key: cord-0833522-m007tl0t authors: Aldhafiri, Fahad K. title: COVID-19 and gut dysbiosis, understanding the role of probiotic supplements in reversing gut dysbiosis and immunity date: 2022-02-09 journal: Nutrition Clinique et Métabolisme DOI: 10.1016/j.nupar.2022.01.003 sha: 7055396c7c9d32ba55ba8343667797f57551fa8c doc_id: 833522 cord_uid: m007tl0t In December 2019, an outbreak of novel beta-coronavirus started in Wuhan, China, spread globally as coronavirus disease 2019 (COVID-19) pandemic and is still underway. The causative agent for COVID-19 identified as a novel strain of beta coronavirus named nSARS-CoV-2. The nSARS-CoV-2 primarily targets the respiratory tract and results in severe acute respiratory distress (ARDS), leading to the collapse of the respiratory tract. The virus internalizes primarily via ACEII receptor, and many tissues reported a significant level of expression of ACEII receptor including lungs, hearts, kidneys, and gastrointestinal tract. The clinical manifestations of COVID-19 are diverse, but growing evidence suggests that gut dysbiosis is one of them and poses a threat to native immunity. The human microbial ecology plays a vital role in human physiology, including building immunity. The gastrointestinal tract (GIT) habitats trillions of beneficial microbes’ precisely bacterial species synchronize with human physiology and remain symbiotic. On the contrary, harmful microbiota seeks an opportunity to break the equilibrium failure of balance between beneficial and detrimental human gut microbiota results in impaired physiology and immunity. The grown research evidence demonstrated that infection caused by the nSARS-CoV-2 result in moderate to severe diarrheal outcomes. The diarrheal conditions in COVID-19 patients are due to alteration of gut microbial ecology. The management of COVID-19 requires specialized therapeutics along with a series of nutraceuticals. Probiotics remain vital nutrient supplements in COVID-19 management, offer relief in diarrhea and improve/restore immunity. This study uses available data/findings to emphasize an association between COVID-19 and gut dysbiosis. The study also provides a scientific basis of impaired immunity during gut dysbiosis in COVID-19 and how probiotics help restore and improve impaired immunity and diarrhea. . Further, a close association of nSARS-CoV-2 with GIT was reported with many immune cells, i.e., plasma and lymphocytes in the lamina propria of the small and large intestine. The gut microbiota plays a vital role in establishing gut immunology, and during nSARS-CoV-2 infections, impaired immunity may result in gut dysbiosis [21] . The critical question here arises: Does viral particles and or components trigger system inflammation? If so, these viruses and or particles might influence gut immunology first. The human gut is the natural habitat of more than trillions of microbes, including bacteria, fungi, archaebacteria, and viruses. The number of microbe's habitat in the human gut, which is nearly 1014, represents a mere number and diversity [22.23] . The studies have also demonstrated that different gut sections allow colonization of various microbes, primarily from Bacteroidetes and Firmicutes [24] . These natural bacterial habitats provide several beneficial roles to human physiology including, immunity. The grown research evidence offers a scientific basis for the diverse habitat of microbes in the human gut, i.e., these microbes play a crucial role in the fermentation process of non-digestible substances like dietary fibers and endogenous mucus. Gut microbiota remains associated with three significant aspects of human health one; beneficial role such as the production of antibiotics, reducing toxins, improving lipid metabolism, low gut inflammation, controlling insulin sensitivity, and minimizing the risk of infections [25] . Secondly, pH and water/mineral control are associated with gut microbiota and homeostatic balance. The studies also demonstrated that gut microbiota, especially harmful microbes and or altered colonization of gut microbiota, results in the onset of various diseases [26] . As The research investigation demonstrated more than 1000 different microbial species habitats in the human gut with an increasingly large number of populations, i.e., 1014. There are helpful and harmful microbes; bacteria, fungi, and viruses. Both valuable and harmful microbial species remain in a close cross-talk and create a homeostatic balance between colonized microbes and the host gastrointestinal tract [30] . The healthy homeostatic balance between microbial ecology restricts the growth of potentially pathogenic microbes. Hence, the human gut remains a reservoir of beneficial microbes and maintains a healthy host-microbial interaction. Studies have demonstrated that host health positively correlates with the homeostatic balance of gut microbial ecology [31] . Gut dysbiosis is when intestinal microbiota fails to restore homeostatic balance in colonized microbial species. Several risk factors such as infection, food, daily lifestyle, age, gender, and environmental factors trigger the breakdown of the homeostatic balance of gut microbial ecology [32] . As a result, the gut environment allows harmful/potentially pathogenic microbes to grow and colonize. The altered microbial ecology results in negative cross-talk with the host and triggers several diseases. Gut microbial ecology remains a highly dynamic state in humans, and any change leads to altered functional composition, metabolic activities, and local distribution [33] . Gut dysbiosis results in the loss of beneficial microbial species, overall microbial biodiversity, and excessive growth of harmful microbes. The studies also investigated that gut dysbiosis affects gut immunology and provides an opportunity for various microbes and microbial products to elicit an immune response. Gut microbiota plays a vital role in gut immunology and immunity, both humoral and cellular. The gut-associated lymphoid tissues (GALT) are predominantly present in the small intestine, and a healthy gut microbiota helps in the functions of gut lymphoid tissues [34] . The physiological changes are related to stimuli from gut microbiota (signaling molecules and gut microbiota-driven metabolites) via hematopoietic cells of the innate immune system [35] . As a result, a healthy gut microbiota establishes a balance (immune homeostasis) between signaling molecules and gut immunology. There is a significant change in microbial population and diversity during gut dysbiosis, resulting in a difference in the whole signaling cascade [36] . Another vital role of gut microbiota in energy homeostasis and during gut dysbiosis the energy homeostasis remains broken that trigger alternate mechanism for energy harvesting [41] . Such alternate mechanisms for energy harvesting synthesis a series of metabolites do have a stimulatory effect on immune system components such as dendritic cells, GALT, and T cells. The research findings also demonstrated that gut dysbiosis promotes oxidative stress and synthesizes a series of free radicals and reactive oxygen species (ROS) [42] . The oxidative stress damages bio-molecules and alters the expression of mitochondrial DNA that encodes several critical enzymes required for energy production. Gut dysbiosis remains associated with both hypo and hyperactivity of the immune system, which triggers several diseases such as diabetes, inflammation, insulin resistance, autoimmune diseases, inflammatory bowel disease, and several forms of cancer. It is interesting to note here that human microbiota is not entirely explored. Based on available research-based evidence, humoral and cellular immunity is closely associated with gut microbial population and diversity [43] [44] [45] . A loss of gut microbial population and diversity, i.e., gut dysbiosis, is a crucial trigger for various diseases and immunity remaining central. Additionally, during gut dysbiosis, microbial population and diversity pose a challenge to characterize them and difficult to establish a metabolic signature [46] . In this pilot study, 15 patients were profiled for gut microbiota and reported significant change in the bacteria over control. The change in gut microbial ecology also depends on severity of disease. [58] 2. The study demonstrates COVID-19 remain associated with not only change in the gut microbial ecology but also specific [59] bacteria such Faecalibacterium prausnitzii, Clostridium butyricum, Clostridium leptum, and Eubacterium rectal. Respiratory infection remain associated with altered gut microbial ecology but the study demonstrated specific viral infection leads to change in particular gut microbes. Here, in the study, gut microbiome signature was entirely different in nSARS-CoV-2 infection compare to influenza. [60] 4. The study demonstrates the change in gut microbial ecology after nSARS-CoV2 infection leads to altered immune response. This is primarily due to change in gut microbial immunology where colonizing microbes play a vital role. [61] In a follow up study, after six month from discharge the gut microbial ecology was not stored and consequently the gut immunology/ immune response reported poor. [62] 6. The study demonstrates, altered gut microbial ecology remains associated with altered Metabolome. Here, in this study, non human primates' shows changes in short chain fatty acids after infection with nSARS-CoV2. The SCFAs are key metabolites from gut microbes. [63] Probiotics represent a group of bacterial species capable of producing valuable bio-molecules, and immune stimulants help establish host immunity. The mechanism of probiotics differs from bacteria in the formulation Table 2) . Probiotics have a wide range of physiological importance precisely in the case of the immune system via increasing Igs for profiling of gut microbiota along with supplement of probiotics may provide molecular insights of probiotics uses in the COVID-19 disease management. 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