key: cord-0967054-1iz0dskk
authors: Lau, Harry Cheuk-Hay; Ng, Siew C.; Yu, Jun
title: Targeting the gut microbiota in COVID-19: hype or hope?
date: 2021-09-08
journal: Gastroenterology
DOI: 10.1053/j.gastro.2021.09.009
sha: 12f517b7d06e9e9be922855fff13f92d2f2032f3
doc_id: 967054
cord_uid: 1iz0dskk

nan

The human gastrointestinal tract harbours trillions of microorganisms that form an ecological community known as the gut microbiota, of which its alteration (termed as dysbiosis) has been associated with various human diseases. Microbial diversity in faecal samples of patients with COVID-19 was found to be decreased and accompanied by enrichment of opportunistic pathogens including Clostridium hathewayi and Ruminococcus species [4] [5] [6] . Data from two studies utilising metagenomic sequencing showed that several beneficial commensals such as Faecalibacterium prausnitzii and Eubacterium rectale were depleted in faecal samples of COVID-19 cases 5, 6 . F. prausnitzii which is a major producer of short-chain fatty acids (SCFAs; crucial for maintaining intestinal homeostasis) in the gut and has antiinflammatory potential via induction of IL-10 production 7 , was found to be low in abundance J o u r n a l P r e -p r o o f in faeces of COVID-19 patients and had inverse correlation with disease severity. In contrast, Clostridium hathewayi and Clostridium ramosum, both known to be associated with bacteraemia and inflammation, were positively correlated with COVID-19 severity. In addition, faecal samples with high SARS-CoV-2 infectivity had higher abundance of opportunistic pathogenic bacteria (e.g. Collinsella species, Morganella morganii) and lower abundance of SCFA-producing bacteria (e.g. Parabacteroides merdae, Lachnspiraceae bacterium) compared with samples with low SARS-CoV-2 viral infectivity 8 . Altogether these findings implicate 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 had persistent symptoms known as postacute COVID-19 syndrome (PACS) and/or developed multisystem inflammation after viral clearance 9 . Multiple studies have reported marked difference in gut microbiota between recovered patients and healthy adults, and dysbiosis can persist up to 30 days after disease resolution 5, 6 . Infectious bacteria such as Bifidobacterium dentium and Klebsiella pneumoniae were enriched in recovered patients, whilst Bacteroides species including Bacteroides dorei, Bacteroides thetaiotaomicron and Bacteroides massiliensis as well as the anti-inflammatory F. prausnitzii were depleted [4] [5] [6] 8 . 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. ACE2, 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). ACE2 is also a key regulator of dietary amino acid homeostasis, microbial ecology and innate immunity 10 . ACE2 can be hijacked as a receptor for SARS-CoV-2 to undergo replication for promoting viral infection [11] [12] [13] [14] . This viral-mediated reduction of ACE2 leads to accumulation of its ligand angiotensin II and RAS imbalance, resulting in enhanced intestinal permeability and the leaky gut syndrome 15 . With disrupted gut barrier, bacteria and endotoxins (e.g. 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 CXCL10 and TNF-α 5 , 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 gut, while hospitalised COVID-19 patients presenting gastrointestinal symptoms were benefited from significant reduction in disease severity 16 . These findings therefore implicate the potential of gastrointestinal tract as well as the gut microbiota in attenuating symptoms of COVID-19. 

Dietary intervention -Dietary nutrients are a convenient and safe way to prevent disease and reduce disease severity. In SARS-CoV-2 infection, excessive production of pro-inflammatory cytokines and acute inflammation occurred hence intake of nutrients with anti-inflammatory and anti-oxidant effect may be beneficial in COVID-19 patients. These dietary components involve omega-3 polyunsaturated fatty acids, vitamins, zinc, plant-based polyphenols (e.g. flavonoids and phenolic acids), polysaccharides, and a panoply of herbs from traditional Chinese medicine 18 . Dietary fibre is protective against gut barrier disruption and can restrict bacterial translocation into the systemic circulation while high fat and protein diet are correlated with mucosal barrier dysfunction 19 . A multi-centre retrospective study with over 7,300 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 20 . These data highlight the feasibility of a low glycaemic index diet with green vegetables and fruits to improve outcome in hospitalised patients. Through appropriate dietary intervention, COVID-19 patients can potentially benefit from strengthened immunity J o u r n a l P r e -p r o o f and reduced inflammation and oxidative stress, thus alleviating disease severity and speeding recovery.

Prebiotics -Specific dietary components can serve as prebiotics (a group of dietary fibres including fructans and galactans that can only be digested by gut microbes in but not the host) to stimulate abundance of probiotics. For instance, plant-based fibre can promote the growth of the probiotics Lactobacillus and Bifidobacterium and reduce opportunistic pathogenic bacteria (e.g. Clostridium) 18 . These prebiotic fibres are degraded by gut microbes to generate SCFAs (e.g. acetate, propionate and butyrate) as end products. SCFAs are immunomodulatory metabolites capable of enhancing effector activities of B cells and CD8+

T cells 21 and producing anti-inflammatory cytokines 7 . 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 5, 6 . To restore its abundance, different nutrients derived from plant-based fibre can stimulate the growth of F. prausnitzii 22 , 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.

Probiotics -Substantial interests have emerged to develop therapeutic strategies against COVID-19 via modulating the 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 T cell-mediated immune response in pneumococcal-infected mice 23 and alleviated symptoms of acute respiratory infection in J o u r n a l P r e -p r o o f children 24 . 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 four-week oral supplementation of a probiotic formula (S1M01) targeted to replenish bacteria species known to be depleted in COVID-19 subjects hastened recovery, enhanced immunity and suppressed serum proinflammatory cytokines in hospitalised patients. Enrichment of beneficial bacteria in faeces of patients receiving the formula were seen at 5 weeks after therapy which was not seen in the standard arm group 25 . Therapeutic approaches that target ACE2 to restore reninangiotensin system (RAS) balance including ACE inhibitors or angiogenesis receptor blockers are rapidly being developed and tested in clinical trials 15 . Gut microbes interacted with ACE2 and microbial alterations in COVID-19 patients were shown to be correlated with ACE2 6 suggesting the feasibility of combined pharmacological agents with probiotics against COVID-19. Caution is however needed as these drugs can also upregulate ACE2 expression and may enhance viral entry into host cells 26 . To address this concern, soluble recombinant human ACE2 (rhACE2) has been emerged which can act as a competitive interceptor by binding the viral spike protein to neutralise SARS-CoV-2, and also minimise organ injuries by rebalancing RAS and lowering circulatory concentration of angiotensin II 15, 27 . Interestingly, bioengineering a probiotic species Lactobacillus paracasei into a live vector for oral delivery of rhACE2 showed positive outcome in mice and this approach may facilitate large-scale production of high-quality ACE2 with sufficient bioavailability in the future 28 .

Previous studies have reported moderate efficacy of probiotics against acute respiratory infection whereas probiotics as adjuvants may improve clinical outcomes 29 Table 1 . 

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 across the globe, given strict implementation of J o u r n a l P r e -p r o o f Table 1 Ongoing clinical studies of gut microbiota regarding to COVID-19 1 . 

Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

Gastrointestinal Manifestations of SARS-CoV-2 Infection and Virus Load in Fecal Samples From a Hong Kong Cohort: Systematic Review and Meta-analysis

COVID-19: gastrointestinal symptoms and potential sources of SARS-CoV-2 transmission

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Author names in bold designate shared co-first authorship.J o u r n a l P r e -p r o o f