1. Introduction

About 150–170 major bacterial species live in the human gut, where they carry out defensive, metabolic, and structural tasks in a nutrient-rich environment [1]. These microbes are crucial to preserving health because they affect a number of physiological functions, including the creation of vital vitamins and the digestion of complex carbohydrates [2]. Furthermore, the regulation of immune responses is significantly influenced by the gut microbiome. [3]. Furthermore, immune response regulation is a crucial function of the gut microbiota [3]. It is essential for immunological regulation, mental wellness, and metabolic processes to have a varied and well-balanced microbial community. Disturbances in this equilibrium, however, have been linked to a number of illnesses, such as those pertaining to the gastrointestinal tract, metabolism, and immune system [4]. A number of illnesses affecting the central nervous system (CNS) have been linked to dysbiosis in the gut microbiota. The microbiota-gut-brain axis, which refers to the bidirectional contact between the gut microbiota and the central nervous system, is becoming more and more evident [5].

This paper aims to provide a comprehensive review of the relationship between the gut microbiome, health, and disease, particularly its involvement in metabolism, immune function, and the brain-gut axis. This review will provide an in-depth analysis of how the gut microbiome influences human health, contributes to disease development, and offers potential treatment strategies such as probiotics, prebiotics and Fecal Microbiota Transplant for various conditions.

2. Impact of Gut Microbiome on Human Health

2.1. Immune System Modulation

The immune response within the tumor microenvironment is influenced by the gut microbiota's interactions with innate and adaptive immune cells. Through the synthesis of metabolites, which can transcend the gut and strengthen systemic as well as local immune responses, they play a crucial role in controlling anticancer immunity and boosting the effectiveness of immune checkpoint inhibitors (ICIs). Mechanistic studies have revealed new possibilities for improving immune checkpoint outcomes (ICI) and advancing microbiota-driven precision medicine in cancer treatment through the use of microbiota-based therapies, including fecal microbiota transplants (FMT), probiotics, engineered microbiomes, and targeted microbial metabolites [3].

2.2. Brain-Gut Axis

The gut and brain communicate via two primary neuroanatomical pathways: the vagus nerve and autonomic nervous system (ANS) in the spinal cord, and the enteric nervous system (ENS) in the gastrointestinal tract. This two-way communication is associated with various neurological and psychiatric conditions, such as anxiety, depression, autism spectrum disorder (ASD), Alzheimer's disease (AD), multiple sclerosis (MS), Parkinson's disease (PD), and gastrointestinal issues, including irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD). Dysbiosis, or imbalances in the gut microbial population, is strongly associated with these health conditions [5].

2.3. Role in Early Development

Microbial colonization in humans begins at birth, as exposure to maternal microbes occurs during pregnancy and delivery. The mode of delivery, whether vaginal or C-section, plays a critical role in shaping the newborn's microbiome, leading to notable differences. Various factors such as prematurity, breastfeeding, maternal health, genetics, and exposure to antibiotics can also affect this early microbial development [5]. Throughout the first year of life, the infant’s microbiome becomes increasingly similar to the mother’s, with reduced variation between individuals. Even before solid foods are introduced, the infant's microbiome is primed for a more complex diet, particularly in digesting plant polysaccharides. With the introduction of solid food, the microbial composition undergoes a significant shift, marked by an increase in Bacteroidetes and the production of short-chain fatty acids. Additionally, there is enhanced microbial activity related to carbohydrate digestion, vitamin production, and detoxification processes [6].

3. Gut Microbiome and Disease

3.1. A. Microbiome Dysbiosis

It is evident that maintaining a balanced microbiome is crucial for sustaining health, as disruptions in the microbiome can transform the relationship between the host and microbes from harmonious to harmful.

3.2. Gut Microbiome and Gastrointestinal Diseases

The intricate condition referred to as inflammatory bowel disease (IBD) arises from a mix of microbial, environmental, and genetic influences that lead to an atypical immune reaction, resulting in inflammation within the intestines. IBD comes in two primary forms: ulcerative colitis (UC) and Crohn's disease (CD). According to research, dysbiosis, or imbalances in the gut microbiota, can cause an abnormal adaptive immune response, which can exacerbate inflammation and worsen gastrointestinal tract damage[7]. Advancements in gene-sequencing technologies and bioinformatics have provided deeper understanding of how microbial communities affect human physiology, including their role in diseases. Over 90% of the gut microbiota consists of bacteria from four main phyla: Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria. 16S rRNA sequencing has shown that microbiota in individuals with inflammatory bowel disease (IBD) differ significantly from healthy people, characterized by reduced diversity and bacterial load, known as “dysbiosis.” Studies on ulcerative colitis (UC) and Crohn’s disease (CD) revealed a decline in Firmicutes, especially Clostridium, and a rise in Proteobacteria, alongside a reduction in protective species like Bacteroides, Eubacterium, and Lactobacillus. Disrupted gut microbiota also leads to lower short-chain fatty acid (SCFA) production, which contributes to IBD pathogenesis due to SCFA's anti-inflammatory properties and their role in gut cell energy. This dysbiosis results in chronic inflammation and damage to gut epithelial integrity, causing harmful leakage from the gut into the bloodstream [8].

3.3. Microbiome and Metabolic Disorders

Obesity is a significant public health concern today, defined by the persistent accumulation of fat within adipose tissue. A range of factors contributes to this condition, but the primary cause is often an imbalance between the calories consumed from food and drinks and the energy expended by the body. Emerging research indicates that alterations in the gut microbiota may contribute to this imbalance. Gut microbes play a critical role in various obesity-related functions, including the absorption and digestion of nutrients, energy regulation, maintenance of the intestinal barrier, and the metabolism of carbohydrates, fats, and bile acids. Moreover, these microbes affect gut motility and help to modulate both the immune and hormonal systems. Changes in the composition and function of gut microbiota can increase the risk of metabolic disorders through several mechanisms. These include enhanced energy extraction from food, heightened gut permeability that may lead to metabolic endotoxemia, and disruptions in bile acid metabolism and signaling pathways associated with G-protein-coupled bile acid receptors (FTR/TGR5). Furthermore, microbial metabolites, such as lipopolysaccharides (LPS), indoles, trimethylamine N-oxide (TMAO), and short-chain fatty acids (SCFAs), significantly influence metabolic health by regulating various metabolic pathways[9].

3.4. Microbiome and infectious Disorders

Clostridium difficile infection (CDI) is the most common hospital-acquired infection in the U.S., affecting over 500,000 people annually. A diverse microbial community in the gut is essential for resisting CDI colonization, and disruptions to this microbiota heighten the risk of infection. Schubert et al. found that key bacteria such as Ruminococcaceae, Lachnospiraceae, Bacteroides, and Porphyromonadaceae were missing in CDI patients but prevalent in healthy controls without diarrhea. These microbial changes are even more evident in patients with recurrent CDI, often due to repeated antibiotic use, showing higher levels of Proteobacteria and lower levels of Bacteroides and Firmicutes. [6].

3.5. Gut Microbiome and Mental Health

There is compelling clinical evidence that the development of autism spectrum disorder (ASD) is influenced by both hereditary and environmental variables. The development of the central nervous system (CNS) has been linked to more than 100 genes and areas, as well as environmental variables such as viral infections, starvation, and maternal autoantibodies that target brain proteins in the developing brain [5].Recent studies reveal a significant link between gut microbiota and ASD, as many individuals with ASD suffer from gastrointestinal (GI) issues like altered bowel movements and chronic pain. Dysbiosis, which disrupts the mucosal barrier, increases intestinal permeability, leading to the entry of harmful peptides and the production of inflammatory cytokines, potentially worsening ASD symptoms[10]. Children with PDD-NOS and autism (AD) exhibit distinct fecal microbiota and metabolome profiles, including differences in neurotransmitter molecules. In particular, levels of free amino acids (FAA) and volatile organic compounds (VOC) vary between AD and PDD-NOS, with the latter resembling healthy controls (HC) more closely. Studies comparing the gut microbiota of children with PDD-NOS and AD to healthy children found microbial imbalances (dysbiosis), with overgrowth of some bacteria and depletion of others. Additional research supports the role of gut microbiota in ASD pathogenesis, with GI issues like abdominal pain, diarrhea, and bloating commonly seen in affected children[11].

Schizophrenia (SCZ) is a serious mental health condition whose molecular mechanisms remain largely unknown. The gut microbiome influences behavior and brain function via the microbiota-gut-brain axis. When compared to healthy controls (HCs), SCZ patients, whether treated or untreated, displayed reduced α-diversity in their microbiomes and significant alterations in gut microbial composition. The severity of SCZ has been linked to particular bacterial families, such as Veillonellaceae and Lachnospiraceae. A microbiological panel that includes Aerococcaceae, Bifidobacteriaceae, Brucellaceae, Pasteurellaceae, and Rikenellaceae demonstrated an accuracy of 0.769 in distinguishing SCZ patients from HCs. Furthermore, germ-free mice that underwent fecal transplants from SCZ patients exhibited behaviors characteristic of SCZ and showed altered levels of glutamate, glutamine, and GABA in their hippocampus, suggesting that the SCZ-associated microbiome may contribute to the neurological changes related to the disorder[12].

4. Therapeutic Potential of Modulating the Gut Microbiome

Probiotics have been suggested as a viable option to prevent gastrointestinal disorders due to their antimicrobial, anti-inflammatory, and anti-cancer properties, which contribute to restoring balance in a disrupted gut microbiome [13]. In a single-center, randomized, double-blind, placebo-controlled study, over 500 adults diagnosed with asymptomatic inflammatory bowel disease (IBD) were recruited. The subjects were given either a probiotic (Symprove) or a placebo for a duration of four weeks. The main outcome measured was the change in scores from the IBD Quality of Life Questionnaire (IBD-QOL), while secondary outcomes included laboratory tests, such as faecal calprotectin (FCAL) levels. Of the 142 patients who completed the trial, 81 had ulcerative colitis (UC), and 61 had Crohn's disease (CD). Although there were no significant differences in IBD-QOL scores or other lab results between the two groups, FCAL levels in UC patients approached significance (p = 0.076). The Post-hoc analysis identified a notable reduction (p < 0.015) in FCAL levels for those taking the probiotic compared to the placebo. This multi-strain probiotic demonstrated reduced intestinal inflammation in UC patients, though it did not exhibit the same effects in those with CD. The probiotic was well tolerated by most participants. Further research is required to explore whether this probiotic can help reduce clinical relapses in IBD patients without symptoms [14]. Prebiotics are typically indigestible components of food that selectively promote the growth and activity of specific bacteria in the gut. It is well-established that individuals with metabolic syndrome (MetS) often experience changes in their gut microbiota composition, along with neuropsychiatric symptoms. As prebiotics can positively influence the microbiota, they present a promising approach to enhance both physical and mental well-being in patients suffering from MetS [15].

In a study examining the influence of prebiotics on metabolic syndrome (MetS) in an obese, type-2 diabetic db/db mouse model, oligofructose was administered for eight weeks to observe its effects on both metabolic and behavioral alterations. Researchers monitored parameters such as body mass, dietary intake, glucose regulation, and anxiety-like behavior, while also focusing on neurobiological aspects, particularly neuroinflammation. The findings showed that prebiotic supplementation reduced overeating and enhanced glycemic control, demonstrated by improvements in glucose tolerance and insulin sensitivity. This was associated with increased plasma concentrations of the anti-inflammatory cytokine IL-10 and enhanced integrity of the blood-brain barrier, evidenced by the restoration of tight junction protein expression. Despite these metabolic benefits and a reduction in hippocampal IL-6 mRNA levels, prebiotics did not improve behavioral symptoms or stimulate neurogenesis in the hippocampus. These results indicate that prebiotics may present potential therapeutic strategies for managing certain MetS-related comorbidities [16].

4.1. Fecal Microbiota Transplant (Use in treating diseases like Clostridium difficile infections)

The way that patients react to immunotherapies, especially immune checkpoint inhibitors (ICIs), can be influenced by the makeup and variety of their gut microbiota. While dysbiosis may lead to treatment resistance, some microbial species seem to improve the immune system's capacity to attack malignancies. Therefore, by altering the gut microbiome, therapies including fecal microbiota transplantation (FMT) are being investigated to enhance immunotherapy outcomes.

The whole gut microbiome of a donor—typically someone who has reacted to immune checkpoint inhibitors (ICI)—is transplanted during fecal microbiota transplantation, or FMT. Delivery methods for the microbiota include gastroscopy, colonoscopy, and oral capsules. FMT was first created to treat Clostridium difficile infections that did not improve with traditional therapies. Recent studies have demonstrated that FMT may assist overcome immunotherapy resistance and improve the efficacy of ICIs [3].

In the experiment, researchers analyzed baseline stool samples from metastatic melanoma patients before immunotherapy using three methods: 16S rRNA gene sequencing, metagenomic shotgun sequencing, and quantitative PCR. They identified 63 operational taxonomic units (OTUs) with different abundances between responders (R) and non-responders (NR), with 39 OTUs more abundant in R and 23 in NR. Through BLAST searches and metagenomic sequencing, they matched 43 of the OTUs to species, confirming 10 key species using qPCR. Eight species, including Bifidobacterium longum and Collinsella aerofaciens, were more abundant in R, while Ruminococcus obeum and Roseburia intestinalis were enriched in NR. Fecal transplants from responders into germ-free mice improved tumor control and T cell responses, suggesting the gut microbiota influences immunotherapy efficacy. A higher ratio of “beneficial” OTUs correlated with positive tumor response, indicating that commensal microbiota composition could serve as a biomarker for predicting response to checkpoint blockade therapy [17].

4.2. Advantages and disadvantages of the treatments

The systematic review of fecal microbiota transplantation (FMT) revealed that it has a high primary cure rate (91.2%) for Clostridium difficile infection (CDI) with low recurrence rates (5.5% overall, 2.7% early, and 1.7% late). Adverse events related to FMT, such as inflammatory bowel disease (IBD) flare-ups and infections, were not significantly associated with the treatment. FMT has been experimentally applied to various gastrointestinal diseases and has shown effectiveness primarily against pseudomembranous colitis and CDI. however, there are documented cases of patients developing bacteremia from extended-spectrum β-lactamase (ESBL)-producing Escherichia coli after receiving FMT, leading to serious complications, including one reported death. To minimize the risk of adverse infection events, there is a need for ongoing screening of donor feces, which is particularly important for immunocompromised patients who may be more susceptible to infections [3]. In contrast, synbiotics, which combine prebiotics and probiotics, offer health benefits by promoting beneficial gut bacteria. They have been linked to reduced anxiety, improved brain barrier function, and enhanced cognitive function in animal models. Probiotics exert their effects through mechanisms such as adhesion to the intestinal lining, competition with pathogens, strengthening the mucosal barrier, and producing antimicrobial substances. However, issues like lactose intolerance affect over 60% of the population, which can be mitigated by probiotics that produce lactase, aiding lactose digestion. Additionally, probiotics may help prevent cardiovascular disease by regulating lipid metabolism. Ongoing research is investigating the role of probiotics in inflammatory diseases, obesity, type 2 diabetes, and cancer [1].

5. Conclusion

Research indicates that the gut microbiome significantly influences immune system regulation, enhances antitumor responses, and interacts with the brain via the microbiota-gut-brain axis. The initial colonization of microbes sets the stage for lifelong health outcomes, with delivery methods and maternal health influencing an individual's microbiome. Dysbiosis, characterized by microbial imbalance, is associated with a range of health issues, including inflammatory bowel disease (IBD), obesity, Clostridium difficile infections, and mental health disorders such as autism and schizophrenia. Changes in microbial composition are linked to the onset of these conditions. Therapies aimed at restoring balance in the gut microbiome, including probiotics, prebiotics, and fecal microbiota transplantation (FMT), have demonstrated promising results. Probiotics and prebiotics may enhance gut health by promoting beneficial bacteria, and they have been shown to alleviate symptoms of metabolic syndrome and gastrointestinal problems. FMT has proven particularly effective in treating CDI and shows potential for enhancing responses to immunotherapy in cancer therapy. However, both FMT and synbiotics come with potential risks, such as adverse reactions and infections, highlighting the need for thorough donor screening and ongoing research into their safety and efficacy. Overall, the gut microbiome is recognized as a key player in health and disease, opening up exciting possibilities for therapeutic interventions aimed at enhancing health outcomes.

Recent studies have largely concentrated on the effects and underlying mechanisms of polysaccharide peptides (PPSP) in the context of obesity and type 2 diabetes. Nonetheless, future research should extend to investigate other metabolic conditions, such as cardiovascular diseases and hyperuricemia [15].The modern lifestyle and increasing environmental pressures pose significant challenges to human survival, as the human species evolves too slowly to keep pace with these changes. Interestingly, the concept of the “hologenome” may provide insights into how we can adapt to shifting environments. Emerging evidence suggests that diets enriched with beneficial microbial communities can enhance human-microbe symbiosis, contributing to improved health outcomes [1]. To improve therapeutic methods, it is essential to verify the findings concerning how the microbiome affects the efficacy of immune checkpoint inhibitors (ICIs). Additionally, clinical trial designs need to be improved to thoroughly consider various factors influencing gut microbiota, including diet, medications, mental well-being, and genetic differences among individuals. A comprehensive research approach that integrates microbiology, genetics, immunology, and other disciplines will be essential for developing personalized therapies. Given the intricate nature of the human microbiome, there is a need for more extensive longitudinal studies and larger clinical trials to gain deeper insights into the relationships between specific microbes and host pathophysiology. This calls for a holistic methodology in exploring conditions such as inflammatory bowel disease (IBD) [18].