Targeting the Gut Microbiota in Coronavirus Disease 2019: Hype or Hope?

Abstract

Coronavirus disease 2019 (COVID-19), an acute respiratory illness caused by novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been a terrible worldwide pandemic since December 2019. As of late August 2021, over 210 million people have contracted COVID-19, with over 4.4 million deaths globally (see https://coronavirus.jhu.edu/map.html). Typical presentations of this infection include fever, cough, fatigue, pneumonia, and loss of taste or smell.1Huang C. Wang Y. Li X. Ren L. Zhao J. Hu Y. et al.Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.Lancet. 2020; 395: 497-506Abstract Full Text Full Text PDF PubMed Scopus (27668) Google Scholar Although relatively less common than respiratory symptoms, gastrointestinal symptoms including anorexia, diarrhea, vomiting, and abdominal discomfort occur in about 18% of COVID-19 patients.2Cheung K.S. Hung I.F.N. Chan P.P.Y. et al.Gastrointestinal manifestations of SARS-CoV-2 infection and virus load in fecal samples from a Hong Kong cohort: systematic review and meta-analysis.Gastroenterology. 2020; 159: 81-95Abstract Full Text Full Text PDF PubMed Scopus (929) Google Scholar Detection of virus RNA in fecal samples in up to 50% of COVID-19 patients infers the importance of gastrointestinal tract infection.2Cheung K.S. Hung I.F.N. Chan P.P.Y. et al.Gastrointestinal manifestations of SARS-CoV-2 infection and virus load in fecal samples from a Hong Kong cohort: systematic review and meta-analysis.Gastroenterology. 2020; 159: 81-95Abstract Full Text Full Text PDF PubMed Scopus (929) Google Scholar Gastrointestinal symptoms have also occurred before the appearance of respiratory conditions, thus supporting viral involvement in the gastrointestinal tract in SARS-CoV-2 infection.3Kotfis K. Skonieczna-Zydecka K. COVID-19: gastrointestinal symptoms and potential sources of SARS-CoV-2 transmission.Anaesthesiol Intensive Ther. 2020; 52: 171-172Crossref PubMed Google Scholar The human gastrointestinal tract harbors trillions of microorganisms that form an ecologic community known as gut microbiota, of which its alteration, termed “dysbiosis,” has been associated with various human diseases. Microbial diversity in fecal samples of patients with COVID-19 was found to be decreased and accompanied by enrichment of opportunistic pathogens including Clostridium hathewayi and Ruminococcus species.4Ren Z. Wang H. Cui G. et al.Alterations in the human oral and gut microbiomes and lipidomics in COVID-19.Gut. 2021; 70: 1253-1265Crossref PubMed Scopus (78) Google Scholar, 5Yeoh Y.K. Zuo T. Lui G.C. et al.Gut microbiota composition reflects disease severity and dysfunctional immune responses in patients with COVID-19.Gut. 2021; 70: 698-706Crossref PubMed Scopus (450) Google Scholar, 6Zuo T. Zhang F. Lui G.C.Y. et al.Alterations in gut microbiota of patients with COVID-19 during time of hospitalization.Gastroenterology. 2020; 159: 944-955Abstract Full Text Full Text PDF PubMed Scopus (707) Google Scholar Data from 2 studies that used metagenomic sequencing showed that several beneficial commensals such as Faecalibacterium prausnitzii and Eubacterium rectale were depleted in fecal samples of COVID-19 cases.5Yeoh Y.K. Zuo T. Lui G.C. et al.Gut microbiota composition reflects disease severity and dysfunctional immune responses in patients with COVID-19.Gut. 2021; 70: 698-706Crossref PubMed Scopus (450) Google Scholar,6Zuo T. Zhang F. Lui G.C.Y. et al.Alterations in gut microbiota of patients with COVID-19 during time of hospitalization.Gastroenterology. 2020; 159: 944-955Abstract Full Text Full Text PDF PubMed Scopus (707) Google Scholar F prausnitzii, a major producer of short-chain fatty acids (SCFAs; crucial for maintaining intestinal homeostasis) in the gut with anti-inflammatory potential due to induction of interleukin-10 production,7Alameddine J. Godefroy E. Papargyris L. et al.Faecalibacterium prausnitzii skews human DC to prime IL10-producing T cells through TLR2/6/JNK signaling and IL-10, IL-27, CD39, and IDO-1 induction.Front Immunol. 2019; 10: 143Crossref PubMed Scopus (55) Google Scholar was found to be low in abundance in feces of COVID-19 patients and had an inverse correlation with disease severity. In contrast, C hathewayi and Clostridium ramosum, both known to be associated with bacteremia and inflammation, were positively correlated with COVID-19 severity. In addition, fecal samples with high SARS-CoV-2 infectivity had a higher abundance of opportunistic pathogenic bacteria (eg, Collinsella species, Morganella morganii) and lower abundance of SCFA-producing bacteria (eg, Parabacteroides merdae, Lachnspiraceae bacterium) compared with samples with low SARS-CoV-2 viral infectivity.8Zuo T. Liu Q. Zhang F. et al.Depicting SARS-CoV-2 faecal viral activity in association with gut microbiota composition in patients with COVID-19.Gut. 2021; 70: 276-284PubMed Google Scholar Altogether these findings imply that gut dysbiosis with enrichment of pathogenic bacteria and depletion of beneficial commensals is closely related to disease severity in COVID-19. SARS-CoV-2 infection not only causes acute infection but also lingering symptoms after the acute episode. Over 80% of COVID-19 patients have persistent symptoms known as post–acute COVID-19 syndrome and/or developed multisystem inflammation after viral clearance.9Carfi A. Bernabei R. Landi F. et al.Persistent symptoms in patients after acute COVID-19.JAMA. 2020; 324: 603-605Crossref PubMed Scopus (1942) Google Scholar Multiple studies have reported a marked difference in gut microbiota between recovered patients and healthy adults, and dysbiosis can persist up to 30 days after disease resolution.5Yeoh Y.K. Zuo T. Lui G.C. et al.Gut microbiota composition reflects disease severity and dysfunctional immune responses in patients with COVID-19.Gut. 2021; 70: 698-706Crossref PubMed Scopus (450) Google Scholar,6Zuo T. Zhang F. Lui G.C.Y. et al.Alterations in gut microbiota of patients with COVID-19 during time of hospitalization.Gastroenterology. 2020; 159: 944-955Abstract Full Text Full Text PDF PubMed Scopus (707) Google Scholar Infectious bacteria such as Bifidobacterium dentium and Klebsiella pneumoniae were enriched in recovered patients, whereas Bacteroides species including Bacteroides dorei, Bacteroides thetaiotaomicron, and Bacteroides massiliensis as well as the anti-inflammatory F prausnitzii were depleted.4Ren Z. Wang H. Cui G. et al.Alterations in the human oral and gut microbiomes and lipidomics in COVID-19.Gut. 2021; 70: 1253-1265Crossref PubMed Scopus (78) Google Scholar,6Zuo T. Zhang F. Lui G.C.Y. et al.Alterations in gut microbiota of patients with COVID-19 during time of hospitalization.Gastroenterology. 2020; 159: 944-955Abstract Full Text Full Text PDF PubMed Scopus (707) Google Scholar,8Zuo T. Liu Q. Zhang F. et al.Depicting SARS-CoV-2 faecal viral activity in association with gut microbiota composition in patients with COVID-19.Gut. 2021; 70: 276-284PubMed Google Scholar Prolonged dysbiosis in COVID-19 patients despite viral clearance may contribute to persistent illness of which secondary invasion of bacterial pathogens and reduction of beneficial commensals may become paramount for complete disease resolution. In SARS-CoV-2 infection, pathogenesis begins with interactions between SARS-CoV-2 and the viral entry receptor, angiotensin-converting enzyme (ACE)-2. ACE-2, a membrane-bound protein highly expressed in gut enterocytes, works with its countering opponent, ACE, to maintain balance of the renin-angiotensin system (RAS; mediator of fluid and electrolyte balance). ACE-2 is also a key regulator of dietary amino acid homeostasis, microbial ecology, and innate immunity.10Hashimoto T. Perlot T. Rehman A. et al.ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation.Nature. 2012; 487: 477-481Crossref PubMed Scopus (812) Google Scholar ACE-2 can be hijacked as a receptor for SARS-CoV-2 to undergo replication for promoting viral infection.11Shang J. Ye G. Shi K. Wan Y. et al.Structural basis of receptor recognition by SARS-CoV–2.Nature. 2020; 581: 221-224Crossref PubMed Scopus (2128) Google Scholar, 12Lamers M.M. Beumer J. van der Vaart J. et al.SARS-CoV-2 productively infects human gut enterocytes.Science. 2020; 369: 50-54Crossref PubMed Scopus (939) Google Scholar, 13Zhou J. Li C. Liu X. et al.Infection of bat and human intestinal organoids by SARS-CoV–2.Nat Med. 2020; 26: 1077-1083Crossref PubMed Scopus (313) Google Scholar, 14Zang R. Gomez Castro M.F. McCune B.T. et al.TMPRSS2 and TMPRSS4 promote SARS-CoV-2 infection of human small intestinal enterocytes.Sci Immunol. 2020; 5: eabc3582Crossref PubMed Scopus (562) Google Scholar This viral-mediated reduction of ACE-2 leads to accumulation of its ligand angiotensin II and RAS imbalance, resulting in enhanced intestinal permeability and leaky gut syndrome.15Penninger J.M. Grant M.B. Sung J.J.Y. The role of angiotensin converting enzyme 2 in modulating gut microbiota, intestinal inflammation, and coronavirus infection.Gastroenterology. 2021; 160: 39-46Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar With a disrupted gut barrier, bacteria and endotoxins (eg, lipopolysaccharides) can enter the systemic circulation and contribute to the exaggerated production of cytokines and eventually trigger endotoxemia and inflammation. Both F prausnitzii and E rectale were found to be negatively associated with the proinflammatory cytokines C-X-C motif chemokine ligand 10 (CXCL10) and tumor necrosis factor-α,5Yeoh Y.K. Zuo T. Lui G.C. et al.Gut microbiota composition reflects disease severity and dysfunctional immune responses in patients with COVID-19.Gut. 2021; 70: 698-706Crossref PubMed Scopus (450) Google Scholar thus implicating their anti-inflammatory potential against SARS-CoV-2 infection. Interestingly, new evidence reported that SARS-CoV-2 infection could reduce local inflammation in the gut, whereas hospitalized COVID-19 patients presenting with gastrointestinal symptoms benefited from significant reduction in disease severity.16Livanos A.E. Jha D. Cossarini F. Gonzalez-Reiche A.S. Tokuyama M. Aydillo T. Parigi T.L. et al.Intestinal host response to SARS-CoV-2 infection and COVID-19 outcomes in patients with gastrointestinal symptoms.Gastroenterology. 2021; 160: 2435-2450Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar These findings therefore implicate the potential of the gastrointestinal tract and gut microbiota in attenuating symptoms of COVID-19. SARS-CoV-2 infection can also alter the profile of gut metabolites (intermediate or end products of microbial metabolism). For instance, an inducer of oxidative DNA damage and cytokine production guanosine and its derivatives 8-hydroxydeoxyguanosine were reported to be enriched in COVID-19 patients.8Zuo T. Liu Q. Zhang F. et al.Depicting SARS-CoV-2 faecal viral activity in association with gut microbiota composition in patients with COVID-19.Gut. 2021; 70: 276-284PubMed Google Scholar Glycolysis and its intermediate product L-serine were found to be increased in patients’ samples, of which pathogenic bacteria could catabolize L-serine to confer a growth advantage against other bacterial competitors in the inflamed gut.17Kitamoto S. Alteri C.J. Rodrigues M. et al.Dietary L-serine confers a competitive fitness advantage to Enterobacteriaceae in the inflamed gut.Nat Microbiol. 2020; 5: 116-125Crossref PubMed Scopus (49) Google Scholar Moreover, depletion of SCFA-producing bacteria, especially F prausnitzii, after viral infection led to decreased synthesis of anti-inflammatory SCFAs. Collectively, SARS-CoV-2 invades gut enterocytes through ACE-2 and causes alterations in gut microbiota and their metabolites, impaired barrier function, and bacterial translocation into the circulation, leading to aggravated systemic inflammation and multiple-organ involvement (Figure 1). Dietary nutrients are a convenient and safe way to prevent disease and reduce disease severity. In SARS-CoV-2 infection, excessive production of proinflammatory cytokines and acute inflammation occurred; hence, intake of nutrients with anti-inflammatory and antioxidant effects may be beneficial in COVID-19 patients. These dietary components involve omega-3 polyunsaturated fatty acids, vitamins, zinc, plant-based polyphenols (eg, flavonoids and phenolic acids), polysaccharides, and a panoply of herbs from traditional Chinese medicine.18Iddir M. Brito A. Dingeo G. et al.Strengthening the immune system and reducing inflammation and oxidative stress through diet and nutrition: considerations during the COVID-19 crisis.Nutrients. 2020; : 12Google Scholar Dietary fiber is protective against gut barrier disruption and can restrict bacterial translocation into the systemic circulation, whereas a high fat and protein diet are correlated with mucosal barrier dysfunction.19Camilleri M. Lyle B.J. Madsen K.L. et al.Role for diet in normal gut barrier function: developing guidance within the framework of food-labeling regulations.Am J Physiol Gastrointest Liver Physiol. 2019; 317: G17-G39Crossref PubMed Scopus (40) Google Scholar A multicenter retrospective study with over 7300 subjects found that outcomes of patients with COVID-19 with pre-existing type 2 diabetes, who are known to have a high mortality rate, can be improved by well-controlled blood glucose.20Zhu L. She Z.G. Cheng X. et al.Association of blood glucose control and outcomes in patients with COVID-19 and pre-existing type 2 diabetes.Cell Metab. 2020; 31: 1068-1077Abstract Full Text Full Text PDF PubMed Scopus (902) Google Scholar These data highlight the feasibility of a low glycemic index diet with green vegetables and fruits to improve outcome in hospitalized patients. Through appropriate dietary intervention, COVID-19 patients can potentially benefit from strengthened immunity and reduced inflammation and oxidative stress, thus alleviating disease severity and speeding recovery. Specific dietary components can serve as prebiotics (a group of dietary fibers including fructans and galactans that can only be digested by gut microbes but not the host) to stimulate an abundance of probiotics. For instance, plant-based fiber can promote the growth of the probiotics Lactobacillus and Bifidobacterium and reduce opportunistic pathogenic bacteria (eg, Clostridium).18Iddir M. Brito A. Dingeo G. et al.Strengthening the immune system and reducing inflammation and oxidative stress through diet and nutrition: considerations during the COVID-19 crisis.Nutrients. 2020; : 12Google Scholar These prebiotic fibers are degraded by gut microbes to generate SCFAs (eg, acetate, propionate, and butyrate) as end products. SCFAs are immunomodulatory metabolites capable of enhancing effector activities of B cells and CD8+ T cells21Trompette A. Gollwitzer E.S. Pattaroni C. et al.Dietary fiber confers protection against flu by shaping Ly6c(-) patrolling monocyte hematopoiesis and CD8(+) T cell metabolism.Immunity. 2018; 48: 992-1005Abstract Full Text Full Text PDF PubMed Scopus (309) Google Scholar and producing anti-inflammatory cytokines.7Alameddine J. Godefroy E. Papargyris L. et al.Faecalibacterium prausnitzii skews human DC to prime IL10-producing T cells through TLR2/6/JNK signaling and IL-10, IL-27, CD39, and IDO-1 induction.Front Immunol. 2019; 10: 143Crossref PubMed Scopus (55) Google Scholar Dietary prebiotics serve as an effective means to stimulate SCFA synthesis through promoting growth of SCFA-producing bacteria. F prausnitzii is a key producer of SCFAs but is consistently depleted in COVID-19 patients.5Yeoh Y.K. Zuo T. Lui G.C. et al.Gut microbiota composition reflects disease severity and dysfunctional immune responses in patients with COVID-19.Gut. 2021; 70: 698-706Crossref PubMed Scopus (450) Google Scholar,6Zuo T. Zhang F. Lui G.C.Y. et al.Alterations in gut microbiota of patients with COVID-19 during time of hospitalization.Gastroenterology. 2020; 159: 944-955Abstract Full Text Full Text PDF PubMed Scopus (707) Google Scholar To restore its abundance, different nutrients derived from plant-based fiber can stimulate the growth of F prausnitzii,22Benus R.F. van der Werf T.S. Welling G.W. et al.Association between Faecalibacterium prausnitzii and dietary fibre in colonic fermentation in healthy human subjects.Br J Nutr. 2010; 104: 693-700Crossref PubMed Scopus (126) Google Scholar thereby rebalancing gut microbiota and dysregulated metabolites in the gut. There is a lack of dietary interventional studies in COVID-19, and it is likely that it may act as an adjunct to current therapeutics. Substantial interest has emerged to develop therapeutic strategies against COVID-19 by modulating gut microbiota. Administration of probiotics, particularly Lactobacillus or Bifidobacterium, has long been associated with health benefits such as improvement of immunity and restoration of microbial balance. For example, commercially used probiotics Lactobacillus rhamnosus enhanced the T cell–mediated immune response in pneumococcal-infected mice23Barbieri N. Herrera M. Salva S. et al.Lactobacillus rhamnosus CRL1505 nasal administration improves recovery of T-cell mediated immunity against pneumococcal infection in malnourished mice.Benef Microbes. 2017; 8: 393-405Crossref PubMed Scopus (20) Google Scholar and alleviated symptoms of acute respiratory infection in children.24Laursen R.P. Hojsak I. Probiotics for respiratory tract infections in children attending day care centers—a systematic review.Eur J Pediatr. 2018; 177: 979-994Crossref PubMed Scopus (47) Google Scholar Although no published studies have reported the efficacy of probiotics for COVID-19 management, several clinical trials using a single strain or a cocktail of probiotics to reduce COVID-19 severity and/or improve treatment efficacy are in progress (Table 1). Results of an open-label pilot study (NCT04950803) showed that 4-week oral supplementation of a probiotic formula (S1M01; GenieBiome, Hong Kong; a probiotic blend of 3 Bifidobacterium) targeted to replenish bacteria species known to be depleted in COVID-19 subjects hastened recovery, enhanced immunity, and suppressed serum proinflammatory cytokines in hospitalized patients. Enrichment of beneficial bacteria in feces of patients receiving the formula were seen at 5 weeks after therapy that was not seen in the standard arm group.25Zhang LXZ, Mak JWY, Chan FKL, et al. SIM01 as a novel microbiome replacement therapy for COVID-19: an open-label pilot study. Asian Pacific Digestive Week 2021. Virtual, Asian Pacific Digestive Week Federation, August 19–22, 2021. 2021:PP–0464.Google ScholarTable 1Ongoing Clinical Studies of Gut Microbiota Regarding COVID-19aThe search was conducted on clinicaltrials.gov in July 2021. Completed, not yet recruiting, suspended, or terminated trials were excluded.Study typeTrial identification and phasebUS Food and Drug Administration definitions of clinical trial phases were used.Main aimCountryEstimated participantsObservationalNCT04770649Phase: N/AInfluence of microbiota and its function on immune system and efficacy of COVID-19 vaccineUnited States10,000ObservationalNCT04359836Phase: N/AChange in faecal microbiota of COVID-19 patientsUnited States250ObservationalNCT04980560Phase: N/AMicrobiota difference among subjects receiving different COVID-19 vaccines and recovered patientsHong Kong200ObservationalNCT04669938Phase: N/AMicrobiota of COVID-19 patients in ICU for outcome prediction of disease severityFrance200ObservationalNCT04447144Phase: N/AInfluence of dietary habits on outcomes of COVID-19 patientsEgypt200ObservationalNCT04497402Phase: N/ASex difference in microbiota of COVID-19 patientsItaly88InterventionalNCT04366089Phase: IIEfficacy of an ozone therapy-based intervention with a probiotic mixture (SivoMixxcProbiotics in SivoMixx are Streptococcus thermophiles (DSM322245), Bifidobacterium lactis (DSM 32246), Bifidobacterium lactis (DSM 32247), Lactobacillus acidophilus (DSM 32241), Lactobacillus helveticus (DSM 32242), Lactobacillus paracasei (DSM 32243), Lactobacillus plantarum (DSM 32244), and Lactobacillus brevis (DSM 2796).) in COVID-19 patients and preventing the need for ICU hospitalizationDose: 500 g azithromycin + 2 × 109 CFU SivoMixxcProbiotics in SivoMixx are Streptococcus thermophiles (DSM322245), Bifidobacterium lactis (DSM 32246), Bifidobacterium lactis (DSM 32247), Lactobacillus acidophilus (DSM 32241), Lactobacillus helveticus (DSM 32242), Lactobacillus paracasei (DSM 32243), Lactobacillus plantarum (DSM 32244), and Lactobacillus brevis (DSM 2796). daily for 21 daysItaly152InterventionalNCT04540406Phase: IIEfficacy of a botanical-based fixed-combination drug NBT-NM108 in early-stage suspected or confirmed symptomatic COVID-19 patientsDose: 4 times (30 g/sachet) daily for 28 daysUnited States100InterventionalNCT04941703Phase: I and IIEfficacy of combining magnesium citrate with probiotics in hospitalized COVID-19 patientsDose: 296 mL magnesium citrate + probiotics twice daily for 6 days or until dischargeUnited States30InterventionalNCT04884776Phase: N/AEfficacy of a microbiome immunity formula to improve immune functions, reduce adverse events associated with COVID-19 vaccinations, and reduce hospitalization in vulnerable subjects (patients with underlying type 2 diabetes mellitus and the elderly)Dose: 1 × 109 CFU of 3 Bifidobacteria and 3 prebiotics twice daily for 12 weeksHong Kong484InterventionalNCT04950803Phase: N/AEfficacy of an oral microbiome immunity formula to enhance immunity and reduce long-term complications in patients recovered from COVID-19Dose: 1 × 109 CFU of 3 Bifidobacteria and 3 prebiotics daily for 3 monthsHong Kong280InterventionalNCT04730284Phase: N/AEfficacy of a synbiotic formula in hospitalized COVID-19 patientsDose: 4 g tailored-made synbiotics daily for 28 daysHong Kong20InterventionalNCT04420676Phase: N/AEfficacy of a probiotic mixture (Omni-Biotic 10 AADdProbiotics in Omni-Biotic 10 AAD include Bifidobacterium bifidum W23, Bifidobacterium lactis W51, Enterococcus faecium W54, Lactobacillus acidophilus W37, Lactobacillus acidophilus W55, Lactobacillus paracasei W20, Lactobacillus plantarum W1, Lactobacillus plantarum W62, Lactobacillus rhamnosus W71, and Lactobacillus salivarius W24.) to improve gastrointestinal symptoms of COVID-19 and disease severityDose: Omni-Biotic 10 AAD (Institut AllergoSan, Graz, Austria) twice daily for 30 daysAustria120InterventionalNCT04813718Phase: N/AEfficacy of a mixture of prebiotics and probiotics Omni-Biotic Pro Vi 5 (Institut AllergoSan, Graz, Austria) against post–COVID-19 syndromeDose: N/AAustria20InterventionalNCT04666116Phase: N/AEfficacy of nutritional supplement by nasopharyngeal smear to decrease viral load in hospitalized COVID-19 patientsDose: Supplement of mixture of probiotics (Bifidobacterium longum, Bifidobacterium animalis ssp. lactis and Lactobacillus rhamnosus), vitamin D, zinc, and seleniumSpain96InterventionalNCT04922918Phase: N/AImpact of probiotics on preventing SARS-CoV-2 infection in elderly living in a nursing homeDose: 1 × 109 CFU of Ligilactobacillus salivarius MP101 daily for 4 monthsSpain25InterventionalNCT04621071Phase: N/AEfficacy of probiotics to reduce duration and symptoms of COVID-19 patients with self-caring at homeDose: 1 × 109 CFU of 2 probiotic strains daily for 25 days or until hospitalizedCanada84InterventionalNCT04486482Phase: N/AEfficacy of a glycan KB109 in COVID-19 patients in the outpatient settingDose: KB109 (Kaleido Biosciences, Lexington, MA) for 35 daysUnited States50InterventionalNCT04847349Phase: N/AEfficacy of a probiotic mixture (OL-1)eProbiotics in OL-1 include Bifidobacterium lactis Bl-04, Bifidobacterium longum subsp. infantis Bi-26, Lactobacillus rhamnosus Lr-32, Lactobacillus paracasei Lpc-37, and Lactobacillus salivarius Ls-33. to boost immunity of unvaccinated patients with previous SARS-CoV-2 infectionDose: OL-1 daily for 21 daysUnited States45InterventionalNCT04734886Phase: N/AImpact of probiotics on SARS-CoV-2 antibody response in healthy adultsDose: 1 × 108 CFU of Lactobacillus reuteri DSM 17938 + 10 μg vitamin D3 twice daily for 6 monthsSweden400CPU, colony-forming unit; ICU, intensive care unit; N/A, not applicable.a The search was conducted on clinicaltrials.gov in July 2021. Completed, not yet recruiting, suspended, or terminated trials were excluded.b US Food and Drug Administration definitions of clinical trial phases were used.c Probiotics in SivoMixx are Streptococcus thermophiles (DSM322245), Bifidobacterium lactis (DSM 32246), Bifidobacterium lactis (DSM 32247), Lactobacillus acidophilus (DSM 32241), Lactobacillus helveticus (DSM 32242), Lactobacillus paracasei (DSM 32243), Lactobacillus plantarum (DSM 32244), and Lactobacillus brevis (DSM 2796).d Probiotics in Omni-Biotic 10 AAD include Bifidobacterium bifidum W23, Bifidobacterium lactis W51, Enterococcus faecium W54, Lactobacillus acidophilus W37, Lactobacillus acidophilus W55, Lactobacillus paracasei W20, Lactobacillus plantarum W1, Lactobacillus plantarum W62, Lactobacillus rhamnosus W71, and Lactobacillus salivarius W24.e Probiotics in OL-1 include Bifidobacterium lactis Bl-04, Bifidobacterium longum subsp. infantis Bi-26, Lactobacillus rhamnosus Lr-32, Lactobacillus paracasei Lpc-37, and Lactobacillus salivarius Ls-33. Open table in a new tab CPU, colony-forming unit; ICU, intensive care unit; N/A, not applicable. Therapeutic approaches that target ACE-2 to restore RAS balance including ACE inhibitors or angiogenesis receptor blockers are rapidly being developed and tested in clinical trials.15Penninger J.M. Grant M.B. Sung J.J.Y. The role of angiotensin converting enzyme 2 in modulating gut microbiota, intestinal inflammation, and coronavirus infection.Gastroenterology. 2021; 160: 39-46Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar Gut microbes interacted with ACE-2, and microbial alterations in COVID-19 patients were shown to be correlated with ACE-2,6 suggesting the feasibility of combined pharmacologic agents with probiotics against COVID-19. Caution is needed, however, because these drugs can also upregulate ACE-2 expression and may enhance viral entry into host cells.26Sanders J.M. Monogue M.L. Jodlowski T.Z. et al.Pharmacologic treatments for coronavirus disease 2019 (COVID-19): a review.JAMA. 2020; 323: 1824-1836PubMed Google Scholar To address this concern, soluble recombinant human ACE-2 has emerged that can act as a competitive interceptor by binding the viral spike protein to neutralize SARS-CoV-2 and also minimize organ injuries by rebalancing RAS and lowering circulatory concentration of angiotensin II.15Penninger J.M. Grant M.B. Sung J.J.Y. The role of angiotensin converting enzyme 2 in modulating gut microbiota, intestinal inflammation, and coronavirus infection.Gastroenterology. 2021; 160: 39-46Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar,27Zoufaly A. Poglitsch M. Aberle J.H. et al.Human recombinant soluble ACE2 in severe COVID-19.Lancet Respir Med. 2020; 8: 1154-1158Abstract Full Text Full Text PDF PubMed Scopus (231) Google Scholar Interestingly, bioengineering the probiotic species Lactobacillus paracasei into a live vector for oral delivery of recombinant human ACE-2 showed positive outcomes in mice, and this approach may facilitate large-scale production of high-quality ACE-2 with sufficient bioavailability in the future.28Verma A. Xu K. Du T. et al.Expression of human ACE2 in Lactobacillus and beneficial effects in diabetic retinopathy in mice.Mol Ther Methods Clin Dev. 2019; 14: 161-170Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar Previous studies have reported moderate efficacy of probiotics against acute respiratory infection, whereas probiotics as adjuvants may improve clinical outcomes.29Suez J. Zmora N. Segal E. et al.The pros, cons, and many unknowns of probiotics.Nat Med. 2019; 25: 716-729Crossref PubMed Scopus (445) Google Scholar Several clinical studies are investigating the efficacy of probiotics in patients with COVID-19. Researchers in Austria are investigating the efficacy of a probiotic mixture to alleviate gastrointestinal symptoms in hospitalized COVID-19 patients (NCT04420676) and complications after discharge (NCT04813718). The combined use of prebiotics and probiotics in hospitalized COVID-19 patients is being studied by researchers in Spain (NCT04666116) and Hong Kong (NCT04730284). The use of probiotics as adjuvant therapy for COVID-19 management is also of interest. A phase II trial in Italy applied ozone therapy plus a probiotic mixture to COVID-19 patients to prevent deterioration, need for hospitalization, or intensive care unit admission (NCT04366089). Studies are also ongoing to investigate whether probiotics can lower the risk of SARS-CoV-2 infection by boosting immunity in uninfected elderly subjects (NCT04922918) and healthy individuals (NCT04734886). Clinical studies targeting gut microbiota as therapeutics in COVID-19 are summarized in Table 1. A case report on 2 subjects showed that fecal microbiota transplantation was safe in patients with recurrent Clostridioides difficile infection and coexisting COVID-1930Bilinski J. Winter K. Jasinski M. et al.Rapid resolution of COVID-19 after faecal microbiota transplantation.Gut. 2021; (gutjnl-2021-325010)PubMed Google Scholar and might have a role in hastening recovery. A larger clinical trial to examine the role of fecal microbiota transplantation in COVID-19 is in progress (NCT04824222). However, the presence of SARS-CoV-2 in fecal samples in asymptomatic individuals has had a large impact on donor screening, and vigilant SARS-CoV-2 testing should be performed in all donors to ensure the safety of fecal microbiota transplantation during the COVID-19 pandemic.31Ianiro G. Mullish B.H. Kelly C.R. et al.Reorganisation of faecal microbiota transplant services during the COVID-19 pandemic.Gut. 2020; 69: 1555-1563Crossref PubMed Scopus (76) Google Scholar At the society level, the long-lasting COVID-19 pandemic has dramatically upended daily lives. Current pandemic control measures and practices will have substantial and potentially long-term effects on the human microbiota worldwide, given strict implementation of hygiene measures, physical separation, travel barriers, and other measures that influence overall microbial diversity and loss. Several studies reported increased rates of cesarean sections in COVID-19–positive women, and initial recommendations discouraged COVID-19–positive mothers from breastfeeding and participating in skin-to-skin care, all of which will impact early microbiota development. Infection control measures must be balanced with strategies that promote microbial diversity to impart optimal health outcomes and potentially modulate susceptibility of children to COVID-19. At the individual level, the World Health Organization has proposed a shift from a Western-style diet with high-fat and high-sugar content to a well-balanced and diversified diet. This is especially crucial in elderly subjects and those with cardiovascular disease, type 2 diabetes, or other chronic diseases who are known to have poorer outcomes with SARS-CoV-2 infection. Intake of adequate nutrients is recommended to avoid malnutrition and maintain immune homeostasis in these high-risk individuals.32Volkert D. Beck A.M. Cederholm T. et al.ESPEN guideline on clinical nutrition and hydration in geriatrics.Clin Nutr. 2019; 38: 10-47Abstract Full Text Full Text PDF PubMed Scopus (507) Google Scholar A diversified diet can also beneficially impact gut microbiota with enrichment of probiotics (eg, Lactobacillus, Bifidobacterium, and Streptococcus thermophilus) and SCFAs.33De Filippis F. Pellegrini N. Vannini L. et al.High-level adherence to a Mediterranean diet beneficially impacts the gut microbiota and associated metabolome.Gut. 2016; 65: 1812-1821Crossref PubMed Scopus (827) Google Scholar Whether modulating gut microbiota with dietary intervention can reduce susceptibility of SARS-CoV-2 infection and severity warrants prospective studies. At the hospital level, the liberal use of antibiotics in COVID-19 patients could have a detrimental impact on gut microbiota. Up to three-fourths of COVID-19 patients received empirical antibiotics to prevent bacterial infection, although coinfection was identified in less than 5% of patients.34Vaughn V.M. Gandhi T.N. Petty L.A. et al.Empiric antibacterial therapy and community-onset bacterial coinfection in patients hospitalized with coronavirus disease 2019 (COVID-19): a multi-hospital cohort study.Clin Infect Dis. 2021; 72: e533-e541Crossref PubMed Scopus (176) Google Scholar Studies have reported no difference in outcomes with or without antibiotics in hospitalized COVID-19 patients.5Yeoh Y.K. Zuo T. Lui G.C. et al.Gut microbiota composition reflects disease severity and dysfunctional immune responses in patients with COVID-19.Gut. 2021; 70: 698-706Crossref PubMed Scopus (450) Google Scholar,6Zuo T. Zhang F. Lui G.C.Y. et al.Alterations in gut microbiota of patients with COVID-19 during time of hospitalization.Gastroenterology. 2020; 159: 944-955Abstract Full Text Full Text PDF PubMed Scopus (707) Google Scholar Gut microbiota in antibiotic-treated patients displayed further dissimilarity to microbiota of healthy individuals with greater depletion of beneficial commensals including F prausnitzii, E rectale, and L bacterium compared with patients treated without antibiotics. Hence, caution is needed when prescribing antibiotics because the unnecessary use of antibiotics can cause more severe gut dysbiosis and depletion of beneficial bacteria and increased antimicrobial resistance. In the latest World Health Organization guidance for COVID-19 clinical management (see https://www.who.int/publications/i/item/WHO-2019-nCoV-clinical-2021-1), antibiotic therapy or prophylaxis was not recommended in patients with mild or moderate COVID-19 unless there is clinical suspicion of bacterial infection. In addition, longer follow-up of patients with COVID-19 up to 12 months after recovery is needed to address questions related to the duration of dysbiosis postrecovery, the link between dysbiosis and post–acute COVID-19 syndrome, and whether the dysbiosis or enrichment/depletion of specific gut microorganisms predisposes recovered individuals to future health issues. Although emerging evidence supports the importance of gut microbiota in COVID-19 pathogenesis and severity, data are mostly derived from descriptive and associative human studies. Extensive in-depth mechanistic and murine studies are required to decipher the causal relationship between gut microbiota and SARS-CoV-2 infection. However, although animal experiments are necessary for mechanistic investigation, a mouse model that can accurately mimic SARS-CoV-2 infection in humans has been poorly established. Although some preprint articles infected a transgenic mouse model with expression of human ACE-2 (namely K18-hACE2) with SARS-CoV-2 to assess drug efficacy35Alvarado D.M. Son J. Thackray L.B. et al.Mesalamine reduces intestinal ACE2 expression without modifying SARS-CoV-2 infection or disease severity in mice.bioRxiv. 2021; (2021.07.23.453393)Google Scholar or dysbiosis-associated bacteremia,36Venzon M. Bernard-Raichon L. Klein J. Axelrad J.E. et al.Gut microbiome dysbiosis during COVID-19 is associated with increased risk for bacteremia and microbial translocation.Res Sq. 2021; (rs.3.rs-726620)PubMed Google Scholar to what extent these mice can replicate viral infection in humans requires further validation. Moreover, to date published clinical trial data supporting the use of probiotics in COVID-19 are scarce, and outstanding challenges include determination of an optimal strain(s), dosing regimen, and duration of intervention as well as selection of the appropriate clinical and mechanistic outcomes At the global level, it is currently unclear how long immunity lasts from SARS-CoV-2 vaccines, and scientists around the world are racing to determine what level of neutralizing antibodies or immune marker is most closely related with COVID-19 vaccine’s effectiveness. The surge in cases caused by the delta variant worldwide has caused some countries to consider booster vaccines in at-risk groups despite the lack of evidence.37Callaway E. COVID vaccine boosters: the most important questions.Nature. 2021; 596: 178-180Crossref PubMed Scopus (64) Google Scholar In 2019 gut microbiota was shown to influence vaccine efficacy because a significant impairment of antibody response was observed in healthy subjects receiving antibiotics before H1N1 influenza vaccination.38Hagan T. Cortese M. Rouphael N. et al.Antibiotics-driven gut microbiome perturbation alters immunity to vaccines in humans.Cell. 2019; 178: 1313-1328Abstract Full Text Full Text PDF PubMed Scopus (248) Google Scholar It is likely that the gut microbiome equally plays an important role in SARS-CoV-2 vaccine immune response and vaccine-related adverse effects. Preliminary results of an ongoing clinical study showed that subjects who took a probiotic formula for 2 months had higher serum SARS-CoV-2 IgG antibody levels and decreased proinflammatory cytokines (NCT04980560). A large population-based study in the United States is recruiting up to 10,000 participants to decipher the correlation between gut microbiota and efficacy of COVID-19 vaccine (NCT04770649). Waning immunity and SARS-CoV-2 variants will likely be a long-term challenge. In light of this, every means to prolong immunity and reduce complications are needed. The central role of gut microbiota in immunity against SARS-CoV-2 infection and microbiota modulation to improve SARS-CoV-2 vaccine efficacy are low-hanging fruit that should be seriously considered.