The COVID-19 pandemic is a global health crisis caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), a single-stranded enveloped positive-sense RNA virus with an average diameter of 75–150 nm that originated in Wuhan, China, at the end of 2019 and spread worldwide [1]. On 11 March 2020, the World Health Organization (WHO) declared COVID-19 a global pandemic [2], and to date, almost 7-million people have died from COVID-19 [3]. The virus predominantly affects the respiratory system, inducing a spectrum of symptoms that can range from mild-to-severe respiratory impairment, with several symptoms such as pyrexia, respiratory distress, pharyngitis, exhaustion, and myalgia [4]. In more severe cases, COVID-19 infection may lead to the development of pneumonia and acute respiratory distress syndrome (ARDS), which may require mechanical ventilation and lead to a significant risk of mortality [5].

In addition to respiratory manifestations, the pathogenesis of COVID-19 may result in systemic consequences such as the failure of multiple organs and physiological systems throughout the body [6]. COVID-19 manifests as inflammation of the cardiac muscle (myocarditis) [7] and vascular organs (endotheliitis), which increases the risk of blood clots, leading to pulmonary embolism and deep vein thrombosis [8]. Several reports have suggested that COVID-19 is associated with arrhythmia [9] and myocardial infarction [10]. A group of neurological manifestations has been observed in patients with COVID-19, including loss of taste and smell [11], generalized headache [12], dizziness with vertigo [13], seizures [14], encephalitis [15], and Guillain–Barré syndrome [16]. However, the exact mechanism underlying these effects is still under the laboratory bench. Several digestive system symptoms, such as nausea, vomiting, diarrhea, and acute abdominal tenderness, have been observed in some COVID-19 patients [17]. Renal impairment with acute renal injury is found in COVID-19 patients as a result of an inflammatory reaction by the body or a direct viral invasion of the kidneys [18].

The human gastrointestinal tract (GIT) is densely populated by the microbiota. The gut microbiota, a collection of bacteria, viruses, and fungi that live in the gastrointestinal tract, not only maintains mucosal immunity but also regulates the host’s systemic immune response [19]. Gut microbiota plays an important role in a broad range of physiological processes, from the digestion of complex polysaccharides to the regulation of neuronal signaling. In recent decades, it is getting more and more attention because of its association with a wide variety of diseases, ranging from metabolic disorders (e.g., diabetes and its complications) ^{[20][21][22][23][24][25]}[20,21,22,23,24,25] to autoimmune diseases (such as rheumatoid arthritis, inflammatory bowel disease, and Type 1 diabetes), obesity [26], cancer [27], reproductive health ^[28][29][30][28,29,30], and sexual disorders ^[31][32][31,32], as well as neurodevelopmental disorders (e.g., autism) and neurodegenerative diseases (e.g., Alzheimer). Furthermore, modifying the microbiota in the human body may be a key factor for the treatment of disease. According to recent research on various respiratory disorders, gut microbiota may influence immunity and inflammation in the lungs [33].

2. Understanding the Composition and Diversity of the Gut Microbiota

Around 100-trillion microorganisms (bacteria, fungi, viruses, protozoa, and viruses) are found in the human gut. The human genome is made up of 23,000 genes, while the microbiome encodes over 3-million genes that produce more than thousands of metabolites, impacting human health [34]. The composition and metabolism of the adult gut microbial communities are affected by a combination of factors, including diet, demographics, use of medication, health status, and environmental components shaping the gut environment ^[35][36][37][35,36,37]. Humans can be herbivorous, carnivorous, etc., depending on the culture, food supply, etc. The diversity of the distinctive microbes of each habitat varies considerably, even in healthy individuals, with a high specialization of niches within and between individuals. According to the Human Microbiome Project Consortium, the overall fecal microbiota richness was estimated to be 226 bacterial genera among 208 donors [38]. The microbiota of the human gut is dominated by two major phyla: Bacteroidetes and Firmicutes ^[39][40][39,40].

3. Factors Influencing Gut Microbiota Composition, Including Diet, Lifestyle, and Medications

The intestinal microbiota is integral to human halobionts. Past studies have shown that various factors, such as diet and drugs, play an important role in the composition and diversity of the intestinal microbiome ^[34][41][42][34,41,42]. Dietary patterns, as well as individual foods, can directly influence the diversity of the microbiome. Artificial sweeteners (sucralose, aspartame, saccharin) significantly increased Bacteroides, Clostridia, and other aerobic bacteria in the gut. Food additives like emulsifiers in processed food reduced microbial diversity and increased inflammation promoting Proteobacteria ^[43][44][43,44]. Popular food-restrictive diets (vegan, raw food, gluten-free diets) can also impact gut microbial diversity. Some studies have shown the advantages of a vegan diet over an omnivorous diet, but others have not proven this theory [45]. Apart from food, drugs are also a key factor in the gut microbiota composition. Drugs such as proton pump inhibitors have a significant impact on microbial composition, which could explain the higher levels of gastrointestinal infection in people consuming these drugs. Antibiotics are impacting the intestinal microbiome [46]. Earlier observational human studies have shown an obesogenic effect in humans, even at low doses of antibiotics on food [47]. A Westernized lifestyle, such as behaviors, habits, and dietary patterns, may involve the alteration of gut microbiota. This lifestyle, which is characterized by a high intake of processed food, fructose corn syrup as an alternative of sugar, and unhealthy fats, was found to result in a higher prevalence of severe COVID-19 cases. Dietary habits can lead to underlying health conditions such as obesity, diabetes, and cardiovascular disorders, which are associated with the advancement of the diseases [48]. Several supplements such as Vitamin C, D, and zinc received attention due to their potential immune-boosting properties [49]. However, some studies suggested the effects of these supplements were inconclusive, and they are not proven cures or preventatives for COVID-19 [50].

4. Gut Microbiota Alterations in COVID-19 Patients

Several research investigations have explored alterations in gut microbiota in COVID-19 patients, illuminating the possible involvement of the gut microbiome in relation to the illness. The aforementioned investigation insights into the association between COVID-19 and gut microbiota dysbiosis, as well as its potential implications for the severity and treatment of the disease. A study conducted by Zuo et al. (2020) examined the gut microbiota composition in COVID-19 patients. The researchers observed a substantial reduction of beneficial commensal bacteria, such as Bifidobacterium and Lactobacillus, along with a corresponding increase in opportunistic pathogens, such as Clostridium hathewayi [51]. Another study conducted by Gu and colleagues in 2020 reported that the alteration of gut microbiota decreased the amount of butyrate-producing bacterial species, which are well-known for their potential anti-inflammatory effects. Furthermore, investigations observed that patients with COVID-19 exhibit a reduction of microbial diversity. A study by Zuo et al. (2021) showed a reduction in the prevalence of bacterial species linked to elevated microbial diversity in COVID-19 cases, in comparison with subjects without any underlying health conditions. The connection between a decline in microbial diversity and higher vulnerability to inflammatory illnesses and infections implies that it may be involved in the development of COVID-19 [52]. Interestingly, modifications in the gut microbiota have also been correlated with the severity of COVID-19. According to Yeoh and colleagues’ investigation conducted in 2021, it was identified that severe cases of COVID-19 were distinguished by a condition of gut dysbiosis, resulting in a decline in the presence of beneficial bacteria while allowing for an overgrowth of potential pathogens [53]. In another investigation conducted by Gu et al. in 2020, it was observed that patients with more severe symptoms have a discernible variation in the composition of their gut microbiota in relation to those experiencing milder symptoms [54]. These studies suggest a possible association between dysbiosis and the severity of symptoms associated with COVID-19. Dysbiosis in the gut microbiota can lead to impaired regulation of the immune response, elevated systemic inflammation, and increased susceptibility to respiratory infections. Several studies have indicated that the dysbiosis of gut microbiota may play a role in the pro-inflammatory conditions witnessed in severe cases of COVID-19. Dhar and Mohanty (2021) reported that the alteration of pro-inflammatory cytokine levels observed in COVID-19 patients, accompanied by the evidence of gut dysbiosis, suggests a potential mechanism by which the gut microbiota influences the variability in disease outcomes [55]. The gut microbiota has recently been identified as a promising diagnostic and prognostic indicator for COVID-19. Researchers have identified specific microbial indicators that enable differentiation between individuals afflicted with COVID-19 from healthy individuals. Qin Liu and colleagues developed a diagnostic model based on gut microbiota demonstrating high efficacy in discerning patients with COVID-19 from those without the infection. Moreover, specific microbial profiles have demonstrated a correlation with the severity of diseases, proposing that gut microbiota analysis could serve as a promising prognostic tool [56]. It is important to consider that the treatment of COVID-19 has a significant effect on gut microbiota. The administration of antibiotics and antiviral agents has been reported to potentially disturb microbial equilibrium, which may ultimately worsen dysbiosis. A study by Lucie et al. reported in 2022 that COVID-19 patients receiving antibiotics had greater dysbiosis compared to those not receiving antibiotics, suggesting the need for prudent administration of antimicrobial agents to ameliorate the potential adverse effects on the gut microbiota [57]. Yeoh and colleagues observed correlations between specific gut microbial taxa and inflammatory markers such as C-reactive protein (CRP) and cytokines with pro-inflammatory properties [53]. Research investigating gut microbiota alterations in COVID-19 patients has elucidated the phenomenon of dysbiosis, a decline in microbial diversity, and potential associations with the severity of the illness. The role of gut microbiota in modulating the immune response and impact of systemic inflammation emphasizes its significance in the pathogenesis of COVID-19.