Swarup K. Chakrabarti^1*, Dhrubajyoti Chattopadhyay^1,2

¹H. P. Ghosh Research Center, New Town, Kolkata, West Bengal 700161, India.

²Sister Nivedita University, New Town, West Bengal 700156, India.

*Corresponding Author: Swarup K. Chakrabarti, H. P. Ghosh Research Center, HIDCO (II), EK Tower, New Town, Kolkata, West Bengal 700161, India.

Abstract
The human gut hosts a varied community of microorganisms, collectively known as the intestinal microbiome, essential for maintaining well- being and implicated in numerous health conditions. Metabolic disorders such as obesity, diabetes, and non-alcoholic fatty liver disease (NAFLD) closely link to dysbiosis, the imbalance of this complex microbial ecosystem. This disruption impacts vital functions like nutrient uptake and the synthesis of critical compounds such as short-chain fatty acids (SCFAs) and bile acids, contributing to persistent inflammation and disturbances in immune function. In neurological conditions, dysbiosis influences neurotransmitter levels, immune system irregularities, and neuroinflammation, thereby impacting the complex interplay of the gut-brain axis. Diseases such as Parkinson's disease, Alzheimer's disease, multiple sclerosis, and autism spectrum disorder are among those influenced by these gut-brain interactions.

Additionally, dysbiosis can exacerbate autoimmune disorders by compromising gut barrier integrity, disrupting immune balance, and potentially triggering autoimmune responses such as molecular mimicry, seen in conditions like rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis. The global COVID-19 pandemic has underscored the microbiome's crucial role in immune response and disease severity, with dysbiosis potentially exacerbating outcomes through its effects on immune function and viral replication. Understanding these mechanisms is pivotal for developing targeted therapies. Promising approaches include dietary adjustments, probiotics, and fecal microbiota transplantation, which hold the potential for restoring microbial balance and improving overall health outcomes in these complex disorders.

Introduction
Within the complex ecosystem of human biology resides a dynamic metropolis comprised of trillions of microorganisms, collectively known as the intestinal microbiome [1–3]. This microscopic community, nestled within the complex folds of our digestive tract, exerts a profound influence on our health and susceptibility to diseases [4–6].

Beyond its conventional digestive functions, the intestinal microbiome serves as a vital regulator, intricately modulating interactions with our immune system, metabolism, and overall well- being [7–13]. Recent scientific investigations have shed light on the profound implications of this microbial community, unveiling its critical role in the onset and progression of diverse human ailments, ranging from metabolic disorders to neurological diseases [4–13, 14, 15].

Consequently, the intestinal microbiome emerges as a pivotal determinant of human health, presenting both opportunities and challenges in our quest to comprehend and harness its therapeutic potential.

This article primarily investigates how the disruption of the intestinal microbiome affects human health, leading to a multitude of diseases, and elucidates the underlying mechanisms that link them. By closely examining these mechanisms and evaluating evidence-based studies found in the literature that connect the intestinal microbiome to human diseases, we aim to enhance our understanding of how perturbations within this microbial community contribute to disease states. This endeavor aspires to pave the way for the development of targeted interventions and innovative therapeutic strategies to mitigate the effects of dysbiosis on human health.

Microbial Dysbiosis:
Implications for Health and Disease
Trillions of microorganisms live harmoniously within the human body, particularly in the gastrointestinal (GI) tract, numbering around 1×10¹⁴ and playing vital roles in intestinal growth, maintaining equilibrium, and defending against pathogens [16, 17]. The gut microbiome is composed of yeasts, viruses, and bacteria, with over a thousand bacterial species representing six primary phyla: Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria, Fusobacteria, and Verrucomicrobia [3]. Among these, Firmicutes and Bacteroidetes are the most prevalent, making up approximately 90% of the gut microbiota.

Notably, shotgun metagenomic sequencing revealed an extensive diversity of unclassified bacterial species, with 1952 species identified beyond the previously cultured 553 bacterial species in the gut [18]. The gut microbiota is predominantly composed of strict anaerobes, which can outnumber facultative anaerobes by up to 100- fold. While estimates of bacterial species abundance in the human gut vary, consensus suggests the presence of over a thousand species- level phylotypes within an individual [19–21].

Individuals exhibit significant variations in their microbiota composition, influenced by factors such as age, ethnicity, diet, and lifestyle [22–24]. The balance of gut homeostasis is often associated with the Firmicutes/Bacteroidetes (F/B) ratio, with fluctuations in this ratio linked to various diseases [25, 26].

While the Bacteroidetes phylum hosts approximately 7000 different species of Gram-negative bacteria, predominantly from genera like Bacteroides, Allistipes, Parabacteroides, and Prevotella, the Firmicutes phylum comprises Gram-positive, spore-forming bacteria with sturdy cell walls, primarily from genera such as Bacillus, Clostridium, Enterrococcus, Lactobacillus, and Ruminicoccus [16, 27, 28].

The preservation of biodiversity and the state of "eubiosis," characterized by balanced metabolism, immune response, and colonization resistance in the human gut, hinge on the relative abundance of Gram-negative Bacteroidetes compared to other phyla like Gram-positive Firmicutes [29, 30]. The concept of microbial networks underscores the coexistence of these organisms within ecosystems, akin to what Paine (1966) referred to as "keystone taxa," suggesting their indispensable role in upholding community organization and integrity [31, 32].

The healthy intestines of normal individuals host a diverse array of bacteria, encompassing over 1,000 species. In these individuals, pathogenic bacteria do not proliferate excessively within the intestinal tract because commensal and potentially harmful bacteria maintain a homeostatic balance. This balance, known as colonization resistance or the "barrier effect," serves as a first line of defense, protecting the host from the infiltration of external microorganisms [7, 33, 34].

Moreover, the gut microbiota plays a complex and essential role in interacting with the host's immune system through the mucosal surface, offering vital immune regulatory functions. These interactions involve priming the mucosal immune system to enhance innate immunity against harmful pathogens and training the immune system to coexist peacefully with beneficial commensal microbes. Additionally, the host gains substantial advantages from the microbiota's metabolic activities, such as breaking down complex carbohydrates and generating short-chain fatty acids (SCFAs).

However, when this delicate balance is disrupted, a condition known as dysbiosis occurs. Dysbiosis manifests through several hallmarks: an imbalance in bacterial composition, altered metabolic activity of bacteria, and shifts in the distribution of bacteria within the gut [39,40]. Dysbiosis can be categorized into three types: 1) loss of beneficial bacteria; 2) overgrowth of potentially harmful bacteria; and 3) reduction in overall bacterial diversity.

The gut microbiome plays a crucial role in metabolizing nutrients and facilitating the absorption of essential compounds from food. Dysbiosis disrupts this process, resulting in nutrient deficiencies and compromising overall health. Efficient nutrient absorption is vital for maintaining vitality and healthy living. Moreover, dysbiosis alters the metabolism of lipids, carbohydrates, and other nutrients, predisposing individuals to metabolic dysfunction and obesity [41, 42, 43].

Furthermore, the microbiome plays a role in breaking down host- derived mucins, as well as ingested sugars and alcohols [44]. Additionally, the gut microbiota demonstrates a remarkable ability to metabolize phytochemicals, particularly polyphenols, through established biochemical pathways [45]. The ample evidence indicating inter-individual differences in the metabolism of dietary polyphenols, mainly from fruits and beverages, underscores the impact of gut microbiota composition on this process. These variations may have implications for the health effects of specific polyphenols [46, 47].

Importantly, dysbiosis is closely associated with dysregulation of the immune system, metabolic dysfunction, and chronic inflammation, which are prevalent in conditions like cardiovascular diseases (CVDs), neurodegenerative diseases (NDs), and cancer [48–50].

The use of gnotobiotic or germ-free (GF) animals—organisms raised in sterile conditions without a gut microbiome—has significantly deepened our understanding of how the microbiome impacts the immune system [51, 52]. This approach enables researchers to investigate immune responses in the absence of microbial influence. Comparative studies between GF mice and those with a normal microbiome suggest that the latter generally exhibit a stronger innate immune system, particularly in terms of macrophage-mediated defense, leading to quicker and more robust immune responses [52– 54].

Consequently, dysbiosis-induced immune dysregulation may play a role in autoimmune diseases and other immune-related disorders [7- 9, 55–57].

Furthermore, studies have shown that antibiotic-induced microbiome depletion (AIMD) in mice disrupts gut homeostasis by reducing populations of luminal Firmicutes and Bacteroidetes species, consequently decreasing the production of SCFAs [58, 59]. This alteration in microbiota composition leads to a shift in energy utilization by colonocytes [60].

Additionally, the commensal microbiota plays a pivotal role in influencing the growth, differentiation, and function of T cells to maintain immune homeostasis [9, 61].

Recent research has emphasized the critical role of the gut-brain axis (GBA) in regulating behavior and brain function [62, 63]. Immune dysregulation from dysbiosis triggers a cascade of events, including increased production of pro-inflammatory cytokines in the gut, which leads to chronic, low-grade inflammation known as inflammaging [64–66].

In essence, the gut microbiome's balance is crucial for health, and dysbiosis can lead to various disorders. Understanding this relationship is key to developing strategies for a healthy microbiome. In the next section, we will explore how intestinal microbial dysbiosis is linked to specific diseases, discussing the underlying biochemical and cellular mechanisms.

Metabolic Meltdown:
The Link Between Dysbiosis and Metabolic Disorders
Recent scientific revelations underscore a critical connection between the balance of our gut microbiota and the integrity of our metabolic health. A myriad of metabolic disorders, including obesity, diabetes, and non-alcoholic fatty liver disease (NAFLD), have increasingly implicated dysbiosis in their onset and progression [67–74].

As we delve deeper into the microbial underpinnings of these conditions, it becomes evident that the gut microbiome is not merely a passive inhabitant but an active player in the metabolic harmony of the human body. This subsection explores the profound impact of dysbiosis on metabolic health, shedding light on the mechanisms through which microbial imbalance triggers metabolic dysfunction and highlighting the potential for microbiome-targeted therapies in combating these widespread ailments.

Early studies with GF mice, AIMD mice, and cohoused mice allowing for microbiota restoration through horizontal transmission provide strong evidence that changes in gut microbiota may play a causal role in metabolic disorders [75–77]. These foundational animal studies propose that lifestyle changes and unhealthy dietary habits, which are significant risk factors for metabolic diseases in humans, combined with the gut microbiome's dynamic and diverse nature influenced by nutrition, suggest a direct impact of the gut microbiota on metabolic disorders. This hypothesis is further supported by accumulating evidence showing that the gut microbiota and its metabolites are essential in the onset and progression of various metabolic disorders, including obesity, diabetes, NAFLD, and CVDs [67–74, 78–80].

For instance, studies have shown that dysbiosis associated with Type 1 diabetes (T1D) is characterized by a decrease in mucin-degrading bacteria, Bifidobacteria, Lactobacillus, and Prevotella, along with an increase in Bacteroidetes and Clostridium [81, 82]. In contrast, dysbiosis associated with type 2 diabetes (T2D) differs, showing a decrease in Clostridium and an increase in Lactobacillus, as well as a rise in Bacteroidetes in non-obese individuals [83, 84].

To elaborate, this study included 36 male adults with a broad range of ages and body mass indices (BMIs), of whom 18 were diagnosed with T2D. The fecal bacterial composition was analyzed using real-time quantitative PCR (qPCR) and tag-encoded amplicon pyrosequencing of the V4 region of the 16S rRNA gene. Results showed that the proportions of the phylum Firmicutes and the class Clostridia were significantly reduced in the diabetic group compared to the control group (P = 0.03).

Overall, these studies suggest that both T1D and T2D are associated with a reduction in overall microbial diversity, including a decrease in butyrate-producing bacteria and Firmicutes. This microbial imbalance contributes to the breakdown of intestinal epithelial barrier integrity and increased gut permeability [83].

Qin and colleagues conducted a study on the gut microbiome of 345 Chinese individuals, 171 of whom had T2D [85]. They discovered a notable decrease in butyrate-producing bacteria and an increase in opportunistic pathogens among the diabetic participants, indicating a connection between gut microbiota composition changes and T2D. Similarly, Karlsson et al. (2013) analyzed fecal samples from 145 European women, including 53 with T2D, and found that the T2D group had a lower abundance of firmicutes and butyrate-producing bacteria [86]. This finding suggests a significant role for the gut microbiota in the development of T2D.

Additionally, Leiva-Gea et al. (2018) examined the gut microbiota of 32 adults with T2D and 32 healthy controls, identifying significant changes in the microbial composition of those with diabetes. Specifically, there was a decrease in beneficial bacteria such as Akkermansia muciniphila and Faecalibacterium prausnitzii [87].

Together, these studies highlight the link between dysbiosis and diabetes, demonstrating how alterations in gut microbiota composition are associated with the onset and progression of T2D. Moreover, recent human studies have solidly linked gut dysbiosis with both obesity and NAFLD [78–80]. Although a detailed exploration of these studies falls outside the scope of this article, they provide compelling evidence for the critical impact of gut dysbiosis on these health conditions. These findings offer valuable insights into the underlying mechanisms and propose potential therapeutic avenues for addressing these significant health challenges.

One prominent connection between dysbiosis and metabolic diseases lies in the nutrient sensing mechanism governed by the gut microbiota [88, 89]. The gut microbiome substantially impacts nutrient sensing by modulating gene expression pertinent to nutrient metabolism and absorption and by modulating the host's immune system to regulate energy equilibrium. Dysbiosis, marked by an imbalance in the composition of the gut microbiota, can disturb these processes, culminating in metabolic imbalances.

Nutrient sensing mechanisms are essential for monitoring and responding to the availability of macronutrients, which are fundamental for life. These intricate processes, evolved to ensure survival during nutrient scarcity, involve various sensors and signaling pathways within cells. One key sensor is AMP-activated protein kinase (AMPK), which activates during low-energy states to help maintain cellular energy balance [90–92].

Another critical component is the mammalian target of rapamycin (mTOR), which integrates signals from amino acids and growth factors to control processes like protein synthesis and cell growth [93]. Nevertheless, in numerous metabolic disorders, these sensing mechanisms may malfunction. For example, the insulin-signaling pathway, essential for managing glucose levels, can experience dysregulation, impacting glucose uptake and metabolism [94].

In essence, dysbiosis-induced changes in the gut microbiota can disrupt nutrient sensing mechanisms, contributing to the development of metabolic diseases. Understanding these processes at a molecular level is crucial for developing targeted therapies for metabolic disorders.

Gut Instincts:
The Role of Dysbiosis in Neurological Diseases-Evidence and Mechanisms
Dysbiosis is increasingly acknowledged as a pivotal element in the etiology of diverse neurological disorders [95–99]. Multiple investigations have underscored the intricate interplay between dysbiosis of the human gut microbiome and an extensive array of neurological maladies. Individuals afflicted with neurological disorders consistently manifest markedly disparate microbiota profiles relative to their healthy counterparts.

For instance, individuals diagnosed with Parkinson's disease (PD) exhibit a distinctive gut microbiota profile typified by diminished levels of Prevotellaceae and heightened levels of Enterobacteriaceae, implicating dysbiosis in the pathogenesis of PD [100]. Likewise, perturbations in the gut microbiota of Alzheimer's disease (AD) patients have been delineated, characterized by an upsurge in pro- inflammatory taxa juxtaposed with a reduction in anti-inflammatory taxa, suggesting a plausible association between dysbiosis and neuroinflammation in AD [101, 102].

Notably, specific gut microbial taxa linked to the risk and progression of multiple sclerosis (MS) have been identified, with MS patients demonstrating an augmented abundance of pro-inflammatory bacteria alongside a diminished presence of anti-inflammatory bacteria, thereby implicating dysbiosis in the pathophysiology of MS [103, 104]. Additionally, investigations have revealed aberrations in the gut microbiota of children afflicted with Autism Spectrum Disorder (ASD), encompassing diminished microbial diversity and alterations in specific bacterial taxa, suggesting a potential nexus between dysbiosis and ASD [105–107].

The complex interplay between gut dysbiosis and neurological disorders is underscored by a plethora of mechanisms, as elucidated in this discourse [108–110]. Recent scientific inquiry has highlighted the reciprocal communication axis linking the gut and the brain, known as GBA. This axis serves as a conduit for bidirectional signaling between the gut microbiome and the central nervous system (CNS), exerting influence over mood, behavior, and cognitive processes [99, 110]. Perturbations in the microbiome have been intricately linked to the pathogenesis of anxiety, depression, and other psychiatric disorders, emphasizing the pivotal role of gut health in maintaining optimal neurological function [111–114].

An illustrative instance of microbial impact on behavior is evident in mammals infected with the rabies virus, where the virus triggers aggressiveness and hydrophobia. The correlation between GI disturbances and the onset of neurological and psychiatric ailments, including depression, schizophrenia, ASD, and NDs, is increasingly recognized [115, 116]. Although the precise mechanisms dictating the influence of gut microbes on brain function and behavior remain intricate and manifold, the pathway involving the enteric nervous system (ENS) and the vagus nerve emerges as a pivotal conduit for gut-derived neurochemical signals to reach the brain [117-119].

Evidence gleaned from preceding investigations by diverse researchers suggests bidirectional communication between the gut microbiome and the brain, particularly implicating the hypothalamic- pituitary-adrenal (HPA) axis, with notable repercussions on neurobehavioral and neuropsychological processes [120–121]. Studies on GF mice have revealed alterations in corticosterone levels and brain-derived neurotrophic factor (BDNF), a protein fundamental for neurogenesis and synaptic plasticity [120, 123–125].

Significantly, a substantial causal link between brain health and the microbiome has been demonstrated by partially mitigating these effects through recolonization with a diverse microbiota in adulthood, employing a gain-of-function strategy [124, 126, 127].

Moreover, studies on GF mice suggest an increased permeability of the blood-brain barrier (BBB) during both fetal development and adulthood. This heightened permeability in GF mice, lacking any microbiota, is attributed to reduced production of endothelial tight junction proteins, specifically occludin and claudin-5 [111, 128, 129]. However, it seems possible to restore BBB integrity in adult GF mice through mono-colonization with either Bacteroides thetaiotaomicron or Clostridium tyrobutyricum. These species elevate levels of BBB constituent tight junction proteins by releasing SCFAs derived from the gut, which directly repair the dysregulated BBB in mice, despite the distance from the source [109, 129].

Signal transmission between neurons, glial cells, and astrocytes, primarily mediated by neurotransmitters, is crucial for the brain's functioning [130–136]. Inhibitory neurotransmitters like GABA, glycine, and serotonin, as well as excitatory neurotransmitters such as glutamate, acetylcholine, and dopamine, intricately regulate movement, sensation, learning, and memory. Certain gut bacteria have the capability to produce neurotransmitters like GABA and serotonin, or their precursors, which can modulate intracellular signaling in neurons and other cells crucial for cognitive function. These neurotransmitter precursors possess the ability to cross the BBB, participating in neurotransmitter synthesis cycles within the brain [135–137].

Moreover, specific gut bacteria can communicate via their metabolites to regulate the production and release of neurotransmitters by intestinal enteroendocrine cells. These cells can act locally on the ENS or rapidly transmit signals to the brain through the vagus nerve [138-140]. Early-life colonization of the gut microbiota has been shown to impact neurodevelopmental processes, including brain development and behavior [141, 142]. Studies in GF animals have revealed alterations in brain morphology, neurotransmitter levels, and behavior, mediated in part by the microbiota's influence on the immune system and the HPA axis [119– 122].

Together, mounting evidence underscores the significant contribution of the gut microbiota to the pathogenesis of neurological disorders through the GBA. Metabolites, chemicals, and endotoxins secreted by intestinal bacteria can impact the expression levels of neurotransmitters, their precursors, and receptors in the CNS via the bloodstream or vagus nerve pathways.

Furthermore, neurotransmitters or other substances originating from gut microorganisms may influence vagus nerve activity, subsequently impacting brain function. These observations suggest that serum metabolites, typically unable to traverse the BBB, may do so when the gut microbiome is in a healthy state. This supports the notion that gut-derived metabolites play a significant role in regulating brain health.

Disrupted Harmony:
How Dysbiosis Propels Autoimmune Disorders
Autoimmune diseases arise from immune system dysfunction that fails to distinguish between self and non-self-antigens. While external environmental triggers are known to contribute, increasing attention is being paid to the role of the microbiome in the body's internal environment, especially the gut microbiome [143–147]. This microbiome acts as a bridge between external environmental factors and the immune system, assisting in programming the immune system to tolerate harmless external and self-antigens [148, 149]. However, when the gut microbiota is disrupted, the immune system can be mistakenly directed toward pro-inflammatory pathways, leading to various autoimmune processes and the development of multiple autoimmune diseases [144–147].

Dysbiosis has emerged as a significant factor in the development and progression of autoimmune disorders. Studies have consistently demonstrated alterations in the fecal microbiota of individuals with autoimmune conditions such as rheumatoid arthritis and systemic lupus erythematosus compared to healthy controls [150–153]. For instance, Vaahtovuo et al. (2008) found differences in the fecal microbiota of early rheumatoid arthritis patients, suggesting a potential role of dysbiosis in the pathogenesis of this condition [154]. Furthermore, Manfredo Vieira et al. (2018) demonstrated that dysbiosis could facilitate the translocation of pathogenic bacteria across the gut barrier, triggering autoimmune responses in genetically susceptible hosts [155]. This finding underscores the importance of gut barrier integrity in autoimmune diseases. Rosenbaum and Asquith (2016) discuss the therapeutic potential of modulating the gut microbiota to manage autoimmune disorders, highlighting the microbiome as a promising target for treatment [156].

Additionally, Hevia et al. (2014) identified dysbiosis in individuals with systemic lupus erythematosus, correlating with increased disease activity, further emphasizing the link between gut microbiota dysregulation and autoimmune pathology [152]. Collectively, these findings underscore the intricate relationship between dysbiosis and autoimmune disorders, suggesting that interventions targeting the gut microbiota could offer novel therapeutic avenues for managing these conditions.

Dysbiosis significantly impacts the development and progression of autoimmune disorders through interconnected pathways [150, 157, 158]. First, it compromises the integrity of the gut barrier, leading to increased permeability, commonly termed 'leaky gut.' This breach allows microbial products like lipopolysaccharides (LPS) to enter the bloodstream from the gut, triggering immune responses and chronic inflammation, thereby contributing to the pathology of autoimmune diseases [159-162].

Second, dysbiosis disrupts immune homeostasis by altering the balance between pro-inflammatory and regulatory immune cells, fostering an environment conducive to autoimmune reactions [163, 164]. Third, dysbiosis triggers molecular mimicry, where pathogenic bacteria share antigens resembling host tissues, prompting immune responses against both microbes and self-antigens [165–167].

Furthermore, dysbiosis modulates metabolic pathways, producing immunomodulatory metabolites such as SCFAs and bile acids, which can impact immune cell function and exacerbate inflammation, thus exacerbating autoimmune processes. Finally, dysbiosis-induced epigenetic changes in host cells, such as alterations in DNA methylation or histone modifications, disrupt immune regulation and intensify autoimmune responses [168–170].

These intricate mechanisms underscore dysbiosis' multifaceted role in autoimmune disorders, emphasizing the necessity of restoring gut microbial balance for effective therapeutic intervention.

Microbiome Mayhem:
The Gut's Role in COVID-19 Pathogenesis
The COVID-19 pandemic, instigated by SARS-CoV-2, has highlighted the urgent need to understand host factors that influence disease susceptibility and severity [171–174]. Among these factors, the human microbiome plays a critical role. This short discussion explores the complex relationship between age-related changes in microbiome diversity and the development of COVID-19. By examining microbiome dynamics, we aim to illuminate their significant impact on COVID-19 susceptibility and severity. This analysis underscores the necessity for further research into the connections between age-related microbiome changes and the progression of the COVID-19 pandemic.

Recent research has identified a significant connection between the gut microbiota and COVID-19, emphasizing the role of dysbiosis in the disease's development [177–179]. Zuo et al. (2020) found that COVID-19 patients had notable shifts in their gut microbiota, with an increase in harmful bacteria and a decrease in beneficial ones, correlating with disease severity. Similarly, Gu et al. (2020) observed a reduction in gut microbiota diversity and richness in COVID-19 patients, hinting at a weakened immune response [176].

Yeoh et al. (2021) also discovered that specific gut microbial signatures could predict the severity of COVID-19, underscoring the microbiome's influence on the host's viral response [177].

Further studies support these findings. Zhuo et al. (2023) reported significant differences in the gut microbiota of COVID-19 patients compared to healthy individuals, particularly a reduction in beneficial bacteria like Faecal bacterium prausnitzii [178].

Zhang et al. (2023) identified distinct microbial profiles in severe versus mild cases of COVID-19, reinforcing the link between gut dysbiosis and disease progression [180]. Zheng et al. (2023) noted that changes in gut microbiota composition persisted even after recovery, indicating long-term impacts on gut health [181]. Collectively, these studies highlight the crucial role of the gut microbiome in COVID-19 susceptibility and severity, pointing to the need for further research into microbiome-targeted therapeutic approaches.

Several mechanisms have been suggested to explain how the microbiota might impact COVID-19 pathogenesis. First, the microbiome's role in modulating the immune system could affect the response to SARS-CoV-2 infection, potentially influencing disease severity [176, 177, 182, 183]. Research indicates that a healthy, balanced gut microbiome is crucial for the development and function of a strong immune system [148, 149]. Conversely, dysbiosis, or an imbalance in the gut microbiota, can lead to weakened immune responses, which may result in more severe outcomes for COVID-19 patients [175, 176].

Additionally, the gut microbiota may regulate the expression of ACE2 (Angiotensin-converting enzyme 2), the receptor utilized by SARS- CoV-2 for host cell entry, thereby influencing virus replication dynamics [184–186]. Research indicates that ACE2 is not only a critical entry point for the virus but also involved in maintaining gut microbial homeostasis and function [186-188]. Alterations in gut microbiota composition could affect ACE2 expression, potentially impacting viral entry and propagation [189].

Moreover, the microbiome's production of metabolites, such as SCFAs, bile acids, and tryptophan metabolites, has the potential to affect virus replication and host immune responses, thereby shaping the trajectory of COVID-19 infection [177–178]. SCFAs, for instance, are known to possess anti-inflammatory properties and modulate the immune system, which could influence the body's ability to combat SARS-CoV-2 [190, 191].

The gut-lung axis also plays a crucial role in this interplay, as gut microbiota can influence respiratory tract immunity through systemic circulation of microbial metabolites and modulation of immune cell functions [192–194]. For example, dysbiosis can lead to increased gut permeability, allowing the translocation of bacterial components such as lipopolysaccharides (LPS) into the bloodstream, which can trigger systemic inflammation and worsen respiratory outcomes in COVID- 19 [176, 182].

These intertwined mechanisms underscore the intricate relationship between the microbiota and COVID-19 pathogenesis, suggesting that maintaining a healthy gut microbiome could be a vital component in managing and mitigating the impact of COVID-19. Further research into the specific microbial species and metabolites involved, as well as their mechanistic pathways, could provide valuable insights for developing targeted therapeutic strategies.

In conclusion, the human microbiome, especially the intestinal microbiome, plays a pivotal role in promoting health and preventing disease. Dysbiosis, characterized by an imbalance in the gut microbiota, correlates with various health conditions such as metabolic disorders, neurological diseases, autoimmune disorders, and even COVID-19. The mechanisms by which dysbiosis affects these diseases are intricate and involve immune dysregulation, metabolic dysfunction, and neurochemical signaling pathways.

Understanding these mechanisms is crucial for devising precise interventions and pioneering therapeutic approaches to rebalance the microbiome and alleviate dysbiosis's impact on human health. Continued exploration of the microbiome's role in disease pathogenesis is essential to fully harnessing its potential for enhancing health outcomes.

Future Directions
As research on the gut microbiome's role in health and disease advances, there is a growing need to explore personalized microbiome interventions tailored to individual health requirements, particularly in the context of dysbiosis-mediated diseases. These diseases, characterized by microbial imbalance, necessitate targeted strategies, such as microbiome replacement therapies, to provide new avenues for treatment.

The field of personalized microbiome interventions has expanded significantly with the rise of shotgun metagenomics-based research and advanced data analysis techniques. This advancement presents a hopeful avenue for precision medicine, enabling customized treatments based on an individual's unique microbiome composition. Through personalized interventions targeting the microbiome, particularly by restoring depleted microbial strains and implementing tailored dietary regimens, the goal is to rebalance gut microbiome signals implicated in diseases associated with dysbiosis [195, 196]. Precision medicine extends its influence to provide personalized dietary recommendations tailored around an individual's microbiome profile [197]. This tailored approach involves avoiding foods that disrupt the microbiome while increasing the intake of microbiome- friendly foods. Moreover, precision medicine explores personalized lifestyle modifications, offering customized suggestions for exercise routines, stress management techniques, and optimal sleep practices to meet individual needs [198, 199].

A critical aspect of precision medicine involves continuous monitoring of the microbiome to assess the effectiveness of interventions. Adjustments are made in response to changes in microbiome composition or alterations in an individual's health status, ensuring a dynamic and responsive approach to treating dysbiosis-mediated diseases.

As our understanding of the microbiome's impact on dysbiosis- mediated diseases expands, so does the potential for targeted interventions. While interventions like fecal microbiota transplantation (FMT) show promise, ethical concerns regarding donor selection and safety remain. Regulatory challenges also loom large, given the personalized nature of microbiome-based therapies. However, the emerging field of synthetic biology holds promise for engineered microbiomes tailored for therapeutic purposes. Ultimately, while microbiome-targeted interventions offer hope for addressing dysbiosis-mediated diseases, further research, ethical considerations, and regulatory frameworks are essential for realizing their full potential in personalized therapy.

Conflict of Interest: The authors declare that they have no conflicts of interest concerning the publication of this research.

Funding: The research is financially supported by an intramural grant generously provided by the Bandhan Group.

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