Faecalibacterium duncaniae as a novel next generation probiotic against influenza.

The gut-lung axis is critical during viral respiratory infections such as influenza. Gut dysbiosis during infection translates into a massive drop of microbially produced short-chain fatty acids (SCFAs). Among them, butyrate is important during influenza suggesting that microbiome-based therapeutics targeting butyrate might hold promises. The butyrate-producing bacterium Faecalibacterium duncaniae (formerly referred to as F. prausnitzii) is an emerging probiotic with several health-promoting characteristics. To investigate the potential effects of F. duncaniae on influenza outcomes, mice were gavaged with live F. duncaniae (A2-165 or I-4574 strains) five days before infection. Supplementation of F. duncaniae was associated with less severe disease, a lower pulmonary viral load, and lower levels of lung inflammation. F. duncaniae supplementation impacted on gut dysbiosis induced by infection, as assessed by 16S rRNA sequencing. Interestingly, F. duncaniae administration was associated with a recovery in levels of SCFAs (including butyrate) in infected animals. The live form of F. duncaniae was more potent that the pasteurized form in improving influenza outcomes. Lastly, F. duncaniae partially protected against secondary (systemic) bacterial infection. We conclude that F. duncaniae might serve as a novel next generation probiotic against acute viral respiratory diseases.

Shotgun metagenomics and systemic targeted metabolomics highlight indole-3-propionic acid as a protective gut microbial metabolite against influenza infection.

The gut-to-lung axis is critical during respiratory infections, including influenza A virus (IAV) infection. In the present study, we used high-resolution shotgun metagenomics and targeted metabolomic analysis to characterize influenza-associated changes in the composition and metabolism of the mouse gut microbiota. We observed several taxonomic-level changes on day (D)7 post-infection, including a marked reduction in the abundance of members of the Lactobacillaceae and Bifidobacteriaceae families, and an increase in the abundance of Akkermansia muciniphila. On D14, perturbation persisted in some species. Functional scale analysis of metagenomic data revealed transient changes in several metabolic pathways, particularly those leading to the production of short-chain fatty acids (SCFAs), polyamines, and tryptophan metabolites. Quantitative targeted metabolomics analysis of the serum revealed changes in specific classes of gut microbiota metabolites, including SCFAs, trimethylamine, polyamines, and indole-containing tryptophan metabolites. A marked decrease in indole-3-propionic acid (IPA) blood level was observed on D7. Changes in microbiota-associated metabolites correlated with changes in taxon abundance and disease marker levels. In particular, IPA was positively correlated with some Lactobacillaceae and Bifidobacteriaceae species (Limosilactobacillus reuteri, Lactobacillus animalis) and negatively correlated with Bacteroidales bacterium M7, viral load, and inflammation markers. IPA supplementation in diseased animals reduced viral load and lowered local (lung) and systemic inflammation. Treatment of mice with antibiotics targeting IPA-producing bacteria before infection enhanced viral load and lung inflammation, an effect inhibited by IPA supplementation. The results of this integrated metagenomic-metabolomic analysis highlighted IPA as an important contributor to influenza outcomes and a potential biomarker of disease severity.

Removal of senescent cells reduces the viral load and attenuates pulmonary and systemic inflammation in SARS-CoV-2-infected, aged hamsters.

Older age is one of the strongest risk factors for severe COVID-19. In this study, we determined whether age-associated cellular senescence contributes to the severity of experimental COVID-19. Aged golden hamsters accumulate senescent cells in the lungs, and the senolytic drug ABT-263, a BCL-2 inhibitor, depletes these cells at baseline and during SARS-CoV-2 infection. Relative to young hamsters, aged hamsters had a greater viral load during the acute phase of infection and displayed higher levels of sequelae during the post-acute phase. Early treatment with ABT-263 lowered pulmonary viral load in aged (but not young) animals, an effect associated with lower expression of ACE2, the receptor for SARS-CoV-2. ABT-263 treatment also led to lower pulmonary and systemic levels of senescence-associated secretory phenotype factors and to amelioration of early and late lung disease. These data demonstrate the causative role of age-associated pre-existing senescent cells on COVID-19 severity and have clear clinical relevance.

A druggable copper-signalling pathway that drives inflammation.

Inflammation is a complex physiological process triggered in response to harmful stimuli1. It involves cells of the immune system capable of clearing sources of injury and damaged tissues. Excessive inflammation can occur as a result of infection and is a hallmark of several diseases2-4. The molecular bases underlying inflammatory responses are not fully understood. Here we show that the cell surface glycoprotein CD44, which marks the acquisition of distinct cell phenotypes in the context of development, immunity and cancer progression, mediates the uptake of metals including copper. We identify a pool of chemically reactive copper(II) in mitochondria of inflammatory macrophages that catalyses NAD(H) redox cycling by activating hydrogen peroxide. Maintenance of NAD+ enables metabolic and epigenetic programming towards the inflammatory state. Targeting mitochondrial copper(II) with supformin (LCC-12), a rationally designed dimer of metformin, induces a reduction of the NAD(H) pool, leading to metabolic and epigenetic states that oppose macrophage activation. LCC-12 interferes with cell plasticity in other settings and reduces inflammation in mouse models of bacterial and viral infections. Our work highlights the central role of copper as a regulator of cell plasticity and unveils a therapeutic strategy based on metabolic reprogramming and the control of epigenetic cell states.

Tirap controls Mycobacterium tuberculosis phagosomal acidification.

Progression of tuberculosis is tightly linked to a disordered immune balance, resulting in inability of the host to restrict intracellular bacterial replication and its subsequent dissemination. The immune response is mainly characterized by an orchestrated recruitment of inflammatory cells secreting cytokines. This response results from the activation of innate immunity receptors that trigger downstream intracellular signaling pathways involving adaptor proteins such as the TIR-containing adaptor protein (Tirap). In humans, resistance to tuberculosis is associated with a loss-of-function in Tirap. Here, we explore how genetic deficiency in Tirap impacts resistance to Mycobacterium tuberculosis (Mtb) infection in a mouse model and ex vivo. Interestingly, compared to wild type littermates, Tirap heterozygous mice were more resistant to Mtb infection. Upon investigation at the cellular level, we observed that mycobacteria were not able to replicate in Tirap-deficient macrophages compared to wild type counterparts. We next showed that Mtb infection induced Tirap expression which prevented phagosomal acidification and rupture. We further demonstrate that the Tirap-mediated anti-tuberculosis effect occurs through a Cish-dependent signaling pathway. Our findings provide new molecular evidence about how Mtb manipulates innate immune signaling to enable intracellular replication and survival of the pathogen, thus paving the way for host-directed approaches to treat tuberculosis.

SARS-CoV-2 infection induces persistent adipose tissue damage in aged golden Syrian hamsters.

Coronavirus disease 2019 (COVID-19, caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2)) is primarily a respiratory illness. However, various extrapulmonary manifestations have been reported in patients with severe forms of COVID-19. Notably, SARS-CoV-2 was shown to directly trigger white adipose tissue (WAT) dysfunction, which in turn drives insulin resistance, dyslipidemia, and other adverse outcomes in patients with COVID-19. Although advanced age is the greatest risk factor for COVID-19 severity, published data on the impact of SARS-CoV-2 infection on WAT in aged individuals are scarce. Here, we characterized the response of subcutaneous and visceral WAT depots to SARS-CoV-2 infection in young adult and aged golden hamsters. In both age groups, infection was associated with a decrease in adipocyte size in the two WAT depots; this effect was partly due to changes in tissue's lipid metabolism and persisted for longer in aged hamsters than in young-adult hamsters. In contrast, only the subcutaneous WAT depot contained crown-like structures (CLSs) in which dead adipocytes were surrounded by SARS-CoV-2-infected macrophages, some of them forming syncytial multinucleated cells. Importantly, older age predisposed to a unique manifestation of viral disease in the subcutaneous WAT depot during SARS-CoV-2 infection; the persistence of very large CLSs was indicative of an age-associated defect in the clearance of dead adipocytes by macrophages. Moreover, we uncovered age-related differences in plasma lipid profiles during SARS-CoV-2 infection. These data suggest that the WAT's abnormal response to SARS-CoV-2 infection may contribute to the greater severity of COVID-19 observed in elderly patients.

Diet-Induced Obesity and NASH Impair Disease Recovery in SARS-CoV-2-Infected Golden Hamsters.

Obese patients with non-alcoholic steatohepatitis (NASH) are prone to severe forms of COVID-19. There is an urgent need for new treatments that lower the severity of COVID-19 in this vulnerable population. To better replicate the human context, we set up a diet-induced model of obesity associated with dyslipidemia and NASH in the golden hamster (known to be a relevant preclinical model of COVID-19). A 20-week, free-choice diet induces obesity, dyslipidemia, and NASH (liver inflammation and fibrosis) in golden hamsters. Obese NASH hamsters have higher blood and pulmonary levels of inflammatory cytokines. In the early stages of a SARS-CoV-2 infection, the lung viral load and inflammation levels were similar in lean hamsters and obese NASH hamsters. However, obese NASH hamsters showed worse recovery (i.e., less resolution of lung inflammation 10 days post-infection (dpi) and lower body weight recovery on dpi 25). Obese NASH hamsters also exhibited higher levels of pulmonary fibrosis on dpi 25. Unlike lean animals, obese NASH hamsters infected with SARS-CoV-2 presented long-lasting dyslipidemia and systemic inflammation. Relative to lean controls, obese NASH hamsters had lower serum levels of angiotensin-converting enzyme 2 activity and higher serum levels of angiotensin II-a component known to favor inflammation and fibrosis. Even though the SARS-CoV-2 infection resulted in early weight loss and incomplete body weight recovery, obese NASH hamsters showed sustained liver steatosis, inflammation, hepatocyte ballooning, and marked liver fibrosis on dpi 25. We conclude that diet-induced obesity and NASH impair disease recovery in SARS-CoV-2-infected hamsters. This model might be of value for characterizing the pathophysiologic mechanisms of COVID-19 and evaluating the efficacy of treatments for the severe forms of COVID-19 observed in obese patients with NASH.

Alteration of the gut microbiota's composition and metabolic output correlates with COVID-19-like severity in obese NASH hamsters.

Obese patientss with nonalcoholic steatohepatitis (NASH) are particularly prone to developing severe forms of coronavirus disease 19 (COVID-19). The gut-to-lung axis is critical during viral infections of the respiratory tract, and a change in the gut microbiota's composition might have a critical role in disease severity. Here, we investigated the consequences of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on the gut microbiota in the context of obesity and NASH. To this end, we set up a nutritional model of obesity with dyslipidemia and NASH in the golden hamster, a relevant preclinical model of COVID-19. Relative to lean non-NASH controls, obese NASH hamsters develop severe inflammation of the lungs and liver. 16S rRNA gene profiling showed that depending on the diet, SARS-CoV-2 infection induced various changes in the gut microbiota's composition. Changes were more prominent and transient at day 4 post-infection in lean animals, alterations still persisted at day 10 in obese NASH animals. A targeted, quantitative metabolomic analysis revealed changes in the gut microbiota's metabolic output, some of which were diet-specific and regulated over time. Our results showed that specifically diet-associated taxa are correlated with disease parameters. Correlations between infection variables and diet-associated taxa highlighted a number of potentially protective or harmful bacteria in SARS-CoV-2-infected hamsters. In particular, some taxa in obese NASH hamsters (e.g. Blautia and Peptococcus) were associated with pro-inflammatory parameters in both the lungs and the liver. These taxon profiles and their association with specific disease markers suggest that microbial patterns might influence COVID-19 outcomes.

Interaction between Bacteria and the Immune System for Cancer Immunotherapy: The α-GalCer Alliance.

Non-conventional T cells, such as γδ T and invariant natural killer T (iNKT) cells, are emerging players in fighting cancer. Alpha-galactosylceramide (α-GalCer) is used as an exogenous ligand to activate iNKT cells. Human cells don't have a direct pathway producing α-GalCer, which, however, can be produced by bacteria. We searched the literature for bacteria strains that are able to produce α-GalCer and used available sequencing data to analyze their presence in human tumor tissues and their association with survival. The modulatory effect of antibiotics on the concentration of α-GalCer was analyzed in mice. The human gut bacteria Bacteroides fragilis, Bacteroides vulgatus, and Prevotella copri produce α-GalCer structures that are able to activate iNKT cells. In mice, α-GalCer was depleted upon treatment with vancomycin. The three species were detected in colon adenocarcinoma (COAD) and rectum adenocarcinoma tissues, and Prevotella copri was also detected in bone tumors and glioblastoma tissues. Bacteroides vulgatus in COAD tissues correlated with better survival. In conclusion, α-GalCer-producing bacteria are part of the human gut microbiome and can infiltrate tumor tissues. These results suggest a new mechanism of interaction between bacteria and immune cells: α-GalCer produced by bacteria may activate non-conventional T cells in tumor tissues, where they can exert a direct or indirect anti-tumor activity.

C910 chemical compound inhibits the traffiking of several bacterial AB toxins with cross-protection against influenza virus.

The development of anti-infectives against a large range of AB-like toxin-producing bacteria includes the identification of compounds disrupting toxin transport through both the endolysosomal and retrograde pathways. Here, we performed a high-throughput screening of compounds blocking Rac1 proteasomal degradation triggered by the Cytotoxic Necrotizing Factor-1 (CNF1) toxin, which was followed by orthogonal screens against two toxins that hijack the endolysosomal (diphtheria toxin) or retrograde (Shiga-like toxin 1) pathways to intoxicate cells. This led to the identification of the molecule C910 that induces the enlargement of EEA1-positive early endosomes associated with sorting defects of CNF1 and Shiga toxins to their trafficking pathways. C910 protects cells against eight bacterial AB toxins and the CNF1-mediated pathogenic Escherichia coli invasion. Interestingly, C910 reduces influenza A H1N1 and SARS-CoV-2 viral infection in vitro. Moreover, parenteral administration of C910 to mice resulted in its accumulation in lung tissues and a reduction in lethal influenza infection.

Clofoctol inhibits SARS-CoV-2 replication and reduces lung pathology in mice.

Drug repurposing has the advantage of shortening regulatory preclinical development steps. Here, we screened a library of drug compounds, already registered in one or several geographical areas, to identify those exhibiting antiviral activity against SARS-CoV-2 with relevant potency. Of the 1,942 compounds tested, 21 exhibited a substantial antiviral activity in Vero-81 cells. Among them, clofoctol, an antibacterial drug used for the treatment of bacterial respiratory tract infections, was further investigated due to its favorable safety profile and pharmacokinetic properties. Notably, the peak concentration of clofoctol that can be achieved in human lungs is more than 20 times higher than its IC50 measured against SARS-CoV-2 in human pulmonary cells. This compound inhibits SARS-CoV-2 at a post-entry step. Lastly, therapeutic treatment of human ACE2 receptor transgenic mice decreased viral load, reduced inflammatory gene expression and lowered pulmonary pathology. Altogether, these data strongly support clofoctol as a therapeutic candidate for the treatment of COVID-19 patients.

Description of a Newly Isolated Blautia faecis Strain and Its Benefit in Mouse Models of Post-Influenza Secondary Enteric and Pulmonary Infections.

The expanding knowledge on the systemic influence of the human microbiome suggests that fecal samples are underexploited sources of new beneficial strains for extra-intestinal health. We have recently shown that acetate, a main circulating microbiota-derived molecule, reduces the deleterious effects of pulmonary Streptococcus pneumoniae and enteric Salmonella enterica serovar Typhimurium bacterial post-influenza superinfections. Considering the beneficial and broad effects of acetate, we intended to isolate a commensal strain, producing acetate and potentially exploitable in the context of respiratory infections. We designed successive steps to select intestinal commensals that are extremely oxygen-sensitive, cultivable after a freezing process, without a proinflammatory effect on IL-8 induction, and producing acetate. We have identified the Blautia faecis DSM33383 strain, which decreased the TNFα-induced production of IL-8 by the intestinal epithelial cell line HT-29. The beneficial effect of this bacterial strain was further studied in two preclinical models of post-influenza Streptococcus pneumoniae (S.p) and Salmonella enterica serovar Typhimurium (S.t) superinfection. The intragastrical administration of Blautia faecis DSM33383 led to protection in influenza-infected mice suffering from an S.p. and, to a lesser extent, from an S.t secondary infection. Altogether, this study showed that Blautia faecis DSM33383 could be a promising candidate for preventive management of respiratory infectious diseases.

Acetate Improves the Killing of Streptococcus pneumoniae by Alveolar Macrophages via NLRP3 Inflammasome and Glycolysis-HIF-1α Axis.

Short-chain fatty acids (SCFAs) are metabolites produced mainly by the gut microbiota with a known role in immune regulation. Acetate, the major SCFA, is described to disseminate to distal organs such as lungs where it can arm sentinel cells, including alveolar macrophages, to fight against bacterial intruders. In the current study, we explored mechanisms through which acetate boosts macrophages to enhance their bactericidal activity. RNA sequencing analyses show that acetate triggers a transcriptomic program in macrophages evoking changes in metabolic process and immune effector outputs, including nitric oxide (NO) production. In addition, acetate enhances the killing activity of macrophages towards Streptococcus pneumoniae in an NO-dependent manner. Mechanistically, acetate improves IL-1ß production by bacteria-conditioned macrophages and the latter acts in an autocrine manner to promote NO production. Strikingly, acetate-triggered IL-1ß production was neither dependent of its cell surface receptor free-fatty acid receptor 2, nor of the enzymes responsible for its metabolism, namely acetyl-CoA synthetases 1 and 2. We found that IL-1ß production by acetate relies on NLRP3 inflammasome and activation of HIF-1α, the latter being triggered by enhanced glycolysis. In conclusion, we unravel a new mechanism through which acetate reinforces the bactericidal activity of alveolar macrophages.

Alteration of the gut microbiota following SARS-CoV-2 infection correlates with disease severity in hamsters.

Mounting evidence suggests that the gut-to-lung axis is critical during respiratory viral infections. We herein hypothesized that disruption of gut homeostasis during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may associate with early disease outcomes. To address this question, we took advantage of the Syrian hamster model. Our data confirmed that this model recapitulates some hallmark features of the human disease in the lungs. We further showed that SARS-CoV-2 infection associated with mild intestinal inflammation, relative alteration in intestinal barrier property and liver inflammation and altered lipid metabolism. These changes occurred concomitantly with an alteration of the gut microbiota composition over the course of infection, notably characterized by a higher relative abundance of deleterious bacterial taxa such as Enterobacteriaceae and Desulfovibrionaceae. Conversely, several members of the Ruminococcaceae and Lachnospiraceae families, including bacteria known to produce the fermentative products short-chain fatty acids (SCFAs), had a reduced relative proportion compared to non-infected controls. Accordingly, infection led to a transient decrease in systemic SCFA amounts. SCFA supplementation during infection had no effect on clinical and inflammatory parameters. Lastly, a strong correlation between some gut microbiota taxa and clinical and inflammation indices of SARS-CoV-2 infection severity was evidenced. Collectively, alteration of the gut microbiota correlates with disease severity in hamsters making this experimental model valuable for the design of interventional, gut microbiota-targeted, approaches for the control of COVID-19.Abbreviations: SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; COVID-19, coronavirus disease 2019; SCFAs, short-chain fatty acids; dpi, day post-infection; RT-PCR, reverse transcription polymerase chain reaction; IL, interleukin. ACE2, angiotensin converting enzyme 2; TMPRSS2, transmembrane serine protease 2.

A Photoactivable Natural Product with Broad Antiviral Activity against Enveloped Viruses, Including Highly Pathogenic Coronaviruses.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak has highlighted the need for broad-spectrum antivirals against coronaviruses (CoVs). Here, pheophorbide a (Pba) was identified as a highly active antiviral molecule against human CoV-229E after bioguided fractionation of plant extracts. The antiviral activity of Pba was subsequently shown for SARS-CoV-2 and Middle East respiratory syndrome coronavirus (MERS-CoV), and its mechanism of action was further assessed, showing that Pba is an inhibitor of coronavirus entry by directly targeting the viral particle. Interestingly, the antiviral activity of Pba depends on light exposure, and Pba was shown to inhibit virus-cell fusion by stiffening the viral membrane, as demonstrated by cryoelectron microscopy. Moreover, Pba was shown to be broadly active against several other enveloped viruses and reduced SARS-CoV-2 and MERS-CoV replication in primary human bronchial epithelial cells. Pba is the first described natural antiviral against SARS-CoV-2 with direct photosensitive virucidal activity that holds potential for COVID-19 therapy or disinfection of SARS-CoV-2-contaminated surfaces.

The SARS-CoV-2 main protease Mpro causes microvascular brain pathology by cleaving NEMO in brain endothelial cells.

Coronavirus disease 2019 (COVID-19) can damage cerebral small vessels and cause neurological symptoms. Here we describe structural changes in cerebral small vessels of patients with COVID-19 and elucidate potential mechanisms underlying the vascular pathology. In brains of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected individuals and animal models, we found an increased number of empty basement membrane tubes, so-called string vessels representing remnants of lost capillaries. We obtained evidence that brain endothelial cells are infected and that the main protease of SARS-CoV-2 (Mpro) cleaves NEMO, the essential modulator of nuclear factor-κB. By ablating NEMO, Mpro induces the death of human brain endothelial cells and the occurrence of string vessels in mice. Deletion of receptor-interacting protein kinase (RIPK) 3, a mediator of regulated cell death, blocks the vessel rarefaction and disruption of the blood-brain barrier due to NEMO ablation. Importantly, a pharmacological inhibitor of RIPK signaling prevented the Mpro-induced microvascular pathology. Our data suggest RIPK as a potential therapeutic target to treat the neuropathology of COVID-19.

Short-Chain Fatty Acids as a Potential Treatment for Infections: a Closer Look at the Lungs.

Short-chain fatty acids (SCFAs) are the main metabolites produced by the gut microbiota via the fermentation of complex carbohydrates and fibers. Evidence suggests that SCFAs play a role in the control of infections through direct action both on microorganisms and on host signaling. This review summarizes the main microbicidal effects of SCFAs and discusses studies highlighting the effect of SCFAs in the virulence and viability of microorganisms. We also describe the diverse and complex modes of action of the SCFAs on the immune system in the face of infections with a specific focus on bacterial and viral respiratory infections. A growing body of evidence suggests that SCFAs protect against lung infections. Finally, we present potential strategies that may be leveraged to exploit the biological properties of SCFAs for increasing effectiveness and optimizing patient benefits.

Influenza Virus Infection Impairs the Gut's Barrier Properties and Favors Secondary Enteric Bacterial Infection through Reduced Production of Short-Chain Fatty Acids.

Along with respiratory tract disease per se, viral respiratory infections can also cause extrapulmonary complications with a potentially critical impact on health. In the present study, we used an experimental model of influenza A virus (IAV) infection to investigate the nature and outcome of the associated gut disorders. In IAV-infected mice, the signs of intestinal injury and inflammation, altered gene expression, and compromised intestinal barrier functions peaked on day 7 postinfection. As a likely result of bacterial component translocation, gene expression of inflammatory markers was upregulated in the liver. These changes occurred concomitantly with an alteration of the composition of the gut microbiota and with a decreased production of the fermentative, gut microbiota-derived products short-chain fatty acids (SCFAs). Gut inflammation and barrier dysfunction during influenza were not attributed to reduced food consumption, which caused in part gut dysbiosis. Treatment of IAV-infected mice with SCFAs was associated with an enhancement of intestinal barrier properties, as assessed by a reduction in the translocation of dextran and a decrease in inflammatory gene expression in the liver. Lastly, SCFA supplementation during influenza tended to reduce the translocation of the enteric pathogen Salmonella enterica serovar Typhimurium and to enhance the survival of doubly infected animals. Collectively, influenza virus infection can remotely impair the gut's barrier properties and trigger secondary enteric infections. The latter phenomenon can be partially countered by SCFA supplementation.

SARS-CoV-2 infection in nonhuman primates alters the composition and functional activity of the gut microbiota.

The current pandemic of coronavirus disease (COVID) 2019 constitutes a global public health issue. Regarding the emerging importance of the gut-lung axis in viral respiratory infections, analysis of the gut microbiota's composition and functional activity during a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection might be instrumental in understanding and controling COVID 19. We used a nonhuman primate model (the macaque), that recapitulates mild COVID-19 symptoms, to analyze the effects of a SARS-CoV-2 infection on dynamic changes of the gut microbiota. 16S rRNA gene profiling and analysis of ß diversity indicated significant changes in the composition of the gut microbiota with a peak at 10-13 days post-infection (dpi). Analysis of bacterial abundance correlation networks confirmed disruption of the bacterial community at 10-13 dpi. Some alterations in microbiota persisted after the resolution of the infection until day 26. Some changes in the relative bacterial taxon abundance associated with infectious parameters. Interestingly, the relative abundance of Acinetobacter (Proteobacteria) and some genera of the Ruminococcaceae family (Firmicutes) was positively correlated with the presence of SARS-CoV-2 in the upper respiratory tract. Targeted quantitative metabolomics indicated a drop in short-chain fatty acids (SCFAs) and changes in several bile acids and tryptophan metabolites in infected animals. The relative abundance of several taxa known to be SCFA producers (mostly from the Ruminococcaceae family) was negatively correlated with systemic inflammatory markers while the opposite correlation was seen with several members of the genus Streptococcus. Collectively, SARS-CoV-2 infection in a nonhuman primate is associated with changes in the gut microbiota's composition and functional activity.