Fluoride-induced gut dysbiosis in metabolic disorders: Mechanisms and public health implications.

3.1. Gut microbiota in insulin sensitivity and glucose metabolism

Reactive oxygen species (ROS), which are elevated due to gut dysbiosis, can lead to inflammation by disrupting the gut barrier’s integrity, activating the immune system, and altering metabolic pathways associated with obesity, metabolic syndrome, and even the incidence of type 2 diabetes [27]. According to studies, gut microbiota is also involved in the loss of glucose tolerance and insulin resistance through several mechanisms [16] (Fig. 3). Gut microbiota metabolites have a significant impact on insulin resistance, which translates to action on insulin signaling pathways that lead to increased skeletal muscle glucose uptake and enhanced lipid oxidation, reduced lipogenesis, and gluconeogenesis associated with high hepatic lipid oxidation, as well as enhanced adipose tissue thermogenesis and inflammation [28]. A higher succinate concentration may occur when the balance is outweighed by bacteria producing succinate (Prevotellaceae and Veillonellaceae) and those utilizing it as their primary source of energy (Odoribacteraceae and Clostridaceae), which hinders the process of glucose metabolic consumption. Succinate, which is an immunogenic compound and a non-cytotoxic metabolite, activates the proinflammatory T lymphocyte formation mediation and cytokine production by Toll-like receptor ligand secretion through the stabilization of hypoxia-inducible factor-1a via its G-protein-coupled receptor (SUCNR1/GPR19). The combination of these processes exacerbates the burden of diabetes and insulin resistance [29]. The gut microbiota also regulates metabolic pathways, including glucose metabolism and insulin resistance. Specific bacterial groups, such as Lactobacillus, can enhance glucose metabolism and insulin sensitivity [30] by producing short-chain fatty acids (SCFAs), including butyrate, which stimulates anti-inflammatory pathways and improves gut barrier function.

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Fig. 3. Key Consequences of Gut Dysbiosis in Metabolic Health. Legend: The figure summarizes the systemic consequences of gut dysbiosis. Alterations in microbial composition lead to increased inflammation, reduced SCFA production, compromised gut barrier function, elevated lipopolysaccharide (LPS) levels, and disrupted bile acid metabolism. These factors collectively contribute to immune dysregulation and metabolic disorders such as obesity and diabetes. Abbreviations: SCFA – Short-Chain Fatty Acids; LPS – Lipopolysaccharides.

Nevertheless, fluoride affects the gut microbiome by decreasing the populations of Lactobacillus and SCFA production, especially butyrate. This perturbation affects gut barrier integrity, leading to the leakage of endotoxins and the subsequent amplification of inflammation, which in turn disrupts insulin signaling. These adaptations lead to insulin resistance and metabolic disorders. Recent research suggests that fluoride’s antibacterial properties can lead to shifts in microbial populations, affecting changes in microbial communities and influencing insulin sensitivity and metabolic well-being [31].

3.2. Fluoride’s impact on beneficial and harmful bacterial populations

The effect of fluoride on the health of the host is most reliant on the dosage consumed. The gut microbiota, often considered a neglected aspect of human health, plays a pivotal role in health and nutritional status [22]. Chen et al. discovered that some gut microbiota can be favorably altered in response to low fluoride concentrations, leading to the growth of beneficial bacteria, including Lactobacillus and Faecalibacterium. Excessive fluoride exposure disrupts the balance of microbial communities by altering both the composition and metabolic functions of intestinal bacteria. Instead of focusing solely on changes in bacterial abundance, recent evidence emphasizes functional dysbiosis—alterations in microbial metabolites, interspecies interactions, and signaling pathways that collectively impair insulin signaling and promote systemic inflammation leading to insulin resistance [32], [33]. Specifically, fluoride-induced dysbiosis affects central insulin signaling cascades, including the PI3K/Akt and IRS-1/GLUT4 pathways, leading to decreased glucose uptake and increased inflammatory cytokine production through NF-_kB and JNK activation. These combined molecular changes ultimately lead to insulin resistance and impaired glucose homeostasis. Enhancement of intestinal permeability is specifically linked to an imbalance of the Bacteroidetes/Firmicutes ratio. The leaky gut allows bacterial byproducts to translocate, causing heightened inflammatory responses that are associated with diabetes [33], [34], [35], [36].

3.3. Influence of microbial metabolites on metabolism

Numerous metabolites are generated by gut bacteria, e.g., SCFAs such as acetate, propionate, and butyrate that regulate metabolism. Fluoride exposure alters the Gut microbiota composition, which causes the development of dysbiosis and metabolic disorders, such as type 2 diabetes mellitus (T2DM), in the future [33], [34]. An example is the food that changes the intestinal barrier, such as a high-fat diet. It alters the microbiome, lowering the levels of SCFA. Conversely, increasing absorption and circulation of LPS and branched-chain amino acids (BCAA) leads to increased adipose mass, insulin resistance, and subclinical inflammation. Based on intestinal barrier breakdown and dysbiosis, the microorganisms and LPS that appear in the bloodstream following Colon colonization can activate the toll-like receptor 4 (TLR4) receptor, causing inflammation and pathological changes in metabolism [35], [37]. Dysbiosis also reduces the production of secondary bile acids that trigger the release of glucagon-like peptide-1 (GLP-1) to counteract the effects of insulin resistance. Fluoride exposure also has implications for SCFA production, which interferes with metabolism and subjects patients to the risk of diabetes [38], [39].

3.4. Mitochondrial dysregulation mediated by gut dysbiosis in energy metabolism

4.1. Obesity and gut microbiota alterations

4.1.2. Effects of adipose tissue and energy homeostasis

4.2.2. Metabolic endotoxemia and insulin resistance

Increased intestinal permeability, influenced by dysbiosis, is associated with metabolic endotoxemia, a condition linked to intestinal bacteria as the primary source of LPS in numerous studies. The long-term effects of low-grade endotoxemia include the increased probability of developing type 2 diabetes caused by inflammation [43]. When the integrity of the tight connection is compromised, intestinal permeability rises. Consequently, LPS enters the bloodstream and interacts with membrane-bound CD14 receptors and LPS-binding proteins. They interact with the TLR4 complex, affecting both the insulin and inflammatory signaling pathways. LPS is the primary trigger of TLR, but other compounds, including endogenous compounds, have also been found to trigger it. Similar to T1DM, T2DM has a higher content of endotoxins in the blood that stimulates TLRs [54]. Although endotoxemia is described as a cause of T2DM, human evidence has not yet been established that fluoride exposure contributes to changes in intestinal permeability and TJ expression [55].

4.2.3. Disrupted bile acid metabolism

The key role of bile acids metabolized by the principal gut bacteria is to normalize blood sugar levels through FXR, TGR5, and other receptors. One of the pathways through which FXR operates is the regulation of hepatic glucose production and lipid metabolism. Stimulation of TGR5 enhances insulin sensitivity by releasing GLP-1 [56]. The gut microbiota-bile acid axis is a potential therapeutic target, as research has shown that disruptions in the interaction between bile acids and gut microbiota result in changes to the composition of the bile acid pool, as well as alterations in the structure of the gut microbiota and endocrine signaling pathways. These changes may impact the progression of type 2 diabetes mellitus (T2DM). Further research is required to translate these results into clinical practice, as there are differences in bile acid composition between humans and rodents [57]. Although considerable research has been conducted on metabolic disorders and gut microbiota, the precise role of gut microbiota in the development of obesity and type 2 diabetes mellitus, particularly in relation to fluoride, remains poorly understood. Formerly, our theories have often relied on studies involving rodents; however, the microbiota of mice differs markedly from that of humans. Additionally, the germ-free animals utilized in experiments are born and maintained in an environment devoid of bacterial contact, where they are subsequently exposed to specific microbes throughout the research process [55].

6.1. Findings from animal models

Most experimental data on the influence of fluoride on intestinal dysbiosis comes from rodent studies. For instance, Chen et al. demonstrated in mice that a high-fat diet (HFD) can increase intestinal permeability and alter gut microbiota, contributing to obesity and related metabolic disorders. Their findings also provided preliminary evidence for the interaction between fluoride exposure and obesity, through modulation of the intestinal microbiome and intestinal barrier, highlighting that changes in gut microbiota, including those affecting glucose metabolism induced by fluoride, act as key drivers of diabetes [42]. Similarly, Zhe Mo et al. reported that the impact of different fluoride concentrations in drinking water on the gut microbiota was investigated, revealing dose-dependent alterations in microbial composition. Higher fluoride levels were associated with structural degradation in the colon and rectum, suggesting potential implications for metabolic health [20]. Using Wistar rats, a study by Komuroglu et al. revealed that the composition of the gut microbiota was significantly altered due to fluoride treatment, with an increase in the amount of Proteobacteria and a decrease in the number of Lactobacillus. Oxidative stress has been linked to microbial changes, characterized by higher levels of malondialdehyde (MDA) and reduced levels of antioxidant enzymes, which may lead to metabolic alterations [60].

Most of the experimental data on the influence of fluoride on intestinal dysbiosis is based on rodent research, while porcine models are particularly valuable for translational research due to their physiological and microbiota similarity to humans. These models allow more accurate extrapolation of fluoride-induced intestinal dysbiosis and its metabolic consequences [61]. Beyond mammals, avian studies in laying hens and ducks have shown disrupted intestinal morphology, reduced digestive enzyme activity, and altered cecal microbial communities following chronic dietary fluoride ingestion [62]. Invertebrate models, such as Bombyx mori (silkworms), further confirm that fluoride-induced intestinal perturbations are not restricted to vertebrates [63]. Finally, in vitro studies using human intestinal epithelial cell lines (Caco-2 and HT-29) demonstrate that fluoride exposure can induce oxidative stress, mitochondrial dysfunction, and apoptosis in intestinal epithelial cells [64], [65].

6.2. Findings from human studies

A human study examines the effects of prolonged fluoride exposure on the gut flora and metabolic characteristics of Pakistani drinking water. Research findings indicate that alterations in the microbial composition of the gut lead to gut dysbiosis, insulin resistance, and type 2 diabetes. Exposure to fluoride in recorded amounts will remodel short-chain fatty acids, increase oxidative stress, and induce low-grade inflammation [66]. A human study conducted by Wang et al. demonstrates that chronic fluoride exposure alters the composition of the gut microbiota, resulting in dysbiosis characterized by an abundance of Proteobacteria and other pathogenic taxa, as well as a deficiency in Firmicutes and Bacteroidetes. The distortion was also associated with metabolic disturbances, such as variations in tryptophan metabolites, which play a significant role in regulating the immune system and systemic inflammation [21]. Knowing that human exposure to various environmental pollutants such as Fluoride and PFAS is associated with gut microbiota dysbiosis that enhances the ratio of Firmicutes/Bacteroidetes and affects bile acid metabolism a study by Sen et al. revealed that obesity, insulin resistance and metabolic disorders were associated with these consequences and the possibility of secondary bile acids created by the gut microbiota being relevant mediators [67].

6.3. Comparative insights: differences between animal and human models

Although animal models have helped gain valuable mechanistic understanding of fluoride-induced intestinal dysbiosis, considerable physiological and microbial differences exist between animals and humans, which must be taken into consideration when interpreting findings. The most commonly utilized models are rodents due to their genetic homogeneity, ease of management, and cost-effectiveness; however, their gut microbiota composition, bile acid metabolism, and immune system functionality vary significantly compared to those of humans. Rodent microbiota have lower microbial diversity, characterized by a higher proportion of Firmicutes and a lower proportion of Bacteroidetes, and exhibit different intestinal physiological parameters, such as transit time and pH gradients, compared to those of the human gastrointestinal tract [20], [68], [69]. Additionally, species differences in diet, enzyme activity, and kidney function reduce the absorption and systemic bioavailability of fluoride [42], [70]. Porcine models, on the contrary, are gradually being considered better translational models due to their close resemblance to the gastrointestinal tract, microbial ecology, and metabolic capabilities of humans. Pig-based studies have also shown that fluoride exposure disrupts gut microbial balance and intestinal morphology, similar to what is observed in human populations [61]. Bird species, including laying hens and ducklings, have demonstrated that chronic intestinal levels of fluoride significantly impact mucosal immunity, digestive enzymes, and the cecal microbial habitat, providing supportive evidence of cross-species intestinal toxicity of fluoride [62]. Moreover, invertebrate models, such as Bombyx mori (silkworm), demonstrate that even in simpler organisms, microbial stability can be disrupted by exposure to fluoride, and thereby this phenomenon has been evolutionarily conserved by fluoride [63].

The human gut microbiota is more complex, and its multifaceted response to various factors, including diet, environmental co-exposure, antibiotic use, and genetics, results in a broader response to fluoride [4], [71], [72]. The human intestinal ecosystem also harbors various microbial metabolic networks through which fluoride and metabolic interactions can occur, including bile acid metabolism and the synthesis of short-chain fatty acids. As such, although animal models cannot be done without in clarifying mechanistic pathways, only controlled human cohort and intervention studies can determine the real translational significance of fluoride-induced dysbiosis and its metabolic implications.

6.4. Conflicting evidence and key research gaps

Research has revealed that the effect of fluoride on the gut microbiome is dose-related. For example, Zhe Mo et al. found that the higher fluoride concentrations in the water resulted in greater changes in microbial composition and structural damage to the rectum and colon [20]. However, other studies suggest that low doses of fluoride may compromise the gut microbiome, posing a problem for safe levels of exposure. According to some studies, fluoride exposure reduces the levels of beneficial microbes (Lactobacillus and Proteobacteria) and promotes the growth of pathogenic taxa, potentially leading to metabolic disorders. However, there are other reports that fluoride exhibits biphasic activity, in that low doses can increase certain healthy bacteria. High doses, however, interfere with the normal integrity of the gut microbiota. These conflicting results underscore the importance of conducting further studies with finer details to explore the concept of dose-response and pathways related to the impact of fluoride on the metabolic health of individuals and the intestinal microbiome. The existing picture of the connections between fluoride exposure, gut microbiota composition, and the likelihood of metabolic disorders has significant gaps. Future studies should focus on conducting high-quality human experiments to investigate the effects of fluoride exposure on human gut microbiota and metabolic health, as well as to elucidate the underlying biological mechanisms and examine dose-response relationships. Filling these gaps with well-conducted human studies will be essential in determining how fluoride exposure affects the health risks associated with the gut microbiota and the risk of diabetes [73].

Although numerous studies have linked exposure to fluoride with changes in gut microbiota, their findings are inconsistent. The results of some studies indicate that high levels of fluoride have a significant adverse effect on the microbial diversity, intestinal barrier integrity, and promote systemic inflammation [20], [23], [24], [74]. The results of others indicate that low levels of fluoride exposure can temporarily increase the abundance of some beneficial taxa, including Lactobacillus and Faecalibacterium [22], [32]. Such discrepancies can be attributed to methodological and biological heterogeneity of studies, as variations in fluoride concentration, duration of exposure, animal model, microbiome sequencing methods, and dietary composition all impact the results [14], [20], [42]. Moreover, mechanistic evidence is found in rodent or in vitro models, the gastrointestinal physiology, microbial ecology, and bile acid metabolism of which differ significantly from those in humans, thus limiting translational interpretation [13], [25], [42], [55], [57]. Human cohort studies are relatively limited, small-scale, and often confounded by co-exposures to arsenic, heavy metals, or PFAS; thus, it is challenging to determine the independent effect of fluoride in causing dysbiosis [15], [21]. In turn, the total body of evidence must be viewed as not conclusive, but indicative. Standardized fluoride exposure measurements, interspecific validation, and longitudinal studies in humans should be employed in future research to establish dose-effect relationships and determine whether the microbial changes are causally relevant to the metabolic outcomes [14], [21], [42].

Although considerable progress has been made in understanding the interaction between fluoride exposure and gut microbiota, several limitations remain in the current evidence. There is a high degree of heterogeneity in the literature regarding fluoride concentration, length of exposure, choice of animal model, dietary composition, as well as methods of analysis, which have resulted in inconsistent and even conflicting data [14], [20]. The vast majority of mechanistic evidence comes from rodent or in vitro research, which does not fully replicate the complexity of human gastrointestinal physiology, microbial diversity, or fluoride metabolism [25]. Human studies are still limited in number and tend to be underpowered, with limited exposure windows and poor control of environmental confounding elements, including arsenic, PFAS, and co-exposure to heavy metals [15].

Future studies should focus on standardizing assessments of fluoride exposure and incorporating multi-omics methods, such as metagenomics, transcriptomics, and metabolomics, to evaluate comprehensive biological responses. Longitudinal human cohort studies are urgently needed to establish the dose-response relationship and identify microbial/metabolic biomarkers of fluoride-induced dysbiosis, as well as the long-term metabolic and immunological consequences of fluoride exposure. It will be necessary to develop unified methodologies to consolidate the current findings from experiments on dietary, genetic, and environmental factors into concise, evidence-based guidelines for population health.

Drinking water is one of the primary sources of fluoride ingestion. The World Health Organization (WHO) has established a limit for fluoride intake in drinking water, which is less than 1.5 mg/L, since it has been gradually determined that excessive fluoride concentration in water harms people’s health [42]. According to the WHO, nearly 200 million people rely on contaminated water, which poses a serious health risk, and more than 25 nations have fluoride concentrations above the allowable level. One of the significant sources of fluoride intake involves drinking water. The amounts of fluoride in some African countries have exceeded the recommended level of fluoride set by the WHO. The Asian countries with the highest amounts of fluoride in their groundwater are Bangladesh, China, India, Indonesia, Iran, Iraq, Jordan, South Korea, Pakistan, Palestine, Saudi Arabia, Sri Lanka, Syria, Thailand, Turkey, and Yemen. Defluoridation is particularly necessary in the United States, Canada, and Mexico because of their high groundwater fluoride levels. Excessive fluoride concentrations in groundwater are also serious in European nations [11].

Fluoride contamination is one of the most critical environmental health issues in India. States like Rajasthan, Bihar, Andhra Pradesh, and Telangana have consistently recorded groundwater fluoride levels of between 3 and 5 mg/L, significantly exceeding the WHO recommendation of 1.5 mg/L. Endemic fluorosis is plagued by both skeletal and non-skeletal manifestations [75]. India has an active National Programme for Prevention and Control of Fluorosis (NPPCF) under the Ministry of Health and Family Welfare, which has been actively monitoring water sources, establishing defluoridation technologies, and promoting community education. However, due to resource constraints and uneven application, fluorosis is still largely prevalent in rural areas [76], [77]. The issue is particularly acute in coal-burning regions in China, including Guizhou, Shanxi, and Inner Mongolia, where coal with a high fluoride content is burned in the air and during indoor combustion, emitting fluoride into the air and the food chain. The latest literature reveals that, similarly to skeletal fluorosis, the inhabitants of such regions face changes in the intestinal microbiota associated with metabolic impairments. The health authorities in China have responded by implementing policies for cleaner fuels, educating the public, and monitoring water quality [21], [78], [79]. In Pakistan, the groundwater in Punjab, Sindh, and Balochistan often contains a high level of fluoride (more than 5?mg/L). Activated alumina, bone char, and reverse osmosis unit-based community-based defluoridation projects are currently being implemented; however, most of them are not well-maintained and sustainable. National surveys indicate the need for an enhanced public awareness campaign, regular water testing, and cooperation between local and federal divisions to mitigate the impact of fluoride [80], [81].

These territorial issues raise concerns about the urgent need to implement localized approaches to mitigate the biological and metabolic hazards of chronic fluoride exposure, including access to safe water, community engagement, defluoridation technology, and routine monitoring.

Though so far there has been no conclusive evidence on the association of fluoride exposure with metabolic risk, some studies have suggested that exposure to fluoride higher than the WHO recommended guideline of 1.5?mg/L can led to the gut dysbiosis in people residing in fluorosis-prone regions, which consequently contributed to several reciprocal metabolic dysregulations such as obesity and insulin resistance leading to type 2 diabetes [42], [66]. The total effects of exposure to fluorides resulting from industrialization, agricultural activities, and water use can also be factored into public health strategies. They also used knowledge, attitudes, and practices (KAP) assessments on a population level to identify gaps in awareness and then provided specific community interventions on fluoride [82]. By staying informed about the origins of fluoride, its effects, and measures to prevent these effects, policymakers and medical professionals can work to reduce the occurrence of fluoride exposure and improve overall health parameters. It is essential to increase awareness of fluoride toxicity among the general population, medical practitioners, legislative bodies, and other relevant stakeholders. This would be achieved through educational programs and effective communication strategies [83], [84].

8.1. Probiotic, prebiotic, or synbiotics for gut restoration

Probiotics have been defined as nonpathogenic living organisms; when taken in sufficient doses, they can reveal beneficial impacts on the host [86]. Efforts have been made to alleviate gastrointestinal discomfort through the use of contemporary probiotics. The most recent findings have stated that the probiotic supplement can successfully balance gut microorganisms, which in turn encourage healthy blood lipid levels, alleviate low-grade inflammation, and reduce weight in obese individuals [50]. The predominant probiotic strains used today are from the genera Lactobacillus, Clostridium, Bifidobacterium, and Streptococcus. Innovative approaches and the implementation of new methodologies, as well as gnotobiotic animal models, suggest that recent discoveries in culturomics have established a basis for developing novel host-specific probiotic medicines [87]. Chen et al. found that people with type 2 diabetes who received probiotics and metformin together experienced an increased hypoglycemic response. The observed effect was likely made possible by altering the gut flora, which affected the metabolism of bile acids and SCFAs. This study demonstrates the benefits of combining probiotics and metformin as a therapeutic approach for individuals with type 2 diabetes mellitus (T2DM) [88]. Prebiotic supplements are undigested materials that alter the behavior and composition of the gut microbiota to benefit the host, particularly (but not exclusively) by their fermentation [86].

The carbohydrates that may survive in the form of prebiotics include inulin, fructo-oligosaccharide, and galacto-oligosaccharide, known to be hard to digest in the small intestine [89]. They are fermented in the large intestine, though, and have been shown to increase the number of Lactobacillus and/or Bifidobacterium. Prebiotics increase the abundance of Lactobacillus, Bifidobacterium, Faecalibacterium, and Bacteroidetes by promoting eubiosis and attenuating pathogenic alterations of dysbiosis [90]. Additional alterations brought about by prebiotics include improvements in gastrointestinal motility and insulin sensitivity, as well as reductions in lipopolysaccharides, oxidative stress, proinflammatory cytokines, and gut permeability. Additionally, prebiotics support peptides YY and GLP-1. It has been demonstrated that prebiotic supplementation can enhance human subjects’ ability to control their appetite [91]. The health effects of prebiotics are many and encompass immunological modulation via enhanced immune-regulatory interleukins and intestinal-specific immunoglobulins; attenuation of proinflammatory interleukins; and the synthesis of SCFAs such as butyrate, propionate, and acetate. SCFAs are acids with carboxylic groups with up to six carbon atoms in their hydrocarbon chains, generated by gut microbes’ anaerobic fermentation of food fibers in the stomach [41].

Microbial fermentation generates SCFAs that maintain gut barrier integrity and minimise inflammation as part of anti-obesity and anti-diabetes protection. They are acknowledged to improve intestinal health by maintaining intestinal barrier function, enacting mucus secretion, defending against intestinal inflammation, and alleviating other metabolic disorders such as diabetes and obesity [92]. Synbiotics comprise probiotics and indigestible dietary components (prebiotics) that influence the host [93]. Jiang et al. revealed in a study on mice that the synbiotics of Lactobacillus plantarum, lactulose, and arabinose effectively modulated the gut microbiome composition and enhanced glucose and lipid metabolism in mice with type 2 diabetes mellitus (T2DM). It also found that treatment reduced triglycerides, total cholesterol, and fasting blood glucose, indicating that it would effectively manage metabolic diseases [94].

Interest in employing probiotics for medicinal purposes has increased as our understanding of human microbiota and dysbiosis has grown. However, intestinal conditions and oxygen sensitivity limit the application of next-generation probiotics (NGPs). Prebiotics, such as fructooligosaccharide, galactooligosaccharide, and polyphenols, enhance intestinal barrier function, colonization, and NGP survivability. However, the lack of research and clinical trials limits its use in clinics. To optimize NGP bioactivity and tailored delivery for disease therapy, future research should focus on cutting-edge in vitro tests, clinical trials, and complex encapsulation technologies [95].

8.2. Fecal microbial transplantation (FMT) in metabolic disorders

Fecal Microbiota Transplantation (FMT) is a procedure in which fecal material is extracted from a donor’s body via the intestinal tract and inserted into the recipient’s intestinal tract, aiming to restore a disturbed intestinal microbial ecosystem or restructure the recipient’s intestine [96], [97]. In the past century, microbiologists have isolated numerous probiotic bacteria. While studies have shown their effectiveness in standard animal models, individual microorganisms exhibit limited capacity in preventing and treating human diseases. As a result, their clinical benefits are constrained. Consequently, collaboration among various microbes is essential for remodeling gut microbiota [57]. While probiotic and prebiotic treatments play a significant role in restoring the gut microbiome, the approach with the most notable potential for altering the gut microbiome is FMT [85]. FMT promotes the elimination of pathogenic microorganisms and boosts the host’s resistance capabilities. There is also the failure of microbial colonization of the gastrointestinal tract after dysbiosis and aberrant microbial colonization, which triggers a hyperactive response or imbalance of the immune system, leading to chronic inflammation and the development of mucosal lesions. In this way, repairing the gut microbiota using FMT helps to minimize host harm and restore immunological function.

On the other hand, FMT contributes to restoring essential metabolites associated with host metabolism development, including SCFA, antimicrobial peptides (AMPs), bacteriocins, and bile acids [98]. Chen et al. conducted studies using the genetic db/db mice model of diabetes by rebuilding the gut microbiota, altering serum metabolites, controlling host immunological alterations, and reducing the inflammatory response, all of which impacted host glucose metabolic phenotypes. This paper further demonstrates that FMT could be a potentially beneficial treatment intervention for T2DM and confirms the notion that FMT can produce a healthy host-microbiota connection, thus opening up new knowledge to appreciate FMT as an effective treatment for diabetes [99]. Wang et al. reported that FMT significantly reduced fasting blood glucose and improved glucose tolerance in diabetic mice, thereby preventing the loss of pancreatic islet ? cells, which restored host homeostasis and gut microbiota equilibrium [100]. In a similar study, another clinical trial established better insulin sensitivity in obese patients upon receiving FMT with donors who were skinny [101]. Wu et al. explored how FMT could change insulin resistance in type 2 diabetes mellitus (T2DM) patients. In this randomized controlled trial, FMT alone or in combination with metformin was found to reverse insulin resistance, improve glycemic control, and modulate gut microbiota composition in individuals with newly diagnosed type 2 diabetes. The study highlights the therapeutic potential of FMT in managing type 2 diabetes by targeting gut dysbiosis and insulin resistance [102]. It is challenging to determine the precise functionality of FMT and to evaluate its therapeutic efficacy and safety due to its complex and variable nature [103]. While FMT holds significant promise as a potential treatment strategy, further research is necessary to fully understand its clinical applicability, effectiveness, and safety across diverse patient populations [104].

8.3. Pharmacological interventions targeting gut microbiota

Metformin is the primary medication for glycemic control in T2DM, particularly in those with obesity-related conditions. Liu et al. [105] demonstrated in their previous studies that intravenous administration of metformin did not lower glucose levels compared with oral administration, and the bioactivity of oral metformin is primarily mediated in the intestine. Evidence shows that metformin is the most commonly encountered pharmacological factor in glycemic control in the management of T2DM, especially in cases induced by obesity. Earlier studies have shown that intravenous administration of metformin does not lower glucose levels as effectively as oral administration, due to the bioactivity of metformin in the intestine [105]. The symptoms suggest that metformin affects the microbiota composition in patients with type 2 diabetes mellitus (T2DM) and healthy individuals [106]. In metagenomics, the microbiota reveals that metformin’s ability to mitigate diabetes is related to its capacity to produce SCFAs and potentially activate microbial genes and pathways. The formation of SCFAs, primarily propionate and butyrate, intensified gluconeogenesis in the intestine, enhanced glycemic responses, and reduced hunger, body weight, and liver glucose [105], [107]. GLP-1 is a hormone, released by the intestinal endocrine cells (L cells) as food is ingested. This substance can increase insulin secretion by pancreatic 8-cells in response to glucose and lower glucagon secretion. Moreover, it also contributes to the activation of appetite suppression and deceleration of gastric evacuation. Numerous experiments have revealed that gut microbiota is a regulator of satiety and glucose homeostasis by induction of the secretion of GLP-1 in mice. Moreover, another type of anti-diabetic drugs called GLP-1 receptor agonists has been noted to interfere with the intestinal environment. It is noteworthy that a change in the gut microbiota has been linked to the use of GLP-1 receptor agonists [108].

The oral hypoglycemic agents are called -glucosidase inhibitors because they hinder the breakdown of the carbohydrates in the small intestine, including disaccharides and starch. They are effective in reducing postprandial hyperglycemia and slowing glucose absorption, which helps control blood glucose levels and their related complications. This group includes acarbose, voglibose, and miglitol. In this way, the sources of nutrients used by bacteria can be altered by ?-glucosidase inhibitors, which break down complex carbohydrates [109]. Emerging evidence suggests that alpha-glucosidase inhibitors affect the composition of microbiota. In patients with type 2 diabetes mellitus, the intestinal levels of Bifidobacterium longum can be increased by the administration of acarbose, and some inflammatory cytokines can be reduced, irrespective of its anti-hyperglycemic effects [110]. Dipeptidyl peptidase 4 (DPP-4) inhibitors, including sitagliptin, saxagliptin, and vildagliptin, influence gut microbiota, thereby improving the management of obesity and diabetes. They maintain active incretins, such as GLP-1, to enhance glucose metabolism and improve insulin sensitivity. The positive outcomes encompass heightened populations of Bifidobacterium and Lactobacillus, a decrease in Prevotella (pathogenic bacteria) populations, and an enhancement of SCFA-producing bacteria, including Ruminococcus Dipeptidyl peptidase 4 (DPP-4) inhibitors, which consist of sitagliptin, saxagliptin, and vildagliptin, act on the source of gut microbiota, and hence, exhibits beneficial effects on the management of obesity and diabetes. They preserve active incretins, including GLP-1, which promotes better glucose management and insulin. The beneficial effects include an increase in the number of Bifidobacterium and Lactobacillus, a reduction in the populations of Prevotella (pathogenic bacteria), and an increase in the number of SCFA-producing microorganisms, such as Ruminococcus [111]. They modulate the Firmicutes/Bacteroides ratio, enhance the gut barrier, and reduce mesenteric fat. The DPP-4 inhibitors are used to improve metabolic and gut health due to their ability to control gut dysbiosis and systemic inflammation [112].