Gut microbiota from patients with mild COVID-19 cause alterations in mice that resemble post-COVID syndrome

Abstract

Background There is mounting evidence that SARS-CoV-2 targets tissues beyond the respiratory tract. Long-term sequelae after COVID-19 are frequent and of major concern. Prolonged virus detection in the gut has been particularly intriguing. Of note, SARS-CoV-2 infection also disturbs the gut microbiota composition, a finding linked with disease severity in patients with COVID-19. Here, we aimed to characterize the functional role of the gut microbiota in the long-term consequences of COVID-19. To this end, we characterized the gut microbiota from COVID-19 human subjects and followed the effects of human fecal transfer to germ-free mice. Results The gut microbiota of post-COVID subjects (up to 4 months from the initial positive test) revealed a remarkable predominance of Enterobacteriaceae strains with multidrug-resistance phenotype compared to healthy controls. After fecal transfer to germ-free mice, animals receiving samples from post-COVID subjects displayed higher lung inflammation and increased susceptibility to pulmonary infection caused by an antimicrobial resistant Klebsiella pneumoniae strain. These mice also showed poorer cognitive performance associated with increased expression of TNF-α, reduced levels of brain-derived neurotrophic factor-BDNF and postsynaptic density protein-PSD-95 in the brain, as well as alterations of several biochemical pathways. These alterations were observed in the absence of SARS-CoV-2, suggesting that alterations in the gut microbiota caused them. Consistent with this hypothesis, brain dysfunctions induced in a mouse model of coronavirus infection were partially prevented by modulation of the microbiota via treatment with the commensal probiotic bacteria Bifidobacterium longum 51A. Conclusions Our results show prolonged impact of SARS-CoV-2 infection in the gut microbiota that persists even after the individuals have cleared the virus. Increased Enterobacteriaceae with antimicrobial resistance phenotype were of particular concern. Moreover, microbiota transfer from post-COVID subjects induced loss of brain cognitive functions and impaired lung defense in mice. Altogether, our work emphasizes the importance of microbiota as a target for therapies to help treat post-COVID sequelae.

Risk Factors of Severe COVID-19: A Review of Host, Viral and Environmental Factors

“…Severe dysbiosis and increased intestinal permeability might lead to the translocation of pathogens, toxins and cytokines to the circulatory system leading to severe complications and multi-organ failure [ 641 ]. The causal role of COVID-19-induced gastrointestinal dysbiosis in the development of symptoms and disease severity is further supported by results obtained with a gnotobiotic mouse model [ 642 ]. Fecal microbiota transplantation from COVID-19 patients to germ-free mice resulted in lung histopathology, an inflammatory cytokine profile, cognitive impairment, and increased susceptibility towards bacterial infection in the animal model indicating that pre-infection differences in microbiota composition might influence COVID-19 susceptibility and severity as well.…”

Long COVID: major findings, mechanisms and recommendations

“…Higher levels of fungal translocation, from the gut and/or lung epithelium, have been found in the plasma of patients with long COVID compared with those without long COVID or SARS-CoV-2-negative controls, possibly inducing cytokine production 141 . Transferring gut bacteria from patients with long COVID to healthy mice resulted in lost cognitive functioning and impaired lung defences in the mice, who were partially treated with the commensal probiotic bacterium Bifidobacterium longum 25 .…”

“…There are likely multiple, potentially overlapping, causes of long COVID. Several hypotheses for its pathogenesis have been suggested, including persisting reservoirs of SARS-CoV-2 in tissues 16,17 ; immune dysregulation [17][18][19][20] with or without reactivation of underlying pathogens, including herpesviruses such as Epstein-Barr virus (EBV) and human herpesvirus 6 (HHV-6) among others 17,18,21,22 ; impacts of SARS-CoV-2 on the microbiota, including the virome 17,[23][24][25] ; autoimmunity 17,[26][27][28] and priming of the immune system from molecular mimicry 17 ; microvascular blood clotting with endothelial dysfunction 17,[29][30][31] ; and dysfunctional signalling in the brainstem and/or vagus nerve 17,32 (Fig. 3).…”

Post-acute COVID-19 syndrome and gut dysbiosis linger beyond 1 year after SARS-CoV-2 clearance

“…We recently published in Gut to show that gut dysbiosis persisted for at least 6 months in patients with post-acute COVID-19 syndrome (PACS) 1. Murine and human studies have also reported microbial alterations associated with different PACS symptoms 2 3. With the pandemic entering its third year, PACS could potentially affect recovered individuals for over 1 year 4.…”