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Can the microbiota help protect against viral infections? Summary of an ISAPP discussion group

/in ISAPP Science Blog /by KC

By Drs. Karen Scott, University of Aberdeen, and Sarah Lebeer, University of Antwerp

As part of the ISAPP virtual annual meeting 2020, around 85 members of the ISAPP community joined us in a Zoom discussion forum to discuss the topic: “Do our resident microbes help protect against viral infections?” A scientific perspective on this topic is especially important during the COVID-19 pandemic, when many members of the general public are wondering about actions (if any) they can take to protect themselves before a SARS-CoV-2 vaccine becomes widely available.

We introduced the topic and were joined by several invited experts, who also gave short presentations:

  • Joel Dore (INRAE France)
  • Tine Licht (Technical University of Denmark)
  • Mary O’Connell-Motherway (APC Microbiome, Cork)

The ensuing conversation, open to all participants, was wide-ranging, starting with the gut microbiota and expanding to include the microbiota at other body sites, and the effects of the gut microbiota around the body gut via transport of metabolites. Here are some of the main take-home messages from this discussion.

Components of the microbiota (bacteria, fungi, archaea, viruses and others) at a body site interact with each other. Although scientists often study one component of the (gut) microbiota at a time, members of the microbiota from different kingdoms interact with each other in ways that can be positive or negative for the host. In particular, specific activities of bacteria can be widespread, frequent or rare among members of the microbiota – and it is often the rare activities that have important impacts on the course of a disease: e.g. specific antimicrobial agents produced by some bacteria prevent Salmonella infections in pigs and cure mastitis in cows.

Mechanistic work shows bacteria in the microbiota can prevent, eliminate or promote viral infections. Studies have shown some microbes can prevent attachment of viruses to cell surfaces by offering alternative receptors. In contrast, virus particles can utilise other bacterial cells to “mask” them and facilitate entry into host cells. Other bacteria can stimulate the immune system to promote elimination of a viral infection, while under specific circumstances this same immune activation may promote viral infection. When it comes to the microbiota of the respiratory tract, studies have shown its bacterial members play a crucial defensive role. Probiotics that are already shown to be effective against other viral upper respiratory tract infections may have promise for COVID-19 (either for preventing infection or enhancing recovery), and currently studies are underway to investigate these.

Probiotics or prebiotics could be useful adjuncts to vaccination, but they are not likely to become a reality for COVID-19. Scientists are perennially interested in the topic of vaccine efficacy, and some probiotics have been shown to increase efficacy for widely available vaccines in certain populations. But in the current pandemic, developing a safe and effective vaccine (or vaccines) is the primary concern. Testing the possibility of probiotic or prebiotic combination therapies would be secondary, since the necessary testing would take longer in order to evaluate the adjuvant potential of different probiotic strains. Because the expression of cell surface molecules that can mediate adjuvant activity is strain-dependent, screening and selecting the best strains would probably take too long to become a reality for COVID-19. Certainly, participants agreed that introduction of a safe, effective vaccine was the priority, without any delays to test out ‘extras’.

A scientific rationale exists for maintaining gut microbiota diversity in order to reduce the development of diseases which, as “underlying health conditions”, may result in more severe COVID-19 outcomes. It is clear that individuals with certain underlying health conditions—related to the central nervous system and gastrointestinal system, and to metabolic and immunological dysfunction—tend to experience a more severe disease, with worse outcomes, following SARS-CoV-2 infection. Many of these conditions are also associated with a gut microbiota that is different from that of healthy controls. Research consistently shows that individuals with metabolic disease, for example, have a less diverse, lower ‘richness’ microbiota, which is often linked to increased intestinal permeability, higher gut inflammation and more oxidative stress throughout the body. This increased oxidative stress then exacerbates the microbial dysbiosis, causing more inflammation and increased intestinal permeability – creating a vicious cycle effect. This cycle is linked with obesity and metabolic disorders. In healthy individuals who are at risk of developing such conditions, the diversity of the existing resident microbiota may be increased by the application of prebiotics or synbiotics, included within a healthy, diverse, high-fibre diet. These approaches may improve bacterial fermentation in the large intestine, resulting in increased production of important bacterial metabolites that help regulate host metabolism, including short-chain fatty acids.

Until a SARS-CoV-2 vaccine is available, supporting a diverse and complex gut microbiota through diet may contribute to maintaining health in at-risk populations. Despite the intense worldwide scientific efforts and collaborations, it is unlikely that an effective vaccine against COVID-19 will be widely available soon. In the meantime, we have to protect ourselves and our local ‘at-risk’ populations as best we can. We are learning more and more about the mechanisms of dietary fibre’s health effects, in which gut bacteria play a major role. Evidence suggests that keeping our gut microbiota as complex and diverse as possible by consuming a high-fibre diet (supplemented by fermented foods, probiotics and prebiotics) might help mitigate susceptibility to infections in general.

How some probiotic scientists are working to address COVID-19

/in ISAPP Science Blog, News /by KC

By ISAPP board of directors

With the global spread of COVID-19, the scientific community has experienced an unusual interruption. Across every field, many laboratories are temporarily shuttered and research programs of all sizes are on hiatus. Principal investigators around the world are doing their part to keep their students and local communities safe, and many are donating lab safety equipment to medical first responders who urgently need it.

In this global circumstance of research being put on hold, it is enlightening to consider what some scientists in the fields of probiotics, prebiotics, and fermented foods are working on—or proposing—in the context of understanding ways to combat viral threats. These individuals are rising to the scientific challenge of finding effective ways to prevent or treat viral infections, which may directly or indirectly contribute to progress against SARS-CoV-2.

Here, ISAPP shares words from some of these scientists—and how they have connected the dots from probiotics to coronavirus-related work with potential medical relevance.

Prof. Sarah Lebeer, University of Antwerp, Belgium: Relevance of the airway microbiome profile to COVID-19 respiratory infection and using certain lactobacilli to enhance delivery or efficacy of vaccines

Could the microbes in our upper and lower airways play a role in how we respond to the virus? Significant individual differences exist in the microbes that are prevalent and dominant in our airways. Lactobacilli are found in the respiratory tract, especially in the nasopharynx. They might originate there from the oral cavity via the oronasopharynx, but we have found some strains that seem to be more adapted to the respiratory environment, for example by expressing catalase enzymes to withstand oxidative stress. Currently we have a Cell Reports paper in press that shows certain lactobacilli are more prevalent in the upper respiratory tract of healthy people compared to those with chronic rhinosinusitis. Further investigation of one strain found in healthy people showed it inhibited growth and virulence of several upper respiratory tract pathogens. Our work on other viruses shows that certain lactobacilli can even block the attachment of viral particles to human cells. This raises the possibility that lactobacilli could be supplemented through a local spray to help improve defenses against the inhaled virus. Based on these data, we are initiating an exploratory study with clinicians and virologists on whether specific strains of lactobacilli in the nasopharynx and oropharynx could have potential to reduce viral activity via a multifactorial mode of action, including barrier-enhancing and anti-inflammatory effects, and reduce the risk of secondary bacterial infections in COVID-19.

Another line of exploratory research from our lab pertains to the delivery or efficacy of SARS-CoV-2 vaccines. Currently, many groups are rapidly developing vaccines, which predominantly use the viral spike S protein or its receptor-binding domain as antigen to induce protective immunity. We are exploring the potential of specific strains of lactobacilli with immunostimulatory effects as adjuvants for intranasal SARS-CoV-2 vaccination, or the potential of a genetically engineered antigen-producing organism for vaccine delivery.

At this year’s virtual ISAPP annual meeting, Dr. Karen Scott and I will also be leading an ISAPP discussion group called “How your gut microbiota can help protect against viral infections”. We will discuss previous work that has shown bacteria can have anti-viral effects. For many years, our colleagues, Profs. Hania Szajewska and Seppo Salminen, have studied a different virus, namely rotavirus, that causes acute diarrhea in children, and have found that Lactobacillus rhamnosus GG (new taxonomy Lacticaseibacillus rhamnosus GG) binds rotavirus and disables it, thereby blocking viral infection/multiplication. This may explain why this probiotic reduces the incidence and duration of acute diarrhea in children. Similar findings have been reported for specific probiotics and prebiotics and prevention of upper respiratory tract infections.

Prof. Rodolphe Barrangou, North Carolina State University, USA: Engineering probiotic lactobacilli for vaccine development

Between NC State University and Colorado State University (CSU) there is a historical collaborative effort aiming at engineering probiotics to develop novel vaccines. The intersection of probiotics and antivirals is the focus here with expressing antigens on the cell surface of probiotics to develop oral vaccines. The CSU infectious diseases center is very much fully operational and focused on COVID-19 now, and we recently received a research exception to open our lab for two individuals assigned to this NIH-funded project, and pivot our rotavirus efforts here to coronavirus. We are actively engineering Lactobacillus acidophilus probiotics expressing COVID-19 proteins to be tested as potential vaccines at CSU in the near future, as progress dictates.

Prof. Colin Hill, University College Cork, Ireland: The microbiome as a predictor of COVID-19 outcomes

We have recently proposed a project to examine oral and faecal microbiomes to identify correlations/associations between COVID-19 disease severity and individual microbiome profiles. If funded, we propose to analyse bacterial and viral components of the microbiome from three body sites (nasopharyngeal swabs, saliva, and faeces) in 200 donors and mine the data for biomarkers of disease risk and clinical severity. We will use machine learning to identify microbiome signatures in patients who contract the virus and remain asymptomatic, those who develop a mild infection, or those who have an acute infection requiring admission to an intensive care unit and intubation. This will enable microbiome-based risk stratification of subjects testing positive, and appropriate clinical management and early intervention, and prioritization of subjects for receiving an eventual vaccine.

Dr. Dinesh Saralaya, Bradford Institute for Health Research, UK: A live biotherapeutic product for targeted immunomodulation in COVID-19 infection

The COVID-19 pandemic presents an unprecedented challenge to our healthcare systems and we desperately require the rapid development of new therapies to ease the burden on our intensive care units. As well as its appropriate mechanism of action (targeted immunomodulation rather than broad immunosuppression), the highly favourable safety profile of MRx-4DP0004 makes it a particularly attractive candidate for COVID-19 patients, and may potentially allow us to prevent or delay their progression to requiring ventilation and intensive care.

The trial is a Phase II randomised, double-blind, placebo-controlled trial to evaluate the efficacy and safety of oral Live Biotherapeutic MRx-4DP0004 in addition to standard supportive care for hospitalised COVID-19 patients. Up to 90 subjects will be randomised 2:1 to receive either MRx-4DP0004 or placebo (two capsules, twice daily) for 14 days. The primary endpoint is change in mean clinical status score as measured by the WHO’s 9-point Ordinal Scale for Clinical Improvement, while secondary endpoints include a suite of additional measures of clinical efficacy such as need for and duration of ventilation, time to discharge, mortality, as well as safety and tolerability. The size and design of the trial are intended to generate a meaningful signal of clinical benefit as rapidly as possible.

Drs. Paul Wischmeyer and Anthony Sung, Duke University School of Medicine, USA: Probiotics for prevention or treatment of COVID-19 infection

We are planning several randomized clinical trials of probiotics in COVID-19 prevention and treatment. These trials are based on multiple randomized clinical trials and meta-analyses that have shown that prophylaxis with probiotics may reduce upper and lower respiratory tract infections, sepsis, and ventilator associated pneumonia by 30-50%. These benefits may be mediated by the beneficial effects of probiotics on the immune system. The Wischmeyer laboratory and others have shown that probiotics, such as Lactobacillus rhamnosus GG, can improve intestinal/lung barrier and homeostasis, increase regulatory T cells, improve anti-viral defense, and decrease pro-inflammatory cytokines in respiratory and systemic infections. These clinical and immunomodulatory benefits are especially relevant to individuals who have developed, or are at risk of developing, COVID-19. COVID-19 has been characterized by severe lower respiratory tract illness, and patients may manifest an excessive inflammatory response similar to cytokine release syndrome, which has been associated with increased complications and mortality. We hypothesize that probiotics will directly reduce COVID-19 infection risk and severity of disease/symptoms. Thus, we are proposing a range of trials, the first of which will be:

A Randomized, Double-Blind, Placebo-Controlled Trial of the PRObiotics To Eliminate COVID-19 Transmission in Exposed Household Contacts (PROTECT-EHC). Objective: Prevent infection and progression of illness in household contacts/caregivers of known COVID-19 patients exposed to COVID-19 (who have a >20-fold increased risk of infection). We will conduct a multicenter, randomized, double blind, phase 2 trial of the probiotic Lactobacillus rhamnosus GG vs. placebo to decrease infections and improve outcomes. This trial will include weekly collection of microbiome samples from multiple locations (i.e. fecal, oral). This trial will utilize a commercial probiotic, delivering 20 billion CFU of Lactobacillus rhamnosus GG, and placebo.

We are currently developing protocols to study prevention and treatment of COVID-19 in a range of other at-risk populations including: 1) Healthcare providers; 2) Hospitalized patients; 3) Nursing home and skilled nursing facilities workers. We are seeking additional funding and potential collaborators/trial sites for this work, and encourage interested funders and collaborators to reach out for further information or to join the effort at: Paul.Wischmeyer@nullduke.edu and also encourage you to follow our progress and our other probiotic/microbiome work on Twitter: @paul_wischmeyer

Prof. Gregor Reid, University of Western Ontario, Canada: Documenting anti-viral mechanisms of certain probiotic strains

While our institute is now studying the cytokine storm in COVID-19 patients, the closure of my lab has meant I have turned to surveying the literature: Prof. Glenn Gibson and I have a paper published in Frontiers in Public Health stating a case for probiotics and prebiotics to help ‘flatten the curve’ and keep patients from progressing to severe illness. There is good evidence that certain orally administered probiotic strains can reduce the incidence and severity of viral respiratory tract infections. Mechanistically this appears to be, in part, through modulation of inflammatory responses similar to those causing severe illness in COVID-2 patients, and antiviral activity — which has not been shown against SARS-Co-V2 but has been documented against common respiratory viruses, including influenza, rhinovirus and respiratory syncytial virus. Improving gut barrier integrity and affecting the gut-lung axis may also be part of these probiotics’ mechanism of action. At a time when drugs are being tried with little or no anti-COVID-19 data, probiotic strains documented for anti-viral, immunomodulatory and respiratory activities should be considered for clinical trials to be part of the armamentarium to reduce the burden and severity of this pandemic.

Rapid, collaborative effort

As the world waits in ‘lockdown’ mode, continued scientific progress for coronavirus prevention or treatment is critically important. ISAPP salutes all probiotic and prebiotic scientists who are stepping up to pursue unique solutions. Addressing the important research questions described above will require a rapid collaborative effort, from obtaining ethical approval and involving medical staff to collecting the samples, to recruiting participants as well as experts to process and analyze samples. All of this has to be done in record time – but from our experience of this scientific community, it’s definitely up to the challenge.

ISAPP provides guidance on use of probiotics and prebiotics in time of COVID-19

/in ISAPP Science Blog, News /by KC

By ISAPP board of directors

Summary: No probiotics or prebiotics have been shown to prevent or treat COVID-19 or inhibit the growth of SARSCoV-2. We recommend placebo-controlled trials be conducted, which have been undertaken by some research groups. If being used in clinical practice in advance of such evidence, we recommend a registry be organized to collect data on interventions and outcomes.  

Many people active in the probiotic and prebiotic fields have been approached regarding their recommendations for using these interventions in an attempt to prevent or treat COVID-19. Here, the ISAPP board of directors provides some basic facts on this topic.

What is known. Some human trials have shown that specific probiotics can reduce the incidence and duration of common upper respiratory tract infections, especially in children (Hao et al. 2015; Luoto et al. 2014), but also with some evidence for adults (King et al. 2014) and nursing home residents (Van Puyenbroeck et al. 2012; Wang et al. 2018). However, not all evidence is of high quality and more trials are needed to confirm these findings, as well as determine the optimal strain(s), dosing regimens, time and duration of intervention. Further, we do not know how relevant these studies are for COVID-19, as the outcomes are for probiotic impact on upper respiratory tract infections, whereas COVID-19 is also a lower respiratory tract infection and inflammatory disease.

There is less information on the use of prebiotics for addressing respiratory issues than there is for probiotics, as they are used mainly to improve gut health. However, there is evidence supporting the use of galactans and fructans in infant formulae to reduce upper respiratory infections (Shahramian et al. 2018; Arslanoglu et al. 2008). A meta-analysis of synbiotics also showed promise in repressing respiratory infections (Chan et al. 2020).

Mechanistic underpinnings. Is there scientific evidence to suggest that probiotics or prebiotics could impact SARS-CoV-2? Data are very limited. Some laboratory studies have suggested that certain probiotics have anti-viral effects including against other forms of coronavirus (Chai et al. 2013). Other studies indicate the potential to interfere with the main host receptor of the SARS-CoV-2 virus, the angiotensin converting enzyme 2 (ACE2). For example, during milk fermentation, some lactobacilli have been shown to release peptides with high affinity for ACE (Li et al. 2019). Recently, Paenibacillus bacteria were shown to naturally produce carboxypeptidases homologous to ACE2 in structure and function (Minato et al. 2020). In mice, intranasal inoculation of Limosilactobacillus reuteri (formerly Lactobacillus reuteri) F275 (ATCC 23272) has been shown to have protective effects against lethal infection from a pneumonia virus of mice (PVM) (Garcia-Crespo et al. 2013). These data point towards immunomodulatory effects involving rapid, transient neutrophil recruitment in association with proinflammatory mediators but not Th1 cytokines. A recent study demonstrated that TLR4 signaling was crucial for the effects of preventive intranasal treatment with probiotic Lacticaseibacillus rhamnosus (formerly Lactobacillus rhamnosus) GG in a neonatal mouse model of influenza infection (Kumova et al., 2019). Whether these or other immunomodulatory effects, following local or oral administration, could be relevant to SARS-CoV-2 infections in humans is at present not known.

Our immune systems have evolved to respond to continual exposure to live microbes. Belkaid and Hand (2016) state: “The microbiota plays a fundamental role on the induction, training, and function of the host immune system. In return, the immune system has largely evolved as a means to maintain the symbiotic relationship of the host with these highly diverse and evolving microbes.” This suggests a mechanism whereby exposure to dietary microbes, including probiotics, could positively impact immune function (Sugimura et al. 2015; Jespersen et al. 2015).

The role of the gut in COVID-19. Many COVID-19 patients present with gastrointestinal symptoms and also suffer from sepsis that may originate in the gut. This could be an important element in the development and outcome of the disease. Though results from studies vary, it is evident that gastrointestinal symptoms, loss of taste, and diarrhea, in particular, can be features of the infection and may occur in the absence of overt respiratory symptoms. There is a suggestion that gastrointestinal symptoms are associated with a more severe disease course. Angiotensin converting enzyme 2 and virus nucleocapsid protein have been detected in gastrointestinal epithelial cells, and infectious virus particles have been isolated from feces. In some patients, viral RNA may be detectable in feces when nasopharyngeal samples are negative. The significance of these findings in terms of disease transmission is unknown but, in theory, do provide an opportunity for microbiome-modulating interventions that may have anti-viral effects (Cheung et al. 2020; Tian et al. 2020; Han et al. 2020).

A preprint (not peer reviewed) has recently been released, titled ‘Gut microbiota may underlie the predisposition of healthy individuals to COVID-19’ (Gao et al. 2020) suggesting that this could be an interesting research direction and worthy of further discussion. A review of China National Health Commission and National Administration of Traditional Chinese Medicine guidelines also suggested probiotic use, although more work on specific strains is needed (Mak et al. 2020).

Are probiotics or prebiotics safe? Currently marketed probiotics and prebiotics are available primarily as foods and food/dietary supplements, not as drugs to treat or prevent disease. Assuming they are manufactured in a manner consistent with applicable regulations, they should be safe for the generally healthy population and can be consumed during this time.

Baud et al. (in press) presented a case for probiotics and prebiotics to be part of the management of COVID-19. Although not fully aligned with ISAPP’s official position, readers may find the points made and references cited of interest.

Conclusion. We reiterate, currently no probiotics or prebiotics have been shown to prevent or treat COVID-19 or inhibit the growth of SARSCoV-2.