusion. All levels of plasma multiomics profiles were previously determined in 139 patients with COVID-19 from their serial blood draws collected during the first week of infection after diagnosis.4 They identified the upregulation of chemokine (C-C motif) ligand 7 (CCL7), interleukin (IL) 10, and IL6 (that barely misses significance between moderate and severe disease with P = .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 IL6, are anticorrelated 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 proinflammatory cytokines (eg, chemokine [C-X-C motif] ligand 6) and proteins associated with immune cell activation (eg, cluster of differentiation 244 and 40) as high contributing factors should be determined in patients with COVID-19 and their controls. In addition, relationships between plasma analytes, clinical measures, and disease severity also deserve to be explored. For example, blood urea nitrogen (in hospitalized patients) has many connections with amino acid metabolism, suggesting amino acid catabolism in advanced COVID-19.4
The discoveries reported by Zhang et al3 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 recovery from SARS-CoV-2 infections. 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.
Footnotes
Conflicts of interest The authors disclose no conflicts.
References
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