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

Abstract

Background & Aims SARS-CoV-2 infection is associated with altered gut microbiota composition. Phylogenetic groups of gut bacteria involved in the metabolism of short chain fatty acids were depleted in SARS-CoV-2-infected patients . We aimed to characterize functional profile of gut microbiome in patients with COVID-19 before and after disease resolution. Methods We performed shotgun metagenomic sequencing on fecal samples from 66 antibiotics-naïve patients with COVID-19 and 70 non-COVID-19 controls. Serial fecal samples were collected (up to 6 times points) during hospitalization and beyond one month after discharge. We assessed gut microbial pathways in association with disease severity and blood inflammatory markers. We also determined changes of microbial functions in fecal samples before and after disease resolution and validated these functions using targeted analysis of fecal metabolites. Results Compared with non-COVID-19 controls, COVID-19 patients with severe/critical illness showed significant alterations in gut microbiome functionality ( P < .001), characterized by impaired capacity of gut microbiome for short chain fatty acid (SCFA) and L-isoleucine biosynthesis and enhanced capacity for urea production. Impaired SCFA and L-isoleucine biosynthesis in gut microbiome persisted beyond 30 days after recovery in COVID-19 patients. Targeted analysis of fecal metabolites showed significantly lower fecal concentrations of SCFAs and L-isoleucine in COVID-19 patients before and after disease resolution. Lack of SCFA and L-isoleucine biosynthesis significantly correlated with disease severity and increased plasma concentrations of CXCL-10, NT-proBNP, C-reactive protein (CRP) (all P < .05). Conclusions Gut microbiome of COVID-19 patients displayed impaired capacity for SCFA and L-isoleucine biosynthesis which persisted even after disease resolution. These two microbial functions correlated with host immune response underscoring the importance of gut microbial functions in SARS-CoV-2 infection pathogenesis and outcome.

Dissecting the Role of the Human Microbiome in COVID-19 via Metagenome-assembled Genomes

“…3j. In line with a previous study at the metabolic capacity level 39 , these results indicate that the gut microbiome of patients with COVID-19 did not return to a relatively healthy status right after their recovery from SARS-CoV-2 infection. We then observed that disease severity of COVID-19 was significantly positively associated with the gut microbiome dissimilarity between COVID-19 patients and Non-COVID-19 controls (Fig.…”

“…Among the 63 protective nrMAGs, the dominant species were Blautia A obeum (13 nrMAGs), Bariatricus comes (9 nrMAGs), Faecalibacterium prausnitzii D (6 nrMAGs), Blautia A wexlerae (6 nrMAGs), Faecalibacterium sp900539945 (4 nrMAGs), Dorea longicatena B (3 nrMAGs), Blautia A sp003480185 (3 nrMAGs), Blautia A sp003471165 (3 nrMAGs), Dorea formicigenerans (2 nrMAGs), Fusicatenibacter saccharivorans (2 nrMAGs), and GCA-900066135 sp900543575 (2 nrMAGs). Importantly, we found that some of these species were previously reported (including in the original study Yeoh et al) to be decreased in patients with COVID-19 such as Blautia obeum 11,18 , Faecalibacterium prausnitzii 17,18,39,47 , and Dorea formicigenerans 17,18 . Interestingly, those protective nrMAGs also showed a similar abundance distribution between patients with COVID-19 and Non-COVID-19 controls in the study of Zuo et al 17 ( Fig.S9 ).…”

Gut microbiome dysbiosis during COVID-19 is associated with increased risk for bacteremia and microbial translocation

“…The loss of diversity and immunosupportive Faecalibacterium in patients with BSIs mirrored a similar loss of diversity in the most severely sick mice deliberately infected with SARS-CoV-2, and as observed by other labs and other model systems 49–51 . Notably, a recent study reproduced these changes in the microbiome in an antibiotics-naïve cohort 52 , suggesting that the viral infection causes gut dysbiosis, either through gastrointestinal infection 53–57 or through a systemic inflammatory response 2, 4 . Furthermore, the pronounced increase in Akkermansiaceae in mice was also observed in our patient samples, and has been reported previously in patients and in K18-hACE2 mice 49, 58 .…”

Liu Shen Capsule Alters Airway Microbiota Composition and Metabolite Profiles in Healthy Humans

“…For instance, oral microbiomes produce vasoactive and anti-inflammatory nitrite, nitric oxide, and other bioactive nitrogen oxides (Koch et al, 2017;Pignatelli et al, 2020). Moreover, specific microbiota-associated metabolites, such as short-chain fatty acids (SCFAs), have been shown to affect the progression of varied diseases, including respiratory diseases (Hecker et al, 2021;Zhang et al, 2021). Lung microbiota comprise nitrate reducers and SCFAs producers, such as Pseudomonas species and Staphylococcus species, which are linked to protection against respiratory diseases by inhibiting histone deacetylases or binding GPR41, GPR43, and GPR109A to alter chemotaxis and phagocytosis, change cell proliferation, and regulate inflammatory responses (McKenzie et al, 2017).…”