Dear Editor:
Since gut represents the largest immunological organ and its resident
microbiota are well-characterized to significantly orchestrate host
immune responses, there were a growing interest in interrogating the
potential impact of the gut microbiota on host susceptibility to
SARS-CoV-2. Various studies have confirmed that alterations in gut
microbiota composition are significantly associated with COVID-19
progression and severity of illness.1,2 However, these
studies to date have not completely eliminated confounding factors,
thereby establishing a definitive causal relationship between COVID-19
and the gut microbiota. Mendelian randomization (MR), as a statistical
methodology utilizing genetic variations as instrumental variables, has
increasingly adopted as a promising tool for revisiting causal
relationships between exposures and outcomes, with the controlling for
confounding factors. MR studies can be conducted by using large-scale
genetic data from biobanks, which can provide high statistical power and
reduce the potential for bias. Mendelian randomization has been
leveraged to investigate the causal effects of multiple influential
factors on outcomes and severity of COVID-19.3-6 These
findings hold tremendous potential to inform public health policies and
interventions aimed at mitigating the burden of COVID-19.
This
study aims to explore the directional relationship between gut
microbiota and the severity of COVID-19 using MR method. The genetic
variants correlated with exposure, the gut microbiota composition
detected in fecal sample, were sourced from the largest genome-wide
meta-analysis to date, conducted by the MiBioGen
consortium.7 The GWAS data of COVID-19 patients were
obtained from the latest r7 version based on COVID-19 Host Genetics
Initiative data (HGI)
(https://www.covid19hg.org/results/r7/).
According to the HGI standard, the outcomes were stratified into three
distinct categories (mild, moderate and severe). In MR analysis, various
methods were applied, including inverse-variant weighted, MR-Egger,
weighted mode, weighted median, and simple median. Only SNPs with a
significant threshold (p <5×10-8) were considered for
instrumental variable selection. Pleiotropy and heterogeneity were
assessed via MR-Egger, Cochran’s Q test and ”Leave-one-out”
sensitivity analysis (Figure 1). All data used in the current study were
publicly accessible.
The results of MR analysis revealed a causal relationship between
certain genera of gut microbiota and the severity of COVID-19, as shown
in Table 1 . Notably, increased composition of Dorea at
genetic level was positively correlated with all outcomes, whileBifidobacterium was related to mild and moderate outcomes, and
the Rikenellaceae RC9 gut group was linked to moderate and severe
outcomes (Supplementary Figure 1). After performing sensitivity
analysis, we have demonstrated that the causal pathway was not
influenced by any potentially influential SNPs, thereby validating the
robustness of our findings. Additionally, MR‒Egger was performed as
well, in which no potentially significant horizontal pleiotropy or
outliers were detected (Supplementary Figure 2-5). To further summarize
the evidence and verify the results of MR, we conducted a meta-analysis
incorporating the original data included in our study. The overall
effect sizes were quantified and no significant evidence of
heterogeneity was found (Supplementary Figure 6).
Since previous studies concerning the relationship between gut
microbiota and COVID-19 susceptibility were limited by a lack of causal
relationships, small sample sizes, insufficient evidence due to the
timing of fecal sample collection and inability to rule out confounding
factors, our study represents the first time that MR has been utilized
to confirm the causal impact of specific genera of gut microbiota on the
severity of COVID-19. Further investigation into the specific bacteria
associated with severity of illness among COVID-19 patients is also
warranted. For instance, Dorea and Bifidobacterium are
crucial producers of short-chain fatty acids (SCFAs), which have been
found to have potent immunomodulatory properties, along with the ability
in mediating CD8+ T cell immune
response.8 Elevated levels of Rikenellaceae RC9
gut group have been shown to modulate TLR signaling pathways, thereby
increasing the susceptibility of the gut to
inflammation.9 Bacteroides play a role in
regulating host immunity and suppressing colonic ACE-2 expression.
Furthermore, an inverse correlation has been observed betweenBacteroides levels and the severity of COVID-19
infection.1 An increased abundance of intestinalPrevotella is associated with adverse outcomes in several
inflammatory disorders, such as rheumatoid arthritis, ankylosing
spondylitis, as well as systemic immune activation in HIV
patients.10 Hence, exploring the microbiota that is
intricately linked with COVID-19 has the potential to unravel the exact
pathophysiological mechanisms that underpin SARS-CoV-2 infection.
In conclusion, our results implied that targeted screening of gut
microbiota compositions in fecal samples for susceptible populations
could become an effective yet feasible strategy for preventing moderate
to severe cases of COVID-19, paving the way for more personalized
treatments.