The New Foe and Old Friends: Are We Ready for Microbiota-Based Therapeutics in Treating COVID-19 Patients?

Dear Editors:

We read with interest the work by Zuo et al reporting altered gut microbiota in patients with coronavirus disease 2019 (COVID-19) during hospitalization. The authors reported that certain beneficial commensals of the patients are in inverse correlation with fecal load of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and/or clinical severity. Although this pioneer study attempts to highlight the potential value of the gut microbiota as a therapeutic target, we believe that extra mechanistic links merit discussion and functional analysis of the readily available metagenomic data would provide further mechanistic insights.

Based on the finding of negative association between the abundances of 4 Bacteroides species and the fecal viral load, the authors anticipated that these bacteria may down-regulate angiotensin-converting enzyme 2 (ACE2), the entry point of SARS-CoV-2 into host cells. This justification was based on a previous report in which mice monocolonized with Bacteroides species. Most members of Bacteroides are able to produce sphingolipids, which play an important role in host–microbial interactions by elevating exogenous sphingolipid (eg, ceramide) levels, while inhibiting de novo synthesis of sphingolipids in both human cells and mice models. , The benefits of elevated exogenous sphingolipid levels and consequently inhibited de novo synthesis of sphingolipids would be multifaceted. For one thing, increased exogenous sphingolipid levels could suppress the replication of coronaviruses by enhancing the differentiation of regulatory T cells, and stimulating dendritic cell maturation that promotes T cell responses to viral infections. For another, reduced de novo synthesis of sphingolipids in host enterocytes may suppress ACE2 expression and synthesis of human cell surface gangliosides, in which sphingolipids are an integral part. Given that the spike protein of SARS-CoV-2 is known to use the ACE2 receptor and could also use sialic acids linked to host cell surface gangliosides for entry, reduced de novo synthesis of sphingolipids will consequently minimize viral entry. In addition, due to structural differences from host-derived sphingolipids, Bacteroides-derived sphingolipids may lower the binding affinity of SARS-CoV-2 spike protein with ACE2 and human cell surface gangliosides and thus reduce viral entry. Given these potential roles of Bacteroides-derived sphingolipids, analysis on functional potentials of the microbiome from the readily available metagenomes in this study could somehow reveal possible mechanistic links between gut microbiota–derived sphingolipids and host defense against SARS-CoV-2, although other omics data and experimental studies are needed for verification. It is worth investigating the therapeutic potentials of exogenous bacterial-derived sphingolipid and/or sphingolipid-producing Bacteroides in patients with COVID-19 while no effective treatment is currently available. Despite having the potential functions mentioned above, none of the 4 Bacteroides species were increased in healthy controls than COVID-19 patients. This is also supported by another study by Gu et al in a population with similar genetic background. The preventive potential of these bacteria in healthy individuals from the viral infection is still questionable.

In addition, Gu et al also reported a decreased microbial diversity, which is a general marker for gut dysbiosis, in patients with COVID-19 compared with healthy controls, but no significant difference between general and severe COVID-19 patients. Because the study by Zuo et al did not measure microbial diversity indices, it remains unknown whether these findings are generalizable. Given that viral loads were determined in this study, it is feasible and will be thought-provoking to explore the relationship between viral loads and microbial diversity.

The authors suggested enhancing intestinal butyrate production by dietary changes for promoting a healthy microbiome in general. One relevant explanation should link to the finding that negative correlations of 2 beneficial commensals, Akkermansia muciniphila and Faecalibacterium prausnitzii, with viral load and disease severity, respectively. Faecalibacterium was also underrepresented in antibiotic-exposed COVID-19 patients in the study and in COVID-19 patients compared with healthy controls, according to Gu et al. These commensals and Bacteroides species are well-known producers of short-chain fatty acids, which play a pivotal role in modulating host immune homeostasis. Perhaps in patients with COVID-19, short-chain fatty acids produced by gut commensals prevent proinflammatory conditions. However, more functional studies are needed to confirm the role of butyrate producers or butyrate itself in preventing viral infection.

Despite that the mechanistic links discussed above somehow support the important role of the gut microbiota in the pathogenicity of SARS-CoV-2 infection, the association of fecal microbial alteration with COVID-19 does not establish causality. This important distinction needs to be made before considering microbiota-based therapy for COVID-19.