GUT-MICROBIOME MANAGEMENT: AN ISSUE WORTH CONSIDERING IN COVID-19 TREATMENT

GUT-MICROBIOME MANAGEMENT: AN ISSUE WORTH CONSIDERING IN COVID-19 TREATMENT

Shahnaz Sultana ¹, Ashfaque Hossain ² and Muhammad Manjurul Karim ^{* 3}                               

Institute of National Analytical Research and Services (INARS) ¹, Bangladesh Council of Scientific and Industrial Research (BCSIR), Dr. Qudrat-I-Khuda Road, New Elephant Rd, Dhaka 1205, Bangladesh.

Department of Medical Microbiology and Immunology ², Ras Al Khaimah Medical and Health Sciences University, Ras Al Khaimah, United Arab Emirates.

Department of Microbiology ³, University of Dhaka, Dhaka 1000, Bangladesh.

ABSTRACT: The human gut is colonized by an inherent group of microorganisms that cohabits with us and plays a critical role in maintaining homeostasis. Evidence is being piled up, showing the roles of gut micro-flora in the severity and consequences of COVID-19. The gut-lung cross talk is thought to mediate this outcome resulting in an alteration of gut-microbiome, a phenomenon known as gut-dysbiosis during the progression of SARS-CoV-2 infection. A destabilization of gut-microbial homeostasis can upset the host immune system causing critical outcomes in COVID-19 patients with preexisting co-morbidities like CVD and diabetes. This review underlies the interaction between gut micro-flora and SARS-CoV-2 infection and the consequent clinical risk factors. While we are still in the hunt for effective medication and vaccine, the administration of prebiotics along with probiotics as a prophylactic treatment for the management of patients with COVID-19 could help reduce the pro-inflammatory state leading to the new insights of novel safeguard.

COVID-19, Gut-dysbiosis, Co-morbidities, Prebiotics, Probiotics

INTRODUCTION: The COVID-19 pandemic, after spreading to 213 countries and territories around the world and 2 international conveyances, has taken the lives of almost 749,868 people as of August 13, 2020 ¹. Showing the highest mortality rate of <4% in some countries ², this viral infection has been found to strike some particular patients more seriously than others. Different variables are suspected of playing a combined role that makes the disease outcome highly unpredictable.

Many reports suggest that the composition of the gut-microbiome could partially explain the difference in susceptibility and severity with the other clinical outcomes like cardiovascular diseases (CVD) and type 2 diabetes (T2D). This adds a new dimension to what is currently known about the disease.

SARS-CoV-2 Affects Gut: Apparently, the linkage of acute respiratory disease-causing SARS-CoV-2 and the gut might seem improbable. However, recent studies revealed that Covid-19 caused gastrointestinal (GI) symptoms, such as nausea, vomiting, and diarrhea in 3.34 to 11.40% of the critically ill patients ^{3, 4}. Moreover, the detection of viral RNA and live viruses in stool samples provides a subtle suggestion about the capacity of SARS-CoV-2 to infect and replicate in the gut ⁵. Another link between the new coronavirus and the gut involves the presence of the viral entry point into host cells, Angiotensin-converting enzyme 2 (ACE-2), in the GI tract, including epithelial cells of oral mucosa ⁶, which has been assumed to cause intestinal inflammation by infecting intestinal epithelial cells and inducing proinflammatory chemokine and cytokine release ⁷. This suggests a presumption of SARS-CoV-2 infection getting involved with the gut-microbiome therein because the shape of the gut-microbiome partly depends on the host’s gut physiology, and vice-versa.

Gut-Lung Axis: The gut-microbiome containing bacteria, fungi (yeast), viruses, and protozoa, is the community of microorganisms living inside the GI tract, mostly in the large bowel. Human gut-microbiota consists of around 10 ¹⁴ resident microorganisms, which contribute to maintaining a balanced ecosystem as well as the immune system ⁸. Several studies have demonstrated that lung infections are related to the alteration of gut-microbiota composition ⁹, supporting the eminent ‘gut-lung axis’ theory. This describes a cross-talk relationship between gut micro-flora and the lungs where the endotoxins and microbial metabolites of gut micro-flora can affect the lung through blood, and once inflammation occurs in the lung, it can alter the gut micro-flora conversely ¹⁰. One study on sub-lethally infected mice with influenza virus measured the production of short-chain fatty acids (SCFAs), one of the major metabolites in the gut that regulates the composition of the gut microbiota and the associated functionality like metabolic activity ¹¹. They found that the SCFAs concentration, including acetate (the predominant SCFA), propionate, and butyrate was lower relative to non-infected mice. This report explains how influenza infection alters the metabolic output of the gut-microbiota and affects gut and blood concentration of SCFAs, a significant group of dietary derived metabolites endowed with a modulatory role on immune functions ¹², host-microbe signaling, energy utilization, and control of colonic pH ¹². Such conditions, where the balance of gut-microbiome gets disrupted, a condition referred to as dysbiosis, results in various metabolic disorders manifested as diabetes and obesity ¹³, and enhanced susceptibility to secondary enteric infections ¹⁴. Interestingly, severe COVID-19 disease is associated with the same consequences ¹⁵.

SARS-CoV-2 and Gut-Microbiome: Reports claim that gut-dysbiosis due to lung injury could further enfeeble lung immunity ¹⁶. As gut bacteria are significantly involved in regulating the immune cells through pro- and anti-inflammatory responses, changes in the gut-microbial composition because of lung infection may affect the susceptibility and severity of various diseases ¹⁶. An experiment on mice, devoid of their intestinal microbiota, noted their disability for pathogen clearance in the lung ¹⁷. A similar report by Enaud et al., revealed that germ-free mice lacking gut-microbiota were more prone to death from lung infections ¹⁸. This indicates the causal relation of the gut microbiome and the risk of developing COVID-19 and vice-versa due to the gut-lung axis. Supporting to this possibility, a recent report claims that Covid-19 patients harbor altered gut flora devoid of health-beneficial species and supporting the growth of opportunistic pathogens compared to healthy controls ⁸.

Gut-microbial Composition in COVID-19 Patients and its Clinical Outcome: A growing body of data suggests that exaggerated immune response and the massive release of pro-in-flammatory cytokines (such as-IL-1, IL-2, IL-7, G-CSF, IP-10, MCP-1, MIP-1A, and TNFα) termed as ‘cytokine storm’ is featured in COVID-19 severe cases ¹⁹. Such inflammation creates possible consequences that increases the gut permeability, and therefore affect the commensal gut-flora ²⁰. Interestingly, these conditions are evident in elderly patients with chronic co-morbidities like cardio-vascular, metabolic and renal diseases suggesting a significant association of gut-dysbiosis with severe viral infection and poor outcome ²¹. Covid-19 patients, similar to other co-morbidities had poor gut-microbiota diversity and levels of butyrate-producers, but supports the growth of opportunistic pathogens, known to cause bacteremia to populate the gut in comparison to healthy controls ²². David et al., revealed Alistipes onderdonkii and Faecali-bacterium prausnitzii as the two prominent bacteria that are correlated with mild Covid-19 prognosis ²³. While Alistipes spp participated in the tryptophan-serotonin metabolism essential for gut homeostasis, F. prausnitzii, one of the largest butyrate producers in the gut, provided an important anti-inflammatory resource ²². This study also pinpointed 14 gut bacteria responsible for efficient viral clearance and 4 Bacteroidetes species known to lower ACE2 expression in the mice gut, which may have a potential protective role in combating SARS-CoV-2 infection by hampering host entry through ACE2. Another striking finding was noted that, in COVID 19 patients, dysbiosis in the form of decreased microbial diversity and decreased Bacteroidetes to Firmicutes ratio has been observed ²⁴. This gut- microbiome pattern can be considered as biomarkers to distinguish between the COVID-19 group and healthy controls.

Heart failure has also been associated with specific gut-microbial species such as increased Escherichia coli, Klebsiella pneumoniae, and Streptococcus viridans ²⁵, similar to COVID-19. Likewise, a decrease in genera, including Bacteroides, Bifido-bacterium, Roseburia, Faecalibacterium, Akker-mansia, Ruminococcus, and Fusobacteriumin patients gut have been reported in a positive association with T2D ²⁶. Since patients with co-morbidities progress to serious adverse clinical outcomes in COVID-19, it is therefore tempting to speculate that the gut-dysbiosis in Covid-19 might resemble its related clinical manifestation like CVD and diabetes Table 1.

TABLE 1: THE PROFILE OF GUT-MICROBIOME IN COVID-19, CVD AND DIABETES MELLITUS PATIENTS

How does the Gut-Microbiome affect the Severity of COVID-19? Gut bacteria like Bacteroidetes and Firmicutes yielding SCFAs can lower serum lipid levels by blocking cholesterol synthesis and/or redirect them to the liver ³²; therefore, they have been suggested as a protective element in Coronary artery disease (CAD) like CVD development. Patients with certain CAD cases ³³ and hypertension ³⁴ have been reported to have reduced SCFAs-producing bacteria. T2D is associated with elevated levels of pro-inflammatory cytokines, chemokines, inflammatory proteins and lipopolysaccharides (LPS) responsible for metabolic endotoxemia and low-grade inflammation.

Several reports claim that Roseburia intestinalis, Bacteroides fragilis, Akkermansia muciniphila, Lactobacillus plantarum and L. casei-induced IL-10 production ^{35, 36} may improve glucose metabolism, as overexpression of this cytokine is reported to protect muscle from aging-related insulin resistance ³⁷. R. intestinalis in the gut might also increase an anti-inflammatory cytokine production like IL-22 ³⁸, known to restore insulin sensitivity and alleviate diabetes ³⁹.

Various gut bacteria have been found to decrease pro-inflammatory cytokines like IL-1β, Monocyte Chemoattractant Protein-1, Intercellular adhesion molecule-1, IL-8, CD36, C-reactive protein ⁴⁰, TNF-α ⁴¹, IFN-γ ³⁸ and increase anti-inflammatory molecules like NF-kB ⁴²; that may contribute to metabolism as well as reduce the formation of plaques and blood clots in the arteries ²⁶.

Hypothetically, gut-dysbiosis due to the lung infection with SARS-CoV-2 may also affect a patient's dietary and cardiovascular system, a possible reason that explains the clinical outcome of critical patients with co-morbidities Fig. 1.

FIG. 1: SARS-COV-2 INFECTION CAUSES ‘GUT-DYSBIOSIS’ THROUGH GUT-LUNG AXIS AND AFFECTS THE GUT FLORA. CONSEQUENTLY, BENEFICIAL FLORA IS REDUCED WITH THE INCREMENT OF OPPORTUNISTIC PATHOGENS. THEY PRODUCE LIPOPOLYSACCHARIDE (LPS) LEADING TO THE MASSIVE PRODUCTION OF PRO- AND ANTI- INFLAMMATORY MOLECULES. THIS SPURRING INFLAMMATION PROMOTES METABOLIC DISORDERS, TYPE 2 DIABETES, FOR EXAMPLE. ON THE OTHER HAND, SUCH INFLAMMATION MIGHT INDIRECTLY DAMAGE THE PULMONARY CELLS AND CAUSE FURTHER LUNG INFECTION. AGAIN, ALTERED GUT-MICROBIOME INCREASES THE SERUM LIPID CONCENTRATION IN BLOOD, RESULTING IN THE FORMATION OF FIBROUS PLAQUE IN ARTERIES. ALTOGETHER, THE OBSTRUCTED AIRWAYS DUE TO LUNG INFECTION AFFECT THE CARDIAC CONDITIONS. HENCE, ANY INDIVIDUAL WITH SARS-CoV-2 WOULD PROBABLY FACE FURTHER COMPLICATIONS IF THEY HAVE OTHER CO-MORBIDITIES LIKE CVD OR T2D DUE TO ALTERED GUT- MICROFLORA. (ORIGINAL IMAGE HAS BEEN CREATED WITH BIORENDER)

Covid-19 Drug and Gut-Microbiome Connection: Although no certain medication has been approved so far to treat COVID-19 patients, physicians around the world keep prescribing some empirical antibiotics as a concern to counter subsequent bacterial infections. Patients undertaking such antibiotics have been reported to show worse gut-dysbiosis and undesirable altered gut-flora ²⁸. Supporting their premise, a study on mice revealed that susceptibility to influenza virus gets escalated owing to antibiotics-induced gut-dysbiosis ¹⁷. Another report on mice showed that antibiotics therapy in early life changed gut-flora, which could possibly enhance the risk of allergic airways diseases in mice ⁴³. Also, antibiotics-mediated gut-microbiome disorder has been reported to affect the effectiveness of vaccines in humans ⁴⁴. All these reports advocate for the cautious use of antibiotics during the infection period of COVID-19 to minimize the possible alteration of gut-flora and to secure the efficacy of vaccines in this crisis ²³.

How the Gut-Microbiome might Assist when Fighting COVID-19: The effects of SARS-CoV-2 on other co-morbidities and its possible link to altered gut-microbiota make GI tract a potential target for management of the disease. Administration of prebiotics and probiotics have indicated decreased inflammation during an infection ⁴⁵, increased SCFAs, improvement of the gut environ-ment, regulation of immune functions, and the prevention of pathogenic infections ⁴⁶.

Orally administered probiotics have been reported to reduce cholesterol in the blood by 22–33% due to their bile salt hydrolase activity ⁴⁷. Probiotics, as immunomodulatory and anti-inflammatory substances, are useful nutritional supplements that show promising effects in respiratory disorders ⁴⁸. Two meta-analyses on humans reported efficacy of probiotics in minimizing the incidence and duration of respiratory virus infections ^{49, 50}. Another study showed that probiotics like Lactobacillus rhamnosus, live Bacillus subtilis, and Enterococcus faecalis could help critically ill patients on mechanical ventilation by developing less ventilator-associated pneumonia ⁵¹.

Besides, investigation on mice model showed that introduction of probiotic bacteria like Lactobacillus rhamnosus, Bifidobacterium lactis, and B. breve can down-regulate allergic response ⁵². Providing support to this observation, some scientists reported that probiotics, after metabolizing dietary fiber, increase the levels of SCFAs in the blood, which help against allergic inflammation in the lungs and liver without affecting blood glucose ²⁶. These studies support the base of using probiotics to calm the ‘cytokine storm’ and slow down the progression of severity in patients with COVID-19.

However, the management of critically ill patients demands more evidence. A balanced diet providing nutrients to the gut-microbes should therefore be prioritized all-time for boosting long time immunity to the lungs to keep it in sound shape.

CONCLUSION: Evidences suggest that a disturbed microbial community in the gut can establish an inflammatory environment that can be exploited by SARS-CoV-2 to augment the fatality of COVID-19 more likely. Therefore, when clinicians prescribe drugs with little anti-COVID-19 data that can be further antagonistic towards the health conditions, probiotic strains documented for gut- microbiome homeostasis could be a part of the regimen to reduce the likely dysbiosis and consequent clinical fragility. Dietary foods, prebiotics, or probiotics can dramatically influence the gut micro-flora, which can rejuvenate the inherent immunity, restore the intestinal mucosa damage during infection, recover the intestinal eubiotic state and attenuate relevant inflammation, thus driving the patients’ health in a favorable direction ⁵³. More research involving the well-reported probiotics and a gut-favoring diet are needed to shed light on the management of the patients to lessen the risk of COVID-19.

Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.

ACKNOWLEDGEMENT: MMK conceptualized the idea, SS and MMK drafted the manuscript and worked on literature review, AH critically reviewed the manuscript. Financial support from the Dean, Faculty of Biological Sciences, University of Dhaka, Bangladesh is gratefully appreciated that covered partially the publication charges of the article.

CONFLICTS OF INTEREST: Nil

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    How to cite this article:

    Sultana S, Hossain A and Karim MM: Gut-microbiome management: an issue worth considering in Covid-19 treatment. Int J Pharm Sci & Res 2021; 12(1): 1-7. doi: 10.13040/IJPSR.0975-8232.12(1).1-7.

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