Gut Microbiome: Composition, Function, Dysbiosis, and Therapeutic Strategies in Metabolic Health

Abstract

The human gut microbiome, a vast and dynamic ecosystem comprising trillions of microorganisms including bacteria, archaea, fungi, viruses, and protozoa, exerts profound influence over a myriad of host physiological processes. Its roles extend from fundamental aspects of digestion and nutrient assimilation to intricate modulation of immune responses, neurotransmitter synthesis, and, critically, metabolic homeostasis. Recent cutting-edge research, empowered by advancements in metagenomics and metabolomics, has definitively established the gut microbiome as a pivotal determinant of metabolic health, particularly in the etiology, progression, and potential management of chronic metabolic conditions such as Type 2 Diabetes Mellitus (T2DM), obesity, and non-alcoholic fatty liver disease (NAFLD). This comprehensive report meticulously explores the elaborate composition and functional capabilities of the gut microbiome, delves into its diverse contributions to human health beyond the metabolic realm, elucidates the sophisticated molecular and physiological mechanisms through which it profoundly influences host metabolic processes, clarifies the concept of dysbiosis as a pathological deviation from a healthy microbial state, and critically assesses current and burgeoning therapeutic strategies that specifically target the gut microbiome for the prevention, management, and potential reversal of metabolic dysregulation.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

1. Introduction

The human gastrointestinal tract is home to an extraordinary community of microorganisms collectively known as the gut microbiome. This complex microbial ecosystem, often referred to as a ‘superorganism’ due to its integrated functions with the host, outnumbers human cells by an estimated 10:1 ratio and possesses a genetic repertoire (the metagenome) that is at least 100 times larger than the human genome [1]. The scientific appreciation of the gut microbiome’s significance has undergone a revolutionary transformation over the past two decades, moving from a peripheral interest to a central focus in biomedical research. This paradigm shift has been largely propelled by the advent of next-generation sequencing technologies, particularly 16S rRNA gene sequencing and whole-metagenome sequencing, coupled with advanced bioinformatics tools, which have enabled unprecedented insights into the diversity, composition, and functional potential of these microbial inhabitants [2, 3].

Historically, microbiology focused primarily on pathogenic organisms. However, contemporary research has unveiled the indispensable symbiotic relationship between the host and its commensal microbiota. These microbes are not mere passengers; they are integral to human health, influencing fundamental physiological processes such as the digestion and absorption of otherwise indigestible nutrients, the maturation and regulation of the host immune system, the synthesis of essential vitamins and biologically active metabolites, and the crucial maintenance of gut barrier integrity [4].

Among the most profound discoveries is the intricate and bidirectional communication between the gut microbiome and host metabolism. Dysregulation within this microbial community, termed dysbiosis, has emerged as a significant contributing factor to the escalating global prevalence of metabolic disorders, most notably Type 2 Diabetes Mellitus (T2DM). T2DM is a chronic metabolic condition characterized by elevated blood glucose levels resulting from defects in insulin secretion, insulin action, or both. The traditional view of T2DM pathogenesis primarily centered on genetic predisposition and lifestyle factors such as diet and physical inactivity. However, an accumulating body of evidence now implicates the gut microbiome as a critical environmental modulator, influencing susceptibility, progression, and therapeutic responses in T2DM [5, 6].

This report aims to provide a comprehensive and in-depth overview of the gut microbiome’s multifaceted roles in human health, with a particular emphasis on its intricate interactions with host metabolism and its implications for T2DM. We will explore the intricate microbial composition, delve into the various mechanisms by which it influences metabolic processes, critically examine the concept of dysbiosis in the context of metabolic diseases, and discuss the burgeoning landscape of therapeutic interventions that harness the power of the gut microbiome for improved metabolic health.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

2. Composition and Function of the Human Gut Microbiome

2.1. Microbial Diversity and Composition

The human gut microbiome represents one of the densest and most complex microbial ecosystems known, housing an estimated 3.8 x 10^13 bacteria alone, alongside a significant proportion of archaea, fungi (the mycobiome), viruses (the virome, predominantly bacteriophages), and protozoa [7, 8]. The collective genome of these microbes, the ‘metagenome’, contains millions of genes, vastly exceeding the gene count of the human genome and endowing the host with an expanded metabolic capacity [9].

The bacterial component is by far the most abundant and well-studied. While thousands of bacterial species inhabit the gut, the majority belong to just a few dominant phyla: Firmicutes (~60-80% of total bacteria) and Bacteroidetes (~15-30%), with Actinobacteria (e.g., Bifidobacterium), Proteobacteria (e.g., Escherichia coli), and Verrucomicrobia (e.g., Akkermansia muciniphila) typically present in lower but functionally significant abundances [10, 11].

Within these phyla, specific genera and species are recognized for their distinct contributions:

• Firmicutes: This diverse phylum includes a wide array of bacteria, many of which are crucial short-chain fatty acid (SCFA) producers, such as Faecalibacterium prausnitzii (a major butyrate producer known for its anti-inflammatory properties) and Roseburia intestinalis. Others, like certain Clostridium species, can be opportunistic pathogens or contribute to a pro-inflammatory state when overgrown [12].
• Bacteroidetes: Represented primarily by the genus Bacteroides (e.g., Bacteroides fragilis, Bacteroides thetaiotaomicron), these bacteria are highly efficient at degrading complex plant polysaccharides that are indigestible by human enzymes. They play a significant role in energy harvest from the diet and can influence the host’s metabolic phenotype [13].
• Actinobacteria: The genus Bifidobacterium is a key member of this phylum, particularly abundant in early life. Bifidobacterium species are known for producing lactate and acetate, contributing to a lower gut pH, and are widely recognized as beneficial probiotics, often associated with improved gut health and immune modulation [14].
• Verrucomicrobia: The primary representative is Akkermansia muciniphila, a mucin-degrading bacterium that resides in the mucus layer of the gut. Its abundance is often inversely correlated with obesity and T2DM, and it is considered a marker of a healthy gut barrier. It produces SCFAs and can improve gut barrier function and glucose metabolism [15].
• Proteobacteria: While generally present in low numbers in a healthy gut, an expansion of Proteobacteria (e.g., Escherichia, Shigella, Salmonella) is often considered a hallmark of dysbiosis and a potential indicator of an unstable microbial community, frequently associated with inflammation [16].

The specific composition of an individual’s gut microbiome is profoundly influenced by a complex interplay of various factors throughout life:

• Diet: This is arguably the most significant modulator. Long-term dietary patterns (e.g., Western vs. Mediterranean diets) have a profound impact, but even short-term changes can induce rapid shifts. Diets rich in fermentable fibers, resistant starches, and polyphenols (found in fruits, vegetables, whole grains, legumes) promote the growth of beneficial bacteria, while diets high in saturated fats, simple sugars, and processed foods can lead to dysbiosis [17].
• Age: The microbiome undergoes dynamic changes from birth to old age. Neonates initially acquire microbes from their mother (vaginal birth vs. C-section, breastfeeding vs. formula feeding). The diversity increases throughout childhood and adulthood, often declining in advanced age, which can be linked to immunosenescence and increased frailty [18].
• Genetics: Host genetics play a role, influencing factors like immune responses, mucus production, and nutrient absorption, which indirectly shape the microbial environment. Twin studies have revealed that while genetics contribute, environmental factors like diet are often more dominant [19].
• Lifestyle: Physical activity can enhance microbial diversity and increase the abundance of beneficial bacteria like Akkermansia and Faecalibacterium. Stress and sleep deprivation can also negatively impact microbial composition and gut barrier function [20].
• Medications: Antibiotics are well-known disruptors, causing significant, sometimes long-lasting, shifts in microbial communities. Non-antibiotic drugs, such as proton pump inhibitors (PPIs) and metformin, also exert considerable effects on the gut microbiome composition and function [21].
• Geography and Environment: Exposure to different environments, including rural versus urban living, and geographical location, can contribute to microbial variations among populations [22].

Maintaining a balanced and diverse microbiome, characterized by a high abundance of beneficial microbes and a rich variety of species, is paramount for ensuring robust health and resilience against disease.

2.2. Functional Roles in Human Health

The gut microbiome is a critical partner in human physiology, performing a myriad of functions that are indispensable for host well-being. Its metabolic, immunological, and protective activities are highly integrated with host systems:

• Digestion and Nutrient Absorption: One of the most fundamental roles of the gut microbiome is to assist in the breakdown of complex carbohydrates (dietary fibers) that human digestive enzymes cannot process. Through fermentation, these microbes convert indigestible polysaccharides into short-chain fatty acids (SCFAs)—primarily acetate, propionate, and butyrate—which serve as important energy sources for the host [23]. Butyrate, for instance, is the primary energy substrate for colonocytes, promoting their health and integrity. Microbes also play a crucial role in synthesizing essential vitamins, such as vitamin K (involved in blood clotting and bone metabolism) and various B vitamins (e.g., B12, folate, biotin) [24]. Furthermore, they are involved in the biotransformation of bile acids, sterols, and xenobiotics, influencing drug metabolism and detoxification [25].

• Immune System Modulation: The gut harbors approximately 70% of the body’s immune cells, making the gut-associated lymphoid tissue (GALT) a major component of the immune system. The gut microbiome is critical for the proper development and maturation of GALT from early life onwards [26]. Commensal microbes constantly interact with immune cells, promoting immune tolerance to harmless antigens (food components, self-antigens) while simultaneously defending against pathogenic invaders. They achieve this through several mechanisms, including maintaining the integrity of the intestinal epithelial barrier by upregulating tight junction proteins, thereby preventing the translocation of harmful substances into the bloodstream [27]. Specific microbial components, such as polysaccharide A (PSA) from Bacteroides fragilis, can directly modulate immune cell differentiation and function, for example, by promoting the development of regulatory T cells (Tregs), which are essential for suppressing excessive inflammatory responses [28].

• Metabolic Regulation: This is a core area of focus for this report. The gut microbiome significantly influences host energy homeostasis, fat storage, and insulin sensitivity primarily through the production of bioactive metabolites and modulation of host signaling pathways. Key metabolites include SCFAs (as discussed above), which are not just local energy sources but systemic signaling molecules. Butyrate, for instance, not only nourishes colonocytes but also possesses potent anti-inflammatory properties and can improve insulin sensitivity in peripheral tissues [29]. Propionate can be a substrate for gluconeogenesis in the liver and may influence satiety signals. Acetate is readily absorbed and can be used for lipogenesis and cholesterol synthesis [30]. Beyond SCFAs, the microbiome also modulates bile acid metabolism, which profoundly impacts glucose and lipid homeostasis. It also influences the metabolism of branched-chain amino acids (BCAAs) and contributes to the production of trimethylamine N-oxide (TMAO), both of which have been linked to metabolic and cardiovascular diseases [31, 32].

• Protection Against Pathogens (Colonization Resistance): A healthy, diverse gut microbiome acts as a formidable barrier against invading pathogens. Beneficial microbes compete with harmful organisms for nutrients and attachment sites on the intestinal lining, physically preventing their colonization and overgrowth. They also produce antimicrobial compounds, such as bacteriocins, which directly inhibit the growth of pathogenic bacteria. Furthermore, the fermentation activities of commensal bacteria produce SCFAs, which lower the pH of the intestinal lumen, creating an unfavorable environment for many acid-sensitive pathogens [33].

• Gut-Brain Axis Communication: An emerging and fascinating area of research is the bidirectional communication between the gut microbiome and the central nervous system, known as the gut-brain axis. Microbes can influence brain function, mood, and behavior by producing neurotransmitters (e.g., serotonin, GABA), modulating inflammatory pathways, and interacting with the vagus nerve. This connection holds implications for neurodevelopmental disorders, depression, anxiety, and neurodegenerative diseases [34].

Many thanks to our sponsor Esdebe who helped us prepare this research report.

3. Gut Microbiome and Metabolic Health

3.1. Influence on Glucose Metabolism and Insulin Sensitivity

The intricate relationship between the gut microbiome and host glucose metabolism, particularly its profound impact on insulin sensitivity and the pathogenesis of Type 2 Diabetes Mellitus (T2DM), has become a cornerstone of metabolic research. Individuals with T2DM consistently exhibit characteristic alterations in their gut microbiome composition, often referred to as dysbiosis, marked by a reduction in beneficial bacteria and an increase in opportunistic pathogens [5]. This microbial imbalance contributes to insulin resistance through a cascade of interconnected mechanisms:

• Inflammation and Metabolic Endotoxemia: One of the most critical pathways linking gut dysbiosis to insulin resistance is the induction of low-grade chronic inflammation, often termed ‘metabolic endotoxemia’ [35]. A healthy gut maintains a robust epithelial barrier, a single layer of cells connected by tight junctions, which acts as a selective filter, allowing nutrient absorption while preventing the translocation of harmful bacterial products into the systemic circulation. Dysbiosis, particularly a reduction in mucin-degrading bacteria like Akkermansia muciniphila or butyrate producers that nourish colonocytes, can lead to increased intestinal permeability, often referred to as ‘leaky gut’ [36].

  When the gut barrier is compromised, bacterial components, notably lipopolysaccharides (LPS) from the outer membrane of Gram-negative bacteria, can translocate from the gut lumen into the portal circulation and subsequently into systemic circulation. LPS acts as a potent endotoxin, binding to Toll-like receptor 4 (TLR4) on immune cells (macrophages, adipocytes, hepatocytes) and activating inflammatory signaling pathways, such as NF-κB and JNK [37]. This activation triggers the release of pro-inflammatory cytokines (e.g., TNF-α, IL-1β, IL-6) which, in turn, interfere with insulin signaling pathways in peripheral tissues (skeletal muscle, adipose tissue, liver), leading to insulin resistance. This persistent, low-grade inflammation is a key driver of metabolic dysfunction in T2DM and obesity [38].

• Short-Chain Fatty Acid (SCFA) Production and Signaling: SCFAs (butyrate, propionate, acetate) are crucial microbial metabolites derived from the fermentation of dietary fibers. Their production is significantly altered in individuals with T2DM. A common finding is a reduction in the abundance of key SCFA-producing bacteria, such as Faecalibacterium prausnitzii and Roseburia intestinalis, leading to diminished levels of circulating SCFAs, particularly butyrate [39].

  • Butyrate: Beyond its role as the primary energy source for colonocytes and its anti-inflammatory properties, butyrate can improve insulin sensitivity through various mechanisms. It is a potent inhibitor of histone deacetylases (HDACs), which can modulate gene expression involved in glucose and lipid metabolism [40]. Butyrate also acts as a ligand for G-protein coupled receptors (GPCRs), specifically GPR41, GPR43, and GPR109A, expressed on enteroendocrine cells (L-cells) in the gut. Activation of these receptors stimulates the release of incretin hormones, such as glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) [41]. GLP-1 enhances glucose-dependent insulin secretion from pancreatic beta-cells and slows gastric emptying, while PYY contributes to satiety. Reduced butyrate levels thus impair these beneficial metabolic effects.
  • Propionate: Also a GPCR ligand, propionate primarily influences hepatic gluconeogenesis and may contribute to satiety signals, influencing energy balance [42].
  • Acetate: The most abundant SCFA, acetate can be utilized for lipogenesis and cholesterol synthesis, but also plays a role in satiety and glucose homeostasis [43]. An imbalance in SCFA ratios or overall reduction in their levels directly impairs metabolic regulation.

• Bile Acid Metabolism Modulation: The enterohepatic circulation of bile acids is a critical physiological pathway involved in fat digestion and absorption, but bile acids also function as important signaling molecules that regulate glucose, lipid, and energy metabolism [44]. Gut microbes play an indispensable role in modifying the host’s bile acid pool. Primary bile acids (e.g., cholic acid, chenodeoxycholic acid) synthesized in the liver are secreted into the small intestine. Gut bacteria, particularly those possessing bile salt hydrolase (BSH) enzymes, deconjugate these primary bile acids. Further microbial enzymatic modifications (e.g., 7α-dehydroxylation) convert primary bile acids into secondary bile acids (e.g., deoxycholic acid, lithocholic acid) [45].

  These primary and secondary bile acids activate host receptors such as the farnesoid X receptor (FXR), a nuclear receptor primarily expressed in the liver and intestine, and TGR5 (a G-protein coupled receptor), expressed in various tissues including enteroendocrine cells, brown adipose tissue, and macrophages. Activation of FXR downregulates bile acid synthesis, promotes hepatic glucose uptake and glycogen synthesis, and improves insulin sensitivity [46]. TGR5 activation stimulates GLP-1 secretion and increases energy expenditure. Dysbiosis in T2DM can alter the composition and pool of secondary bile acids, leading to impaired FXR and TGR5 signaling and contributing to metabolic dysfunction [47].

• Branched-Chain Amino Acid (BCAA) Metabolism: Elevated circulating levels of branched-chain amino acids (leucine, isoleucine, valine) have been consistently associated with insulin resistance and an increased risk of T2DM [48]. Recent research suggests that the gut microbiome may play a role in regulating BCAA metabolism. Certain gut bacterial species are involved in the synthesis or degradation of BCAAs, and dysbiotic changes can lead to altered BCAA profiles, potentially contributing to metabolic pathology [49].

• Trimethylamine N-oxide (TMAO) Production: TMAO is a microbial-derived metabolite increasingly linked to cardiovascular disease risk and, more recently, to insulin resistance [50]. It is produced from dietary precursors like phosphatidylcholine and L-carnitine (abundant in red meat and some dairy products). Gut bacteria metabolize these precursors into trimethylamine (TMA), which is then absorbed and oxidized to TMAO in the liver by flavin-containing monooxygenases (FMOs) [51]. Elevated TMAO levels have been shown to exacerbate glucose intolerance and insulin resistance by impairing insulin signaling and promoting inflammation, highlighting another mechanism by which the gut microbiome impacts metabolic health [52].

3.2. Dysbiosis and Its Implications

Dysbiosis, the qualitative and quantitative alteration in the gut microbiome composition and functional capabilities, is a hallmark of numerous disease states, including metabolic disorders. It is not merely a change in the numbers of specific bacteria but often involves a reduction in overall microbial diversity (alpha-diversity) and stability, leading to an ecosystem less capable of performing its beneficial functions and more prone to pathogenic colonization [53].

In the context of metabolic diseases, specific patterns of dysbiosis have been consistently observed:

• Type 2 Diabetes Mellitus (T2DM): The gut microbiome of individuals with T2DM frequently exhibits a distinct signature. Common findings include:

  • Reduced Beneficial Bacteria: A significant decrease in the abundance of butyrate-producing bacteria like Faecalibacterium prausnitzii and Roseburia intestinalis, which are critical for gut barrier integrity and anti-inflammatory effects [39]. Akkermansia muciniphila, known for its mucus-degrading properties and association with improved metabolic health, is also often diminished [15]. Some studies show reduced Bifidobacterium and Bacteroides species, although findings can vary depending on population and methodology [54].
  • Increased Opportunistic Pathogens/Pro-inflammatory Bacteria: There is often an enrichment of genera like Ruminococcus gnavus, Bacteroides (in some contexts, certain species can be pro-inflammatory), and members of the Proteobacteria phylum (e.g., Escherichia, Shigella), which are associated with increased LPS production and inflammation [55, 56].
  • Altered SCFA Profiles: Reduced production of beneficial SCFAs (butyrate, propionate) and sometimes an altered ratio between them [39].
  • Changes in Carbohydrate Metabolism: Shifts in microbial genes encoding enzymes for carbohydrate metabolism, favoring species that efficiently extract energy from complex carbohydrates, potentially contributing to increased calorie harvest [57].

• Obesity: The ‘lean’ versus ‘obese’ microbiome hypothesis, while debated, posits that certain microbial compositions may predispose individuals to obesity. Obese individuals often exhibit a lower diversity and an altered Firmicutes-to-Bacteroidetes ratio (though this ratio is highly variable and not universally consistent across studies) [58]. Dysbiosis in obesity can contribute to:

  • Increased Energy Harvest: Certain microbial communities are more efficient at fermenting indigestible dietary polysaccharides into SCFAs, leading to greater energy extraction from food and potentially contributing to weight gain [59].
  • Altered Satiety Signals: Microbiome-derived metabolites can influence gut-hormone release (e.g., GLP-1, PYY) and neural pathways, affecting appetite regulation and satiety [60].
  • White Adipose Tissue (WAT) Inflammation: Similar to T2DM, increased gut permeability and LPS translocation can lead to chronic inflammation in adipose tissue, promoting insulin resistance and dysfunctional fat storage [61].

• Non-alcoholic Fatty Liver Disease (NAFLD) and Non-alcoholic Steatohepatitis (NASH): Dysbiosis is increasingly recognized as a key factor in the progression of NAFLD/NASH. Increased gut permeability facilitates the translocation of bacterial products (LPS, ethanol, SCFAs) to the liver via the portal vein, promoting hepatic inflammation, fibrosis, and steatosis [62]. Alterations in bile acid metabolism mediated by gut bacteria also play a significant role in NAFLD pathogenesis [63].

• Cardiovascular Disease (CVD): Beyond TMAO, dysbiosis can contribute to CVD risk factors by promoting systemic inflammation, influencing lipid metabolism, and affecting blood pressure regulation [64].

• Inflammatory Bowel Disease (IBD): While not directly a metabolic disease, IBD (Crohn’s disease, ulcerative colitis) is a quintessential example of how profound dysbiosis can lead to chronic inflammation and compromise gut barrier function, underscoring the critical role of a balanced microbiome for intestinal health [65].

• Neurological Disorders (Gut-Brain Axis): Dysbiosis has been implicated in various neurological and psychiatric conditions, including Parkinson’s disease, Alzheimer’s disease, autism spectrum disorders, depression, and anxiety, through its influence on neurotransmitter synthesis, inflammatory pathways, and neurotrophic factors [34].

Understanding the precise nature of dysbiosis in these conditions is crucial for developing targeted and personalized therapeutic interventions aimed at restoring microbial balance and improving host health outcomes.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

4. Therapeutic Strategies Targeting the Gut Microbiome

The burgeoning understanding of the gut microbiome’s role in metabolic health has opened up novel therapeutic avenues. Strategies aim to restore microbial balance, enhance beneficial microbial functions, or directly introduce beneficial microbes or their metabolites. These interventions range from broad dietary modifications to highly targeted microbial transplantation.

4.1. Probiotics

Probiotics are defined by the Food and Agriculture Organization of the United Nations (FAO) and the World Health Organization (WHO) as ‘live microorganisms which, when administered in adequate amounts, confer a health benefit on the host’ [66]. In the context of metabolic health, particularly T2DM, certain probiotic strains have shown promise:

• Mechanisms of Action: Probiotics exert their beneficial effects through multiple mechanisms:

  • Modulation of Gut Microbiome Composition: They can transiently colonize the gut, competitively exclude pathogens, and promote the growth of indigenous beneficial bacteria [67].
  • Enhancement of Gut Barrier Function: Specific strains (e.g., Lactobacillus plantarum, Bifidobacterium lactis) can upregulate tight junction proteins (e.g., zonulin-1, occludin, claudin), thereby reducing intestinal permeability and mitigating metabolic endotoxemia [68].
  • Reduction of Inflammation: Probiotics can modulate immune responses by influencing cytokine production (e.g., reducing pro-inflammatory TNF-α and IL-6, increasing anti-inflammatory IL-10) and interacting with immune cells in the GALT [69].
  • Production of SCFAs: While probiotics themselves may produce SCFAs, their primary contribution often comes from stimulating the growth and activity of native SCFA-producing bacteria [70].
  • Modulation of Bile Acid Metabolism: Some probiotic strains possess bile salt hydrolase (BSH) activity, influencing the host bile acid pool, which can impact glucose and lipid metabolism [71].
  • Direct Metabolic Effects: Certain probiotics can directly ferment carbohydrates, produce enzymes that break down specific dietary components, or even produce specific bioactive molecules that influence host metabolism [72].

• Clinical Evidence: Numerous clinical studies have investigated the efficacy of probiotics in individuals with T2DM or metabolic syndrome. Meta-analyses suggest that supplementation with certain strains, particularly combinations of Lactobacillus and Bifidobacterium species, can lead to modest but significant improvements in glycemic control (e.g., reduction in fasting blood glucose, HbA1c), insulin sensitivity (e.g., HOMA-IR), and lipid profiles (e.g., reduced total cholesterol and LDL-C) [73, 74]. For instance, specific strains like Lactobacillus acidophilus NCFM, Bifidobacterium lactis HN019, and multispecies combinations have shown promise. However, results are often strain-specific, dose-dependent, and subject to considerable inter-individual variability, necessitating more rigorous, large-scale, and well-designed clinical trials [75]. Challenges include ensuring viability of microbes, appropriate dosing, and long-term efficacy.

4.2. Prebiotics

Prebiotics are defined as ‘a substrate that is selectively utilized by host microorganisms conferring a health benefit’ [76]. They are typically non-digestible dietary fibers that resist hydrolysis by host enzymes and reach the colon intact, where they are selectively fermented by beneficial gut bacteria.

• Mechanisms of Action: Prebiotics primarily function by:

  • Selective Stimulation of Beneficial Bacteria: They selectively promote the growth and activity of beneficial commensals, such as Bifidobacterium, Lactobacillus, and SCFA-producing bacteria like Faecalibacterium and Akkermansia [77].
  • Enhanced SCFA Production: By fueling the growth of fermentative bacteria, prebiotics lead to increased production of SCFAs, which subsequently confer systemic metabolic benefits (improved insulin sensitivity, reduced inflammation, enhanced gut barrier) [78].
  • Improved Mineral Absorption: Some prebiotics (e.g., fructans) can enhance the absorption of minerals like calcium and magnesium, impacting bone health [79].
  • Appetite Regulation: By promoting SCFA production and influencing gut hormone release, prebiotics can contribute to satiety and improved glucose regulation [80].

• Clinical Evidence: Consumption of various prebiotics, including fructooligosaccharides (FOS), inulin, galactooligosaccharides (GOS), and resistant starch, has been associated with improved metabolic parameters. Studies have reported reductions in fasting glucose, HbA1c, and inflammatory markers, as well as improvements in lipid profiles in individuals with T2DM or metabolic syndrome [81]. For example, resistant starch has been shown to improve insulin sensitivity in healthy and insulin-resistant individuals [82]. The effects are often dependent on the type and dose of prebiotic, as well as the baseline microbiome composition of the individual.

4.3. Synbiotics

Synbiotics are synergistic combinations of probiotics and prebiotics, designed to provide both beneficial microorganisms and the specific substrates (prebiotics) that enhance their growth, survival, and activity in the gut. The goal is to maximize the health benefits beyond what either component could achieve alone [83].

• Mechanisms of Action: Synbiotics combine the mechanisms of both probiotics and prebiotics. The prebiotic component acts as a selective nutrient source for the co-administered probiotic strain, enhancing its survival through the upper gastrointestinal tract, promoting its colonization, and increasing its metabolic activity in the colon. This synergistic effect can lead to more robust and sustained improvements in gut microbial balance and host metabolic function [84].

• Clinical Evidence: Some studies have demonstrated that synbiotic supplementation can lead to superior improvements in glycemic control, lipid profiles, and markers of inflammation in individuals with T2DM compared to monotherapy with probiotics or prebiotics [85]. For instance, combinations of Lactobacillus and Bifidobacterium strains with FOS or inulin have shown promising results in improving fasting glucose, insulin levels, and HOMA-IR [86]. However, similar to probiotics, careful selection of both the probiotic strains and the prebiotic type is crucial, as the synergistic effect is highly specific.

4.4. Fecal Microbiota Transplantation (FMT)

Fecal Microbiota Transplantation (FMT) involves the transfer of fecal material, containing a diverse community of gut microorganisms, from a healthy donor to a recipient. The primary aim is to restore a healthy, diverse, and functional gut microbiome in individuals with dysbiosis [87].

• Mechanisms of Action: FMT represents the most comprehensive form of microbiome intervention, aiming to re-establish an entire microbial ecosystem rather than introducing a few specific strains. The mechanisms are complex and thought to include:

  • Reintroduction of Missing Taxa: Transferring beneficial bacteria (e.g., SCFA producers, Akkermansia) that are depleted in the recipient’s dysbiotic gut.
  • Restoration of Microbial Diversity: Increasing overall microbial richness and evenness, which is often reduced in metabolic diseases.
  • Improved Metabolic Functions: Re-establishing the production of beneficial metabolites (SCFAs, secondary bile acids) and modulating host metabolic pathways through direct and indirect interactions [88].
  • Enhanced Gut Barrier Integrity: By restoring a healthy microbial community, FMT can improve tight junction integrity and reduce intestinal permeability, thereby decreasing metabolic endotoxemia [89].

• Clinical Evidence: FMT has been remarkably successful and is now a well-established therapy for recurrent Clostridioides difficile infection (rCDI), with cure rates exceeding 90% [90]. Its application in metabolic diseases like T2DM, however, is still in its nascent stages and results are inconsistent.

  Early pilot studies in individuals with metabolic syndrome or T2DM have shown some promising, albeit transient, improvements in insulin sensitivity, glucose metabolism, and an increase in butyrate-producing bacteria and Akkermansia muciniphila following FMT [91, 92]. However, these studies are typically small, short-term, and show variable efficacy. Challenges for broader application in metabolic diseases are significant:
  * Donor Screening: Rigorous and extensive screening of donors is crucial to prevent the transmission of pathogens (bacteria, viruses, parasites) and potential predisposition to chronic diseases [93].
  * Safety Concerns: While generally safe for rCDI, long-term safety in metabolic conditions is not yet established. Potential risks include transfer of unknown pathogens, long-term metabolic or immune alterations in the recipient, and adverse events related to the procedure itself (e.g., colonoscopy) [94].
  * Standardization: Lack of standardized donor selection criteria, fecal processing methods, and delivery routes (oral capsules, colonoscopy, enema) makes comparison across studies difficult.
  * Efficacy and Consistency: The response to FMT in metabolic diseases is highly variable among individuals, suggesting that the complexity of the donor-recipient interaction and host factors play a critical role [95].
  * Regulatory and Ethical Hurdles: FMT is often considered a biologic drug, posing significant regulatory challenges and ethical considerations regarding its widespread use outside of C. difficile infection.

Despite these challenges, FMT remains a powerful tool for research into host-microbe interactions and a potential future therapeutic avenue, perhaps in more refined forms like defined microbial consortiums.

4.5. Dietary Interventions

Diet is the most potent and practical modulator of the gut microbiome. Long-term dietary patterns significantly shape the composition and functional output of the microbial community, with profound implications for metabolic health [17].

• Mechanisms of Action: Dietary components directly provide substrates for microbial metabolism, influencing their growth, activity, and metabolite production. Indirectly, diet affects host physiology (e.g., gut transit time, bile acid secretion), which in turn influences the microbial environment.

• Clinical Evidence and Specific Dietary Components/Patterns:

  • Fiber-Rich Diets: Diets high in dietary fiber, found in fruits, vegetables, whole grains, legumes, nuts, and seeds, are consistently associated with increased microbial diversity and the proliferation of beneficial SCFA-producing bacteria [96]. Soluble fibers (e.g., pectin, psyllium, beta-glucans) and resistant starches are particularly fermentable by gut microbes, leading to robust SCFA production and improved glucose and lipid metabolism [97].
  • Polyphenols: These bioactive compounds, abundant in berries, dark chocolate, red wine, green tea, and colorful vegetables, act as prebiotics by promoting the growth of beneficial bacteria (e.g., Akkermansia, Bifidobacterium) and exhibiting antioxidant and anti-inflammatory properties [98]. They can also be metabolized by gut microbes into absorbable compounds with systemic benefits.
  • Fermented Foods: Consumption of fermented foods like yogurt, kefir, kimchi, sauerkraut, kombucha, and tempeh directly introduces live microorganisms (probiotics) into the gut. They also contain pre-digested nutrients and unique metabolites, contributing to microbial diversity and metabolic health [99].
  • Mediterranean Diet: Characterized by high intake of fruits, vegetables, whole grains, legumes, nuts, olive oil, and fish, and low intake of red meat and processed foods, the Mediterranean diet is strongly associated with a diverse and healthy gut microbiome. It promotes the growth of SCFA producers and anti-inflammatory bacteria, leading to improved glycemic control, reduced inflammation, and better cardiovascular outcomes [100].
  • Plant-Based Diets (Vegetarian/Vegan): Generally higher in fiber and lower in saturated fat compared to omnivorous diets, plant-based diets are consistently linked to a more diverse gut microbiome, an increased abundance of beneficial bacteria (e.g., Prevotella, Roseburia), and improvements in markers of metabolic health, including lower body weight, improved insulin sensitivity, and better lipid profiles [101].
  • Western Diet: In contrast, a typical Western diet, high in refined sugars, saturated fats, processed foods, and low in fiber, is a major driver of gut dysbiosis. It leads to reduced microbial diversity, an increase in pro-inflammatory bacteria (e.g., Proteobacteria), compromised gut barrier function, and contributes significantly to obesity, T2DM, and NAFLD [102].

Dietary interventions offer a sustainable and accessible approach to modulating the gut microbiome for metabolic health, often serving as a foundational therapy for T2DM management.

4.6. Emerging Strategies

The field of gut microbiome therapeutics is rapidly evolving, exploring more targeted and sophisticated interventions:

• Postbiotics: These are ‘preparations of inanimate microorganisms and/or their components that confers a health benefit on the host’ [103]. Postbiotics include microbial metabolites (e.g., purified SCFAs, vitamins), cell wall components, or inactivated microbial cells. They offer advantages over live probiotics, such as better stability, easier standardization, and reduced risk of transferring live organisms. SCFA supplements, in particular, are being explored for their direct metabolic benefits [104].
• Phage Therapy: Bacteriophages are viruses that specifically target and lyse bacteria. Phage therapy involves using specific phages to selectively eliminate undesirable pathogenic or pro-inflammatory bacteria while preserving beneficial commensals, offering a highly targeted approach to correct dysbiosis [105].
• Genetically Engineered Microbes (GEMs): Advances in synthetic biology allow for the engineering of gut bacteria to produce specific therapeutic compounds (e.g., GLP-1 agonists, enzymes that degrade harmful metabolites) or to restore specific metabolic functions within the gut. This represents a highly precise and personalized therapeutic avenue [106].
• Defined Microbial Consortiums: Instead of whole fecal transplants, researchers are developing ‘defined microbial products’ consisting of a precise mixture of beneficial bacterial strains known to restore specific functions or outcompete pathogens. This approach offers greater control, safety, and reproducibility compared to FMT [107].
• Targeted Antibiotics/Pre-screened Antibiotics: While broad-spectrum antibiotics are generally detrimental to the microbiome, the concept of using highly specific antibiotics to selectively eliminate problematic taxa, followed by targeted re-seeding with beneficial microbes, is being explored to reshape the microbial landscape beneficially [108].
• Exercise: Regular physical activity has been shown to positively influence gut microbiome diversity and composition, increasing beneficial bacteria (e.g., Akkermansia, Faecalibacterium) and enhancing SCFA production, independent of diet. This contributes to improved metabolic health and reduced inflammation [109].
• Circadian Rhythm and Time-Restricted Feeding: The gut microbiome exhibits its own circadian rhythm, and this rhythm is influenced by host feeding patterns. Disruptions to sleep and irregular eating schedules can negatively impact the microbiome and contribute to metabolic dysregulation. Time-restricted feeding, which aligns eating with the body’s natural circadian rhythm, may positively influence the gut microbiome and improve metabolic parameters [110].

These emerging strategies represent the next frontier in microbiome-targeted therapies, promising more precise, personalized, and effective interventions for metabolic diseases.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

5. Conclusion

The human gut microbiome stands as an undeniably integral component of human health, profoundly influencing a broad spectrum of physiological processes, from rudimentary digestion to sophisticated immune modulation, neurotransmitter synthesis, and critically, host metabolic homeostasis. Its intricate interactions with glucose metabolism, insulin sensitivity, and the fundamental pathogenesis of chronic metabolic conditions such as Type 2 Diabetes Mellitus are now unequivocally established. The realization that alterations in this complex microbial ecosystem, termed dysbiosis, can directly contribute to the development and progression of metabolic diseases marks a pivotal shift in our understanding of these global health challenges.

The mechanisms by which the gut microbiome exerts its metabolic influence are multifaceted and interconnected, encompassing the modulation of systemic inflammation via metabolic endotoxemia, the production of vital short-chain fatty acids (SCFAs) that act as signaling molecules, the intricate biotransformation of bile acids impacting nuclear receptor signaling, and the regulation of circulating branched-chain amino acids and trimethylamine N-oxide. A healthy and diverse microbiome characterized by a balanced community of beneficial bacteria is essential for maintaining optimal metabolic function, whereas dysbiosis contributes to insulin resistance and other metabolic derangements.

This expanding comprehension of the complex interactions between the gut microbiome and host metabolism has unlocked unprecedented avenues for novel therapeutic strategies. Current interventions, including the judicious use of probiotics, prebiotics, and their synergistic combinations (synbiotics), offer promising approaches to restore microbial balance and ameliorate metabolic parameters. Dietary interventions, particularly those emphasizing high fiber, diverse plant-based foods, and fermented products, remain a cornerstone for shaping a beneficial microbial landscape. Fecal Microbiota Transplantation (FMT), while highly efficacious for recurrent Clostridioides difficile infection, is still under rigorous investigation for metabolic diseases, highlighting the need for more standardized procedures, robust safety data, and consistent efficacy.

Looking ahead, the field is poised for transformative advancements with the development of more targeted and sophisticated interventions, such as postbiotics, phage therapy, genetically engineered microbes, and precisely defined microbial consortiums. These emerging strategies hold the potential for highly personalized and effective treatments. However, significant challenges persist, including a deeper elucidation of precise molecular mechanisms, the design of large-scale and long-term clinical trials to establish efficacy and safety, the standardization of microbial interventions, and the critical need to move towards personalized approaches where therapeutic strategies are tailored to an individual’s unique microbiome profile. Translating the vast potential of microbiome research into routine clinical practice for metabolic disease management requires continued collaborative effort across basic science, clinical research, and regulatory bodies. Ultimately, understanding and strategically manipulating the gut microbiome offers a profound new frontier in the prevention and treatment of metabolic diseases, paving the way for a healthier future.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

References

1. Sender, R., Fuchs, S., & Milo, R. (2016). Revised estimates for the number of human and bacteria cells in the body. PLoS Biology, 14(8), e1002533.
2. Relman, D. A. (2012). The human microbiome: an ecosystem at the interface of health and disease. Journal of Clinical Investigation, 122(2), 415-417.
3. Quince, C., et al. (2017). The microbiome and the metagenome: from sequencing to function. Microbiome, 5(1), 127.
4. O’Hara, A. M., & Shanahan, F. (2006). The gut flora as a forgotten organ. EMBO Reports, 7(7), 688-693.
5. Tilg, H., & Moschen, A. R. (2014). Metabolic endotoxemia: a link between gut microbiota and metabolism. Frontiers in Immunology, 5, 597.
6. Karlsson, F. H., et al. (2013). Gut metagenome in a Swedish cohort with type 2 diabetes. Nature, 498(7452), 99-103.
7. Qin, J., et al. (2010). A human gut microbial gene catalogue established by metagenomic sequencing. Nature, 464(7285), 59-65.
8. Sender, R., et al. (2016). Are We Really Ten Times More Bacterial Than Human?. Cell, 167(6), 1475-1478.e1.
9. Turnbaugh, P. J., et al. (2007). The human microbiome project. Nature, 449(7164), 804-810.
10. Eckburg, P. B., et al. (2005). Diversity of the human intestinal microbial flora. Science, 308(5726), 1635-1638.
11. Arumugam, M., et al. (2011). Enterotypes of the human gut microbiome. Nature, 473(7346), 174-180.
12. Louis, P., et al. (2014). The effect of diet on the human gut microbiota: a systematic review. Nutrition Research Reviews, 27(2), 241-267.
13. Xu, J., et al. (2007). A genomic view of the human-Bacteroides thetaiotaomicron symbiosis. Science, 318(5850), 665-669.
14. Fukuda, S., et al. (2011). Bifidobacteria-mediated immune system development in the gut. Nature, 469(7331), 527-531.
15. Dao, M. C., et al. (2016). Akkermansia muciniphila and the gut microbiome in obesity: insights from a pilot study. Microbiome, 4(1), 52.
16. Rizzatti, G., et al. (2017). Proteobacteria: A new microbial signature of obesity and metabolic syndrome? European Journal of Clinical Investigation, 47(11), 843-853.
17. David, L. A., et al. (2014). Diet rapidly and reproducibly alters the human gut microbiome. Nature, 505(7484), 559-563.
18. Claesson, M. J., et al. (2012). Gut microbiota composition correlates with diet and health in the elderly. Nature, 488(7410), 178-184.
19. Rothschild, D., et al. (2018). Environment dominates over host genetics in shaping human gut microbiota composition. Nature, 555(7695), 210-215.
20. Monda, V., et al. (2017). Exercise modifies the gut microbiota composition and function in different pathological conditions. Journal of Functional Morphology and Kinesiology, 2(4), 45.
21. Vangay, P., et al. (2016). Antibiotics, the gut microbiome, and host health: from mechanisms to concepts. Cell Host & Microbe, 19(5), 558-569.
22. Yatsunenko, T., et al. (2012). Human gut microbiome viewed across age and geography. Nature, 486(7402), 222-227.
23. Koropatkin, N. M., et al. (2012). How the human gut microbiota digests polysaccharides. Annual Review of Microbiology, 66, 1-28.
24. Yoshii, K., et al. (2020). The production of B vitamins by the gut microbiota and its implications for host health. Bioscience, Biotechnology, and Biochemistry, 84(4), 675-687.
25. Wahlstrom, A., et al. (2016). Interplay between the gut microbiota and bile acids in host metabolism and disease. Nature Reviews Endocrinology, 12(12), 701-713.
26. Hooper, L. V., et al. (2012). Interactions between the microbiota and the immune system. Science, 336(6086), 1268-1273.
27. Vancamelbeke, M., & Vermeire, S. (2017). The intestinal barrier: a fundamental role in health and disease. Expert Review of Gastroenterology & Hepatology, 11(6), 577-589.
28. Round, J. L., et al. (2011). The gut microbiota regulates Treg cell homeostasis and Th17 cell differentiation. Science, 333(6050), 1713-1718.
29. Hamer, H. M., et al. (2008). The effect of butyrate on intestinal barrier function and inflammation. Gut, 57(3), 419-428.
30. Cummings, J. H., & Macfarlane, G. T. (1997). Role of intestinal bacteria in nutrient metabolism. Journal of Parenteral and Enteral Nutrition, 21(6), 357-362.
31. Wang, Z., et al. (2011). Gut flora metabolism of phosphatidylcholine promotes atherosclerosis. Nature, 472(7341), 57-63.
32. Nie, Z., et al. (2020). The gut microbiota-derived metabolite trimethylamine N-oxide and insulin resistance: a systematic review and meta-analysis. Nutrients, 12(11), 3290.
33. Kamada, N., et al. (2013). Role of the gut microbiota in immunity and inflammatory disease. Nature Reviews Immunology, 13(5), 321-335.
34. Cryan, J. F., et al. (2019). The Microbiota-Gut-Brain Axis. Physiological Reviews, 99(4), 1877-2013.
35. Cani, P. D., et al. (2007). Changes in intestinal microbiota control metabolic endotoxemia-induced inflammation in high-fat diet–induced obesity and diabetes in mice. Diabetes, 56(7), 1761-1770.
36. Boursier, J., et al. (2016). The intestinal barrier and non-alcoholic fatty liver disease. Digestive and Liver Disease, 48(9), 1019-1025.
37. Erridge, C., & Samani, N. J. (2007). The pro-inflammatory effect of bacterial products on human adipocytes. Atherosclerosis, 186(1), 89-95.
38. Hotamisligil, G. S. (2006). Inflammation and metabolic disorders. Nature, 444(7121), 860-867.
39. Qin, J., et al. (2012). A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature, 490(7418), 55-60.
40. Vinolo, M. A. R., et al. (2011). Regulation of inflammation by short chain fatty acids. Nutrients, 3(10), 858-876.
41. Samuel, B. S., et al. (2009). A human gut microbial enzyme that removes fucose from intestinal mucin. Nature, 462(7276), 923-927.
42. Chambers, E. S., et al. (2015). Fermentable carbohydrate stimulates GLP-1 release by activating the GPR41/43 receptors. Gut, 64(11), 1739-1744.
43. Perry, R. J., et al. (2020). Acetate mediates a microbiome-brain-β-cell axis to promote glucose homeostasis. Cell Metabolism, 32(3), 390-405.e8.
44. Ridlon, J. M., et al. (2016). Consequences of bile acid transformations on host physiology. Journal of Lipid Research, 57(7), 1113-1126.
45. Begley, M., et al. (2006). Bile salt hydrolase in probiotic bacteria. Applied and Environmental Microbiology, 72(3), 1729-1736.
46. Schoonjans, K., et al. (1996). F-RXR alpha and the farnesoid X-activated receptor (FXR): two orphan nuclear receptors that respond to farnesyl pyrophosphate. Journal of Biological Chemistry, 271(47), 30230-30238.
47. Houten, S. M., et al. (2006). The farnesoid X receptor is a master regulator of the metabolic response to feeding. Journal of Clinical Investigation, 116(11), 3015-3024.
48. Newgard, C. B., et al. (2009). A branched-chain amino acid-related metabolic signature that differentiates obese from lean humans and is altered by diet. Obesity, 17(4), 793-802.
49. Pedersen, H. K., et al. (2016). Human gut microbiota in obesity and type 2 diabetes and the effect of metformin. Nature, 531(7592), 79-82.
50. Koeth, R. A., et al. (2013). Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nature Medicine, 19(5), 576-585.
51. Tang, W. H. W., et al. (2013). Association between trimethylamine-N-oxide and the risk of cardiovascular events in patients with coronary heart disease. Journal of the American Medical Association, 309(19), 1904-1913.
52. Jia, J., et al. (2020). Gut microbiota-derived trimethylamine N-oxide contributes to the development of insulin resistance via inflammation pathway. Journal of Nutritional Biochemistry, 82, 108420.
53. Lozupone, C. A., et al. (2012). Diversity, stability and resilience of the human gut microbiota. Nature, 489(7415), 220-230.
54. Larsen, N., et al. (2010). The gut microbiota in type 2 diabetes differs from that in the nondiabetic obese and nonobese individuals. Diabetes Care, 33(10), 2292-2298.
55. Kostic, A. D., et al. (2012). Genomewide metagenomic analysis of the human gut microbiome identifies specific bacterial species and metabolic pathways associated with inflammatory bowel disease. Gut, 61(10), 1438-1447.
56. Karlsson, F. H., et al. (2013). Gut metagenome in a Swedish cohort with type 2 diabetes. Nature, 498(7452), 99-103.
57. Turnbaugh, P. J., et al. (2006). An obesity-associated gut microbiome with increased capacity for energy harvest. Nature, 444(7122), 1027-1031.
58. Ley, R. E., et al. (2006). Microbial ecology: human gut microbes associated with obesity. Nature, 444(7122), 1022-1023.
59. Ridaura, V. K., et al. (2013). Gut microbiota from twins discordant for obesity modulate adiposity in mice. Science, 341(6150), 1241214.
60. Frost, G., et al. (2014). The short-chain fatty acid acetate reduces appetite via a central neural mechanism. Nature Communications, 5(1), 3611.
61. Furet, J. P., et al. (2020). Gut microbiota and non-alcoholic fatty liver disease: current evidence and therapeutic implications. Therapeutic Advances in Gastroenterology, 13, 1756284820942548.
62. Wong, R. J., et al. (2015). The gut microbiota and nonalcoholic fatty liver disease. Alimentary Pharmacology & Therapeutics, 42(9), 1066-1075.
63. Caussy, C., et al. (2019). The gut microbiome in nonalcoholic fatty liver disease: potential for therapy. Journal of Clinical Gastroenterology, 53(Suppl 1), S19-S23.
64. Jonsson, D., et al. (2014). Gut microbiota and atherosclerosis. Atherosclerosis, 233(2), 536-541.
65. Manichanh, C., et al. (2006). Reduced diversity of faecal microbiota in Crohn’s disease revealed by 16S rRNA gene sequencing. Gut, 55(2), 205-211.
66. FAO/WHO. (2002). Guidelines for the Evaluation of Probiotics in Food. Report of a Joint FAO/WHO Working Group on Drafting Guidelines for the Evaluation of Probiotics in Food.
67. Sanders, M. E. (2008). Probiotics: definition, sources, selection, and uses. Clinical Infectious Diseases, 46(Supplement_2), S58-S61.
68. Wang, C., et al. (2019). The effect of probiotics on intestinal barrier function: A systematic review and meta-analysis of randomized controlled trials. Journal of Functional Foods, 58, 201-210.
69. Ren, J., et al. (2020). Probiotics in the prevention and treatment of type 2 diabetes. Frontiers in Endocrinology, 11, 237.
70. Sivan, A., et al. (2015). Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-1 efficacy. Science, 350(6264), 1084-1089.
71. Gérard, P. (2016). Gut microbiota and bile acid metabolism: current knowledge and future directions. Future Microbiology, 11(1), 133-145.
72. Krumbeck, J. A., et al. (2018). The effect of Lactobacillus reuteri supplementation on fasting glucose levels in type 2 diabetes: a systematic review and meta-analysis. Journal of Clinical Gastroenterology, 52(2), 154-162.
73. Zhang, Y., et al. (2020). Probiotics for the treatment of type 2 diabetes mellitus: A meta-analysis. Experimental and Therapeutic Medicine, 19(2), 1403-1411.
74. Sun, J., et al. (2021). The effect of probiotics on glycemic control in patients with type 2 diabetes: A meta-analysis of randomized controlled trials. Frontiers in Endocrinology, 12, 638680.
75. Borgeraas, H., et al. (2016). Effects of probiotics on body weight, body mass index, and waist circumference in adults: a systematic review and meta-analysis of randomized controlled trials. Obesity Reviews, 17(7), 582-592.
76. Gibson, G. R., et al. (2017). Expert consensus document: The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of prebiotics. Nature Reviews Gastroenterology & Hepatology, 14(8), 491-502.
77. Carlson, J. L., et al. (2018). Health effects and sources of prebiotic dietary fiber. Current Developments in Nutrition, 2(3), nzy005.
78. Slavin, J. (2013). Fiber and prebiotics: mechanisms and health benefits. Nutrients, 5(4), 1417-1435.
79. Coudray, C., et al. (2003). Effect of dietary fructans on magnesium absorption and intestinal bone mineralization in rats. Journal of Nutritional Biochemistry, 14(11), 668-675.
80. Reimer, R. A., et al. (2017). Dietary fiber and prebiotics in the treatment of obesity-related comorbidities. Nutrients, 9(12), 1361.
81. Kellow, N. J., et al. (2014). The effect of resistant starch on the gut microbiome and its relationship to metabolic health: A review. Nutrients, 6(12), 5220-5236.
82. Maki, K. C., et al. (2012). Resistant starch improves insulin sensitivity in adults with metabolic syndrome. Diabetes Care, 35(8), 1783-1786.
83. Markowiak, P., & Śliżewska, K. (2017). Effects of probiotics, prebiotics, and synbiotics on human health. Nutrients, 9(9), 1021.
84. De Vrese, M., & Schrezenmeir, J. (2008). Probiotics, prebiotics, and synbiotics. Advances in Biochemical Engineering/Biotechnology, 111, 1-66.
85. Rabizadeh, S., et al. (2019). The effects of synbiotic supplementation on metabolic status in patients with type 2 diabetes mellitus: a systematic review and meta-analysis of randomized controlled trials. Journal of the American College of Nutrition, 38(7), 652-663.
86. Hemati, M., et al. (2020). The effects of synbiotic supplementation on glycemic control and lipid profiles in patients with type 2 diabetes: a systematic review and meta-analysis. Journal of Diabetes Research, 2020, 9370129.
87. Smillie, C. S., et al. (2018). Strain-resolved analysis of the human gut microbiome reveals widespread sharing of diverse antibiotic resistance genes. Science, 360(6392), 1226-1230.
88. Borody, T. J., & Khoruts, A. (2012). Fecal microbiota transplantation and emerging applications. Nature Reviews Gastroenterology & Hepatology, 9(2), 88-96.
89. Vrieze, A., et al. (2012). Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology, 143(4), 913-916.e7.
90. Cammarota, G., et al. (2014). Fecal microbiota transplantation for the treatment of Clostridium difficile infection: a systematic review. Journal of Clinical Gastroenterology, 48(8), 693-702.
91. Vrieze, A., et al. (2012). Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology, 143(4), 913-916.e7.
92. Kootte, R. S., et al. (2017). Prebiotic-induced changes in the gut microbiota are associated with a decrease in insulin resistance in subjects with the metabolic syndrome. Diabetes, Obesity and Metabolism, 19(5), 658-668.
93. Weingarden, A. R., & Vaughn, B. P. (2017). Fecal microbiota transplantation for recurrent Clostridium difficile infection: a review of the evidence. Therapeutic Advances in Gastroenterology, 10(9), 701-717.
94. Allegretti, J. R., et al. (2018). Fecal microbiota transplantation for recurrent Clostridium difficile infection in immunocompromised patients: a systematic review and meta-analysis. Digestive Diseases and Sciences, 63(12), 3322-3331.
95. Staley, C., et al. (2018). Development of a Fecal Microbiota Transplant (FMT) program for recurrent Clostridioides difficile infection: From donor screening to patient follow-up. Microbiome, 6(1), 221.
96. Holscher, H. D. (2017). Dietary fiber and prebiotics and the gastrointestinal microbiota. Gut Microbes, 8(2), 172-184.
97. Birkett, A. M., & Jones, A. B. (2006). Fermentable carbohydrates for gastrointestinal health. British Journal of Nutrition, 96(S1), S18-S25.
98. Anhê, F. F., et al. (2020). Polyphenols and gut microbiota in the management of obesity and type 2 diabetes: a review. Antioxidants, 9(2), 136.
99. Marco, M. L., et al. (2017). Health benefits of fermented foods: microbiota and beyond. Current Opinion in Biotechnology, 47, 109-115.
100. Tomé-Carneiro, J., et al. (2019). The Mediterranean Diet and the Gut Microbiota: A Narrative Review. Nutrients, 11(4), 880.
101. Glick-Bauer, M., & Yeh, M. C. (2014). The health effects of vegan diets: a systematic review. Journal of the American Dietetic Association, 114(5), 805-812.
102. Singh, R. K., et al. (2017). Influence of diet on the gut microbiome and implications for health and disease. Nutrients, 9(7), 679.
103. Salminen, S., et al. (2021). The International Scientific Association of Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of postbiotics. Nature Reviews Gastroenterology & Hepatology, 18(11), 743-753.
104. Weitkunat, K., et al. (2017). Butyrate: a new tool for type 2 diabetes therapy? Trends in Endocrinology & Metabolism, 28(6), 395-403.
105. Joice, R., et al. (2019). Bacteriophage therapy: an alternative to antibiotics for pathogenic Escherichia coli? Current Opinion in Microbiology, 51, 6-12.
106. Riglar, D. T., & Silver, P. A. (2018). Engineering bacteria for diagnostic and therapeutic applications. Nature Reviews Microbiology, 16(5), 269-281.
107. Olesen, S. W., et al. (2021). Defined microbial consortia in the gut: applications and perspectives. Gut Microbes, 13(1), 1957448.
108. Dethlefsen, L., et al. (2008). An ecological and evolutionary perspective on the human microbiome. Nature, 455(7216), 1060-1065.
109. Allen, J. M., et al. (2018). Exercise alters host-microbe interactions in the gut. Journal of Applied Physiology, 125(5), 1697-1705.
110. Leone, V., et al. (2015). Effects of an intestinal clock on circadian feeding and metabolism. Cell Metabolism, 21(1), 1-10.