The Gut Microbiome in Human Obesity: A Comprehensive Review

Obesity results from the chronic accumulation of adipose tissue, primarily driven by a sustained imbalance between caloric intake and energy expenditure [1]. At present, an estimated 2.6 billion individuals, equivalent to 40% of the global population, are living with overweight or obesity. It is projected that this number could exceed 4 billion by 2035, approaching half of the world’s population [2,3]. The persistent rise in obesity rates reflects the convergence of numerous interrelated factors, including but not limited to high-fat diets, sedentary lifestyles, neurohormonal dysregulation, and genetic and epigenetic susceptibility, as well as environmental and behavioral influences. Unless this increasing trajectory is effectively addressed, the trend is expected to continue in the coming years [4].

Individuals with obesity are predisposed to a multitude of obesity-related pathologies, including metabolic dysfunction-associated steatotic liver disease (formerly non-alcoholic fatty liver disease), metabolic syndrome (e.g., dyslipidemia, insulin resistance, hypertension, and elevated fasting glucose), type 2 diabetes mellitus (T2D), hepatic disorders, cardiovascular diseases, and certain cancers [5,6,7]. Moreover, obesity has been associated with diminished life satisfaction and the emergence of adverse mental health conditions, such as anxiety and depression [8]. Consequently, obesity constitutes a major contributor to the increased morbidity and mortality rates observed in contemporary populations [9]. This can be explained by evidence indicating that excessive adipose tissue accumulation in obesity activates cells of the innate immune system, which in turn promotes a state of chronic low-grade inflammation [10].

Traditionally linked to caloric intake and physical inactivity, obesity is now increasingly recognized as being influenced by the gut microbiome (GM), a diverse and dynamic microbial community residing in the gastrointestinal tract [10,11]. Emerging evidence indicates that the GM affects host metabolism through bioactive metabolites, which may regulate pivotal processes such as insulin sensitivity, lipogenesis, neurohormonal signaling, and systemic inflammation [5,12]. However, although research links the GM to obesity, an integrative synthesis connecting microbial mechanisms, dietary interventions, and GM-targeted therapies remains lacking. In this context, the prevailing hypothesis suggests that an imbalance in GM composition, known as dysbiosis, contributes to the activation of numerous signals via multiple pathways, resulting in obesity and its related complications. Indeed, dysbiosis plays a crucial role by influencing hunger regulation, satiety, and nutrient absorption [13]. It also promotes oxidative stress, inflammatory responses, increased adiposity, and metabolic dysfunction, including disturbances in glucose metabolism and adipocyte distribution. Despite these insights, the development of effective screening, diagnostic, and therapeutic approaches for obesity and its comorbidities remains limited, largely due to incomplete understanding of its underlying pathophysiology [5].

Classical approaches to obesity management have included pharmacotherapy, bariatric surgery, and lifestyle interventions [14]. Although significant progress has been made in pharmacological treatments in recent years [15,16], most anti-obesity drugs remain contraindicated for use during adolescence and pregnancy [17]. In turn, bariatric surgery carries considerable risks and potential complications [18]. Evidence-based lifestyle approaches typically encompass a combination of dietary modification, increased physical activity, and behavioral change therapies, which synergistically support sustainable weight management and contribute to improved metabolic outcomes [19,20,21]. Despite lifestyle-based interventions increasing the likelihood of achieving clinically significant weight loss in individuals with obesity, long-term weight maintenance remains a major obstacle, as weight regain over time is common, even among individuals who adhere to treatment protocols [22]. In light of these challenges, emerging therapeutic approaches, such as probiotic and prebiotic supplementation, brown adipose tissue transplantation, fecal microbiota transplantation (FMT), glucagon-like peptide-1 receptor agonists, poly-agonist pharmacotherapies, ultrasound stimulation of the vagus nerve, and precision nutrition strategies, have shown promise for clinical application [15,23,24,25,26,27,28].

Excessive adiposity significantly impairs quality of life and is associated with numerous comorbidities, collectively heightening the risk of preventable mortality. The GM has emerged as a central regulator of host metabolism and energy homeostasis, making its detailed characterization crucial for the advancement of innovative therapeutic strategies and for elucidating mechanisms underlying metabolic health and disease. Understanding these microbiome-mediated mechanisms is therefore essential for developing targeted interventions to manage obesity. In fact, these insights may also reveal that modulation of the GM can offer broader human health outcomes beyond metabolism. Based on these considerations, it is hypothesized that GM dysbiosis contributes causally to obesity by modulating energy balance, inflammation, and metabolic signaling, highlighting a knowledge gap in current obesity research. This review offers a novel and integrative perspective by connecting current evidence on GM functions with potential GM-focused strategies for obesity therapy. More specifically, it examines human obesity through the lens of the GM, providing a comprehensive overview of its role by addressing GM alterations, microbiome-driven mechanisms, dietary influences, prebiotic effects, microbiome-based therapeutics, and other approaches in the treatment of obesity and related metabolic disorders.

The composition and function of the human GM play a pivotal role in the development and management of obesity. Several studies have demonstrated that GM composition differs not only between obese and lean subjects but also across geographic regions, with marked variations observed between countries [29]. A review of the literature highlights consistent alterations in the GM of individuals with obesity compared to eutrophic subjects, notably a decrease in microbial richness and diversity [30,31,32]. These compositional changes have been linked to increased adiposity, dyslipidemia, heightened low-grade inflammation, and impaired glucose metabolism, underscoring the relevance of GM alterations in obesity pathophysiology [33].

In terms of GM composition, individuals with obesity often exhibit an increased Bacillota/Bacteroidota (B/B) ratio in their fecal microbiota, regardless of dietary intake [34,35]. However, this microbial signature is not consistently observed, likely due to confounding factors that influence GM composition, including fasting status, dietary pattern, antibiotic use, age, geographic location, exercise habits, genetic background, and methodological or clinical variables [36,37]. In this context, a decreased B/B ratio was reported in overweight and obese individuals without dietary restrictions [38], suggesting that body mass index (BMI)-related differences in GM composition may not follow a universal pattern [39]. These discrepancies may stem from interpretive bias caused by methodological differences in sample processing and DNA sequencing. Alternatively, they could reflect insufficient characterization of the study participants, especially the omission of lifestyle-related factors known to affect GM composition and diversity [40].

In some cases, differences in GM have been detected at the genus and family levels within the same cohort, without significant variation at the phylum level. For instance, a recent study in Korean adolescents found that individuals with normal weight had higher levels of Bacteroides/Bacteroidaceae, whereas obese participants exhibited increased levels of Prevotella/Prevotellaceae. However, the relative abundance of Bacillota, Bacteroidota, and Pseudomonadota, as well as the B/B ratio, did not differ significantly between groups [37]. Although there is a general consensus on the increase in Bacillota [41], other studies suggest that obesity risk may be more closely linked to reductions in Bifidobacterium spp. (Actinomycetota) [35] or Akkermansia muciniphila (Verrucomicrobiota) [42], rather than changes in the B/B ratio.

Other studies have revealed marked differences in GM bacterial composition among individuals with obesity. Kasai et al. [43] found that certain bacterial species, including Blautia hydrogenotrophica, Blautia (formerly Ruminococcus) obeum, Coprococcus catus, Eubacterium ventriosum, and Ruminococcus bromii, were linked to obesity in a Japanese population. In turn, Gao et al. [44] reported that in individuals with obesity, beneficial bacteria such as Bifidobacterium, Faecalibacterium, and butyrate-producing Ruminococcaceae are significantly reduced, whereas potential opportunistic pathogens, including Escherichia/Shigella and Fusobacterium, are increased. In addition, Crovesy et al. [45] conducted a systematic review of 32 studies and reported that individuals with obesity exhibit an increased abundance of members of the phyla Bacillota, Fusobacteriota, and Pseudomonadota, as well as the species Limosilactobacillus (formerly Lactobacillus) reuteri. Conversely, a decline has been observed in the abundance of the phylum Bacteroidota and species such as A. muciniphila, Faecalibacterium prausnitzii, Methanobrevibacter smithii, Lactiplantibacillus (formerly Lactobacillus) plantarum, and Lacticaseibacillus (formerly Lactobacillus) paracasei.

In a review conducted by Cani et al. [46], it was reported that members of the genera Clostridium, Lactobacillus, and Ruminococcus are elevated in obese patients, while F. prausnitzii is more prevalent in healthy individuals and reduced in those with obesity. Similarly, Duan et al. [30] observed significant differences in GM composition between obese patients and control subjects. At the phylum level, Bacillota, Bacteroidota, Actinomycetota, and Fusobacteriota showed significant disparities between the groups. At the genus level, 16 major genera exhibited notable differences, with Prevotella, Megamonas, Fusobacterium, and Blautia markedly increased in obese patients. Conversely, the remaining 12 genera, specifically Faecalibacterium, Lachnospiracea_incertae_sedis, Clostridium XIVa, Coprococcus, Gemmiger, Ruminococcus, Parabacteroides, Bifidobacterium, Clostridium IV, Alistipes, Oscillibacter, and Barnesiella, demonstrated reduced prevalence. At the species level, nine species showed significant differences, with an increased abundance of Megamonas funiformis, Segatella (formerly Prevotella) copri, and Fusobacterium mortiferum in obese subjects, whereas Bacteroides uniformis, F. prausnitzii, Fusicatenibacter saccharivorans, Barnesiella intestinihominis, Parabacteroides distasonis, and Alistipes putredinis were decreased.

Palmas et al. [47] conducted a study characterizing the GM signatures of overweight and obese individuals compared to normal-weight controls in Sardinia, Italy. Their findings revealed a significant reduction in the relative abundance of multiple Bacteroidota taxa within the microbial communities of obese patients, including members of the families Flavobacteriaceae, Porphyromonadaceae, and Sphingobacteriaceae, as well as the genera Bacteroides, Flavobacterium, Parabacteroides, Pedobacter, and Rikenella. However, several Bacillota taxa exhibited a marked increase in the same subjects, including members of the families Gemellaceae, Lachnospiraceae, Paenibacillaceae, Streptococcaceae, and Thermicanaceae and the genera Acidaminococcus, Eubacterium, Gemella, Megamonas, Megasphaera, Mitsuokella, Ruminococcus, Streptococcus, Thermicanus, and Veillonella. Body fat (BF) percentage and waist circumference (WC) showed a negative correlation with the abundance of Bacteroidota taxa. In contrast, Bacillota taxa showed a positive correlation with BF and a negative correlation with muscle mass and/or physical activity levels. Furthermore, the obese group exhibited an increased relative abundance of several bacterial taxa within the Enterobacteriaceae family, known for their endotoxic activity, compared to normal-weight controls.

In a systematic review, Xu et al. [48] identified bacterial taxa specifically associated with obesity and metabolic disorders across Western and Eastern populations. The phylum Pseudomonadota was the most frequently reported in obese individuals, while the genera Faecalibacterium, Akkermansia, and Alistipes were negatively correlated with obesity. In turn, Ruminococcus and Prevotella were identified as obesity-related genera in studies conducted in Western regions. Conversely, these genera were found to be lean-related in studies conducted in Eastern regions. Moreover, the genera Roseburia and Bifidobacterium were associated with a lean BMI in the Eastern population, while Lactobacillus was associated with obesity in the Western population. Yan et al. [49] employed whole-genome shotgun sequencing to reveal that the GM of patients with high visceral fatty areas (VFAs) exhibited a distinct microbial composition compared to those with low VFAs, characterized by an increased abundance of 18 bacterial species in the high-VFA group and 9 species that were more prevalent in the low-VFA group. A total of 16 gut microbial species exhibited strong correlations with VFA, with E. coli showing the highest association, followed by Bifidobacterium longum, Dialister succinatiphilus, Eubacterium hallii, Escherichia unclassified, Mitsuokella unclassified, Ruminococcus gnavus, and Mediterraneibacter (formerly Ruminococcus) torques. Furthermore, only two species (i.e., E. hallii and Solobacterium moorei) were found to be positively linked with BMI, while two species (i.e., D. succinatiphilus and Mitsuokella unclassified) demonstrated a positive correlation with WC. Figure 1 provides a summary of GM alterations in patients with obesity, according to several studies [30,43,44,45,46,47,48].

Various mechanisms have been proposed to explain the association between GM composition and the pathogenesis of obesity [50]. The first mechanism involves the microbial fermentation of non-digestible carbohydrates into metabolic byproducts, primarily short-chain fatty acids (SCFAs) such as acetate, butyrate, and propionate [51,52]. SCFAs are produced through anaerobic fermentation and function as ligands for G-protein-coupled receptors (GPRs). Acetate binds GPR43, butyrate binds GPR41, and propionate binds both. In states of dysbiosis and obesity, the expression of these receptors may be downregulated, contributing to hepatic lipogenesis and disruptions in energy homeostasis [53,54]. On the other hand, SCFAs have also been shown to promote fat oxidation and energy expenditure while inhibiting lipolysis. These effects support thermogenesis in brown adipose tissue and the browning of white adipose tissue [55], as well as enhanced insulin sensitivity [56]. Moreover, SCFAs have been implicated in the upregulation of peroxisome proliferator-activated receptors (PPARs), which play a key role in adipogenesis regulation [57].

A human pilot study demonstrated that oral butyrate supplementation positively influences glucose metabolism in lean individuals but not in those with metabolic syndrome, likely due to altered SCFA handling in insulin-resistant subjects [58]. Similarly, Li et al. [59] reported that butyrate can suppress appetite and activate brown adipose tissue through the gut–brain neural axis. Additional studies have identified associations between SCFA levels and improved insulin sensitivity, as well as regulatory effects on adipose tissue development, lipid storage, and substrate metabolism in the liver and skeletal muscle [60]. SCFAs that are not absorbed or metabolized by intestinal epithelial cells are transported to the liver via the portal vein, where they serve as substrates for gluconeogenesis, lipogenesis, and cholesterologenesis [61]. In addition, SCFAs have been shown to inhibit histone deacetylase activity, thereby influencing epigenetic modifications such as histone acetylation and methylation [62]. These changes can modulate the expression of genes involved in lipid metabolism and contribute to the restoration of chromatin structure and function [63].

According to Iqbal et al. [3], SCFAs exhibit a dual role in obesity, exerting both anti-obesogenic and pro-obesogenic effects. (i) SCFAs promote the secretion of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), hormones that suppress appetite and reduce caloric intake. (ii) They also activate the AMP-activated protein kinase (AMPK) pathway, enhancing fatty acid oxidation and decreasing fat accumulation. (iii) In contrast, in the context of dysbiosis, SCFAs have been shown to downregulate fasting-induced adipose factor (FIAF) expression in enterocytes, thereby increasing lipoprotein lipase (LPL) activity and promoting lipid storage in adipocytes. (iv) Excessive SCFA production, particularly acetate, can be utilized by the liver for fatty acid synthesis, contributing to lipid accumulation and increased energy extraction. A schematic representation of the dual role of SCFAs in obesity is shown in Figure 2 (modified from Iqbal et al. [3]).

The second mechanism involves the capacity of the GM to modulate circulating lipopolysaccharide (LPS) levels by impairing epithelial barrier integrity, thereby initiating endotoxemia and the onset of moderate chronic systemic inflammation [64,65]. Once in the bloodstream, LPS binds to LPS-binding protein (LBP), which facilitates its recognition by the CD14 receptor. This interaction subsequently activates adipose tissue macrophages through the Toll-like receptor 4 (TLR4) pathway. LPS-TLR4 binding has been shown to upregulate genes involved in immune responses via the nuclear factor-kappa B (NF-κB) signaling pathway, promoting the secretion of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) [66,67]. This persistent low-grade inflammation, termed metabolic inflammation, impairs insulin signaling in peripheral tissues and contributes to systemic insulin resistance, which is a hallmark of obesity and metabolic syndrome [3]. Moreover, these inflammatory processes can drive genetic and epigenetic modifications that elevate the risk of obesity-related comorbidities [63]. In murine models, a single acute injection of LPS has been shown to enhance glucose disposal and glucose-stimulated insulin secretion through activation of the GLP-1 pathway [68].

The third mechanism is based on the hypothesis that the GM can modulate host genes implicated in energy storage and utilization, favoring fat accumulation [69]. In this context, Li et al. [70] conducted a comprehensive metagenomic analysis of 192 patients and reported functional gene variations in Bacteroides and Prevotella related to amino acid and carbohydrate metabolism. In addition, the authors identified a human genetic variant (rs878394) in the lysophospholipase-like 1 (LYPLAL1) gene, which is associated with BF distribution, insulin sensitivity, and the relative abundance of Prevotella. The GM has also been shown to regulate appetite and satiety through vagal nerve activation and immune–neuroendocrine signaling pathways [71]. Notably, lower levels of anorexigenic hormones involved in appetite suppression, such as GLP-1 and PYY, have been consistently observed in individuals with obesity [72].

The GM also plays a pivotal role in modulating bile acid (BA) metabolism, thereby influencing liver triglyceride (LT) levels and glucose homeostasis through the activation of the farnesoid X receptor (FXR) [73]. FXR activation in both the liver and intestines has been shown to inhibit hepatic lipogenesis, improve insulin sensitivity, and enhance energy expenditure, ultimately contributing to the mitigation of obesity risk. In addition, BAs have been implicated in preserving intestinal barrier integrity, thereby limiting LPS translocation into the systemic circulation and reducing the onset of chronic low-grade inflammation, which constitutes a key contributor to the pathogenesis of obesity and metabolic syndrome [74].

Furthermore, the GM may inhibit the expression of the FIAF gene, thereby increasing LPL activity and promoting lipid accumulation in white adipose tissue [75]. FIAF, which constitutes a protein produced by adipose tissue, the gastrointestinal tract, the liver, and skeletal muscle in response to fasting, plays a pivotal role in lipid metabolism by inhibiting LPL, which reduces triglyceride uptake in adipose and muscle tissues [76]. This inhibitory effect limits fatty acid uptake, potentially preventing excessive fat storage and serving as a mechanism to attenuate obesity [77].

In the context of obesity management, short-term weight loss is primarily driven by calorie restriction rather than diet composition, with the most effective diet being the one that the individual can adhere to [78]. However, beyond caloric intake, dietary quality plays a pivotal role in obesity management and related health outcomes, with patterns such as the Mediterranean diet, vegetarian diets, ketogenic diets, and dairy-inclusive approaches showing benefits in weight control, metabolic health, and inflammation reduction [79,80,81,82,83,84,85,86,87]. Moreover, dietary quality is crucial in obesity-related conditions such as asthma, where high-fat, low-fiber diets are linked to increased airway inflammation and impaired medication responsiveness [20]. The Mediterranean diet, characterized by consumption of high-quality plant-based foods and moderate fat intake, demonstrates weight-loss effects comparable to low-fat and low-carbohydrate diets, while offering added cardiometabolic benefits and long-term sustainability when combined with energy restriction and physical activity [79,80]. Vegetarian diets are also associated with lower BMI and favorable weight outcomes, with key contributors including fiber content, lower caloric density, microbiota regulation, and the release of gastrointestinal appetite-regulating hormones [81,82,83]. Ketogenic diets, via mechanisms such as appetite suppression, reduced lipogenesis, increased lipolysis, and enhanced fat oxidation, have shown short- to medium-term benefits in terms of weight loss and cardiometabolic health in obese patients, although careful monitoring and a gradual transition to a normal diet are essential for safety and adherence [84,85]. In addition, dairy-inclusive, energy-restricted diets may enhance fat loss while preserving lean mass, with growing evidence supporting the benefits of whole-fat and fermented dairy products for body composition and cardiometabolic health [86,87].

Regarding diet outcomes, the GM has become a central focus in recent research due to its substantial contribution to obesity and related comorbidities. GM dysbiosis has been demonstrated to impact adiposity and glucose metabolism, thereby promoting obesity. Furthermore, modulating the GM through dietary strategies has emerged as a promising therapeutic approach in obesity management [5,6]. A high-calorie diet rich in fats and sugars, typical of the Western dietary pattern, combined with a sedentary lifestyle, has been identified as a major risk factor for obesity and its related metabolic disturbances [88]. Such dietary and lifestyle patterns induce the accumulation of adipose tissue, leading to an increase in visceral and subcutaneous fat. Once adipose tissue reaches its storage capacity, excess energy such as triglycerides leads to an increase in blood lipids and ectopic fat accumulation [89]. This progressive adiposity is accompanied by enhanced adipogenesis and the release of pro-inflammatory cytokines and adipokines, which are central to the pathogenesis of obesity-related disorders [90]. In contrast, the Mediterranean diet has been widely studied for its demonstrated efficacy in ameliorating chronic conditions, including T2D and metabolic syndrome [91,92]. These positive effects are largely attributable to the high intake of plant-based foods rich in dietary fiber and antioxidant compounds, such as terpenes and flavonoids, which enhance the production of SCFAs by the GM [93,94]. Consistently, elevated levels of SCFAs have also been observed in individuals following vegetarian diets [95].

High-calorie diets have been shown to modulate GM composition by increasing the abundance of Bacillota members while concurrently decreasing Bacteroidota abundance [96,97]. This shift in the B/B ratio has been particularly noted in obese animal models carrying leptin gene mutations, in contrast to their lean counterparts without such mutations, indicating a link between obesity and altered microbial diversity [98]. Despite the existence of numerous studies documenting variations in the B/B ratio among obese adults, other evidence suggests that obesity is more broadly characterized by an increased prevalence of Actinomycetota and Bacillota phyla, along with a decreased prevalence of species within the Bacteroidota and Verrucomicrobiota phyla, including A. muciniphila, as well as a reduction in F. prausnitzii [99,100].

Several human studies have shown that a high-fat diet can reduce the abundance of Bacteroides spp., Bifidobacterium spp., Clostridium coccoides, and Eubacterium rectale in individuals with obesity. However, these alterations can be reversed via dietary interventions [32,101,102]. Thingholm et al. [103] observed that the abundance of L. reuteri in the GM of obese patients was substantially elevated compared to other bacterial genera such as Akkermansia, Alistipes, Faecalibacterium, and Oscillibacter, as well as the archaeal species M. smithii, which tended to decrease. In addition, increased sugar intake has been linked to GM dysbiosis, characterized by a rise in the relative abundance of intestinal Pseudomonadota and a reduction in Bacteroidota, contributing to pro-inflammatory effects and impaired epithelial barrier function [104]. An in vivo study in obese adolescents undergoing a calorie-restricted diet combined with increased physical activity demonstrated that weight-loss interventions induced alterations in GM composition. As observed in corresponding animal studies, these changes, which include increased inflammation and intestinal permeability, resulted in endotoxemia, enhanced fat accumulation, and steatosis [105].

Dietary fiber intake plays a pivotal role in maintaining host health and regulating body weight (BW). Adoption of a vegetarian diet, characterized by a high intake of indigestible fibers, has been shown to decrease the β-diversity of the human GM. This decrease is linked to an increased abundance of the genera Prevotella and Faecalibacterium, alongside a reduced prevalence of Bacteroides [95]. While high Prevotella abundances have been demonstrated to promote weight loss in healthy adults with overweight [106], F. prausnitzii may play a pivotal role in obesity and related metabolic disorders, as it is frequently found in lower abundance in obese subjects and it is associated with reduced inflammation and enhanced gut barrier integrity and has even been shown to reduce appetite [107]. In addition, plant polyphenols increase the populations of Bifidobacterium and Lactobacillus, which exert anti-inflammatory effects, improve metabolic parameters, and confer cardiovascular protection in humans [108,109]. This modulation of the GM is particularly relevant in the context of obesity, as chronic low-grade inflammation and cardiovascular risk are common comorbidities associated with excessive adiposity [110]. Furthermore, fermented vegetables have been proposed as potential therapeutic agents in managing obesity, as they are particularly rich in Lactobacillus species, reduce cholesterol, inhibit adipogenesis, and have anti-diabetic properties [111].

Ketogenic diets are normocaloric, high-fat, and very low-carbohydrate dietary patterns that induce a state of ketosis [112]. This state leads to a reduction in insulin levels due to carbohydrate restriction, thereby suppressing lipogenesis and fat storage, while depleting glucose reserves. Although ketogenic diets are generally normocaloric, they are frequently modified to very-low-calorie versions in certain applications, further enhancing fat loss and other metabolic benefits [108]. The therapeutic effects of ketogenic diets in obese patients are likely mediated by their capacity to augment fatty acid oxidation and lipolysis while suppressing de novo lipogenesis, as well as by modulating hepatic glucose metabolism through decreased circulating insulin and increased glucagon levels, which together inhibit gluconeogenesis and promote elevated resting energy expenditure [112]. Recent studies have emphasized the pivotal involvement of the GM in mediating the effects of the ketogenic diets [113,114]. In human subjects, these dietary patterns have been shown to alter GM composition by decreasing the abundance of the phylum Bacillota and increasing the abundance of members belonging to the phylum Bacteroidota [115,116]. At the genus level, decreases in the abundance of Bifidobacterium and Lachnobacterium, as well as increases in Akkermansia and Slackia, have been reported [108,117]. Specifically, A. muciniphila may play a significant role in obesity and related metabolic disorders, as it can help to prevent weight gain, reducing visceral fat and improving glucose homeostasis [118]. Moreover, Gong et al. [119] noted that Bifidobacterium substantially decreased in visceral obesity, with serum uric acid potentially acting as a mediator between decreased Bifidobacterium and increased visceral adipose tissue, which suggests that supplementation with this microorganism might be a crucial complement for ketogenic diets in order to promote visceral adipose tissue reduction.

Prebiotics are typically polysaccharides defined as substances that induce specific changes in the composition and/or function of the GM, thereby conferring health benefits to the host [120]. To qualify as prebiotics, these substances must meet three criteria: (i) resistance to digestion by host enzymes, gastric acid, and bile; (ii) the ability to selectively stimulate the growth and/or activity of beneficial commensal microbiota; and (iii) fermentability by the GM [121].

Administration of various prebiotics has been shown to alter metabolic functions and GM composition, leading to increased levels of the anorexigenic gastrointestinal peptides GLP-1 and PYY, alongside decreased concentrations of the orexigenic hormone ghrelin [122]. Specifically, prebiotics such as inulin, fructans, and oligofructose promote the proliferation of beneficial bacteria, including lactobacilli and bifidobacteria [123]. Preclinical studies have linked Bifidobacterium species to reduced FM, lower BW gain, and diminished inflammation and metabolic endotoxemia [124]. In addition, prebiotic supplementation has been reported to increase the abundance of A. muciniphila, a species positively associated with improved insulin sensitivity, reduced FM gain, lower systemic inflammation, decreased metabolic endotoxemia, and regulation of energy homeostasis [42,125,126]. These findings in animals have been corroborated by clinical evidence demonstrating that oligofructose intake modulates GLP-1, ghrelin, and PYY levels in humans, thereby reducing hunger sensations and postprandial glucose fluctuations [122,127,128]. In a seminal study, Genta et al. [129] reported that consumption of oligofructose-rich syrup derived from yacon (Smallanthus sonchifolius) roots increased satiety and resulted in reductions in BW, BMI, and WC among obese premenopausal women. This intervention also decreased low-density lipoprotein (LDL) cholesterol and fasting insulin levels. Similarly, supplementation with inulin-type fructans in obese women significantly decreased BW, WC, BMI, homeostasis model assessment for insulin resistance (HOMA-IR), and fasting insulin, while improving satiety compared to the placebo group [130]. Table 1 summarizes the effects of various prebiotics administered in both animal models and human studies.

The GM offers a novel perspective on potential therapies by linking inflammation, energy homeostasis, metabolism, and obesity. Several reviews have extensively discussed microbiota modulation strategies [5,148], proposing various microbial approaches to restore gut dysbiosis associated with obesity. Among these, probiotics and synbiotics remain the primary treatment modalities, while FMT has recently shown promising efficacy.

This review presents an updated synthesis of current evidence on the role of the GM in human obesity, including diet, prebiotics, probiotics, synbiotics, and FMT as therapeutic strategies for GM modulation. To our knowledge, no previous review has addressed the GM in human obesity in such a comprehensive and integrative manner, covering microbial alterations, underlying mechanisms, dietary influences, prebiotic modulation, and microbiome-targeted therapies, as well as current and emerging therapeutic approaches. While microbial-based interventions are emerging as promising tools for managing obesity and related pathologies, several challenges must be addressed to enhance their efficacy and reproducibility. One critical issue is the heterogeneity in patient responses, as individuals often exhibit varying outcomes despite receiving similar treatments, a discrepancy influenced by factors such as baseline microbiota composition and host-specific variables. Genetic differences among individuals may further modulate immune responses, nutrient metabolism, and host–microbiota interactions, thereby impacting therapeutic effectiveness. Moreover, a significant limitation lies in the insufficient mechanistic understanding of these interventions. For instance, the FMT interventions reviewed were generally performed in pilot trials with small sample sizes and heterogeneous study populations. In turn, clinically significant outcomes, such as weight loss and alterations in BMI, are typically assessed up to 12 months following an intervention [202,203]. However, the efficacy of a single donor in terms of inducing a sustained effect remains uncertain. In contrast, multiple FMTs did not produce substantial metabolic improvements in subjects with metabolic syndrome [204]. As noted, metabolic and microbiome responses among FMT recipients exhibited considerable variability, and the studies lacked sufficient statistical power to analyze outcomes by recipient subgroups or to evaluate donor-specific effects. Finally, the FMT protocols did not include dietary interventions, and the majority of participants consumed typical high-fat, low-fiber Western diets. Therefore, the influence of diet needs to be validated in larger randomized controlled trials encompassing participants from diverse ethnic backgrounds [261].

Although the beneficial effects of microbial therapies are increasingly being recognized, the precise molecular pathways, particularly those involving microbial metabolites such as SCFAs and BAs, and their interactions with host metabolic networks remain insufficiently elucidated. Integrating multi-omics technologies, including metagenomics, metabolomics, and proteomics, may offer comprehensive insights into the dynamic interplay between the GM, the immune system, and host metabolism. Ultimately, the development of an integrative conceptual framework that incorporates microbial metabolites, immune modulation, and systemic metabolic regulation is essential for optimizing microbiota-targeted interventions aimed at improving metabolic health.

It is increasingly evident that inter-individual variability in GM composition significantly influences responses to dietary interventions aimed at obesity management. Studies assessing fecal microbiota before and after dietary interventions have revealed the stability of the microbiome over time and demonstrated marked heterogeneity in microbial and physiological responses among individuals subjected to identical diets [262]. This variability means that two individuals adhering to the same diet may experience markedly different physiological and microbial outcomes. For instance, Hjorth et al. [263] demonstrated that individuals with Prevotella-dominant microbiomes exhibited greater BF loss on a Nordic diet compared to those with Bacteroides-dominant microbiota, underscoring the role of microbial profiles in modulating dietary responsiveness. These findings underscore the potential of precision nutrition approaches that customize dietary strategies based on individual microbiome characteristics to maximize metabolic benefits. Thus, dietary interventions for obesity should not overlook inter-individual heterogeneity in their design.

Precision nutrition aims to customize dietary interventions by predicting individual metabolic responses, typically involving three main strategies: (i) increasing fiber intake, (ii) restricting caloric intake, and (ii) supplementing with prebiotics and probiotics [264]. Although these resemble conventional approaches, precision nutrition differs in that it incorporates assessment of prior individual responses, such as shifts in GM composition or glycemic control, to design customized plans, as opposed to a standardized dietary model. The success of this approach is often evaluated through microbial markers (e.g., increases in Prevotella abundance), anthropometric outcomes (e.g., weight loss, BMI, and FM reduction), and metabolic indicators like glycemic responses [265]. For instance, Zeevi et al. [266] developed an algorithm that accurately predicted postprandial glucose responses based on individual microbiome and clinical data, demonstrating superior predictive capacity compared to traditional metrics such as the glycemic index. Despite these advances, the application of personalized nutrition within the context of the microbiota–gut–brain axis remains underexplored. There is a critical need for long-term studies to investigate how sustained dietary modifications affect the GM and associated biochemical pathways, particularly those influencing hunger hormones, inflammatory cytokines, and other neuroendocrine signals implicated in obesity and T2D.

Obesity has been linked to dysregulated glycolysis, impaired oxidative phosphorylation, increased production of reactive oxygen species, and mitochondrial fragmentation. Current therapeutic approaches aim to reduce cellular stress and restore metabolic homeostasis, primarily through antioxidants or by modulating mitochondrial dynamics. Considering this, mitochondria-targeted therapies hold promise as a novel strategy to correct metabolic dysfunction in affected individuals [267]. However, to date, interventions specifically targeting mitochondrial dynamics for obesity treatment have yielded limited success, highlighting a gap and an opportunity for further research in this area. Notably, one study demonstrated that a synthetic sphingolipid could modulate mitochondrial dynamics in mice fed a high-fat diet, leading to restoration of healthy body weight [268]. This finding suggests that physiological manipulation of mitochondrial function may represent a viable therapeutic option. Nevertheless, the complexity of mitochondrial involvement in obesity-related metabolic disturbances requires comprehensive investigation to elucidate precise mechanisms and optimize targeted treatments. Future research should focus on understanding the interplay between mitochondrial dynamics, energy metabolism, and systemic metabolic regulation to fully unlock the therapeutic potential of mitochondria-targeted interventions in obesity.

Within the framework of this discussion, it is essential to acknowledge a key interconnection between obesity, mental health, and the GM, which serves as a central regulator of both metabolic and neuropsychological functions. Diet, as a major external factor, shapes the composition and metabolic activity of the GM, thereby influencing host health through modulation of immune development, nutrient metabolism, and bioactive molecule synthesis [93]. The GM is implicated in the etiology of various mental disorders, such as anxiety and depression, with substantial evidence linking its composition and functional dynamics to nervous system development and regulation [252]. Communication between the central nervous system and the GM occurs via immune, endocrine, and neural routes, including the vagal nerve, forming a complex gut–brain axis that impacts metabolic homeostasis and mental well-being [252]. Research indicates that obesity is associated with reductions in quality of life and increases in adverse mental health outcomes, underscoring a predominant influence of obesity on psychological distress [269,270,271]. Epidemiological data further indicate that individuals with obesity or overweight exhibit significantly diminished quality of life and heightened depression scores compared to normal-weight counterparts, with obesity exerting the most pronounced effect [269]. The high co-prevalence of obesity and mental illness poses a critical public health challenge, positioning the GM as a promising target for interventions aimed at improving metabolic and psychological outcomes. In recent years, the emerging field of nutritional psychiatry has begun to reshape clinical approaches, emphasizing the necessity for scientifically rigorous evaluation of dietary supplements and nutraceuticals due to their widespread use among individuals with and without mental health disorders [272]. Psychobiotics, a novel class of psychotropics comprising live microorganisms and bioactive substances, have demonstrated efficacy in ameliorating psychological conditions such as anxiety, stress, and depression, as well as in improving cognitive function, sleep quality, emotional regulation, and mood symptoms [273,274]. Given that diet constitutes a key element in obesity management, precision nutrition offers the opportunity not only to improve obesity-related metabolic dysfunctions but also to enhance mental health outcomes by modulating the GM. Concurrently, microbiome-based therapies, which have shown promise in managing obesity, could be strategically directed to address comorbid psychological conditions, particularly depression, which is highly prevalent among individuals with obesity. In this respect, a strictly vegetarian ketogenic diet has been proposed as a potential nutritional intervention to promote overall health, including improvements in both metabolic and mental health outcomes [108]. Considering the potential efficacy of vegetarian and ketogenic diets in obesity management, the implementation of a strictly vegetarian ketogenic dietary protocol, complemented by structured physical exercise and appropriately designed microbiome-based therapies, could constitute a promising, non-pharmacological, and non-surgical strategy for the effective treatment of obesity. This integrative approach may synergistically modulate metabolic regulation and the gut–brain axis, addressing the complex etiology of obesity and its associated mental health comorbidities. Furthermore, integrating components that address individual motivation, environmental factors, and long-term behavioral reinforcement may be key to improving maintenance outcomes.

Beyond its well-established medical implications, obesity often exposes individuals to stigma and discrimination across various social domains, including the workplace, education, and interpersonal relationships. Indeed, this pervasive stigma has become widely normalized and frequently goes unrecognized as a legitimate form of discrimination [275]. Addressing obesity stigma requires a coordinated societal response, beginning with dispelling common misconceptions about its causes and the rejection of simplistic notions of personal responsibility. A shift toward greater societal understanding and empathy may foster environments in which stigmatizing behaviors are challenged and ultimately eradicated [275]. In the healthcare setting, actionable strategies to mitigate stigma include shifting the clinical focus away from weight, adopting patient-centered communication, ensuring inclusive facilities and equipment, and improving access to specialized obesity care by removing administrative barriers [276]. In Spain, recent data reveal that individuals with obesity often report more aversion toward the condition than those of normal weight, and younger populations report higher frequencies of stigmatizing encounters [277]. These findings underscore the urgent need to confront negative societal beliefs and attitudes as an integral component of public health efforts. It is also noteworthy that even after bariatric surgery, patients continue to experience high levels of stigma, highlighting the persistence of weight-related prejudice despite clinical improvements [277]. While public visibility and advocacy from individuals living with obesity are essential to drive systemic changes and resource allocation, caution is warranted when individuals with self-induced overweight attempt to affiliate with this group. Although excessive weight due to unhealthy lifestyle choices remains a concern, equating it with medically defined obesity threatens the legitimacy of the condition and may overload limited healthcare resources intended for those truly affected. Sustainable progress will depend not only on individual and healthcare-level interventions but also on comprehensive public education campaigns and policy reforms that promote inclusivity and dismantle structural barriers contributing to obesity-related stigma. Ultimately, scientific progress driven by ongoing research must provide future approaches that effectively address obesity and mitigate its consequences, aiming to reduce its impact sufficiently to ensure an improved quality of life across affected demographics.

Lastly, it should be noted that obesity in adolescents is strongly associated with an increased likelihood of experiencing bullying compared to their healthy-weight peers [278]. The co-occurrence of obesity and bullying among children and adolescents remains a critical global concern, with evidence indicating a close relationship between these factors during key developmental stages [279]. While multiple strategies have been developed to manage and treat obesity, including cognitive and behavioral interventions, it seems that the role of certain emotional processes in the etiology and maintenance of this condition is not sufficiently considered. Bullying can provoke intense emotional responses such as humiliation, shame, and anger [280], which may contribute to maladaptive coping mechanisms, including emotional eating, which is defined as the tendency to consume food in response to negative emotions [281]. Since this phenomenon can exacerbate weight gain and complicate obesity management, integrating an assessment of the emotional experiences and coping strategies of individuals with obesity, particularly in the context of bullying and psychosocial stressors, could provide critical insights into underlying psychological mechanisms. Therefore, this approach would foster the development of more effective, comprehensive interventions addressing both the physiological and emotional dimensions of obesity.

Despite the comprehensive coverage of current findings, this review presents several limitations: (i) the heterogeneity in intervention types, including differences in intensity, duration, and methodology, as well as variability in outcome measures; (ii) sample sizes varied substantially, ranging from small pilot studies to large cohort trials; (iii) the uneven geographic distribution of the included studies, with limited representation from developing regions; (iv) inconsistencies in adverse event reporting and inadequate follow-up in several studies; (v) difficulties in translating microbiota-targeted therapies from controlled trials into routine clinical practice, including the lack of standardized operating procedures across diverse patient populations, variability in the quality and reproducibility of biological specimens, and infrastructural constraints, especially regarding advanced therapies such as FMT; (vi) limited clinical accessibility due to specialized equipment requirements for microbiota intervention preparation, storage, and delivery; (vii) burdens on healthcare providers and systems arising from the need for customized approaches in personalized microbiome-based therapies; (viii) high costs associated with microbiome analysis, therapeutic formulation, and delivery, particularly in resource-constrained settings.

Building on these identified limitations, it is also necessary to acknowledge that the clinical translation of emerging therapies faces several critical challenges, including the development of standardized treatment protocols, the assurance of patient safety, and the confirmation of long-term efficacy. These challenges must be considered in conjunction with future research priorities, such as clarifying inter-individual variability, elucidating the still opaque mechanisms of obesity and related diseases, and integrating multi-omics data to capture complex host–microbiome interactions. Furthermore, the precise mechanisms through which microbiome-targeted interventions exert clinical effects remain incompletely understood, limiting mechanistic insight and rational optimization. A central barrier to the development of standardized treatment processes lies in the heterogeneity of research findings, which highlights the need for consistent, evidence-based clinical protocols. The absence of standardized outcome measures further complicates comparisons across studies and the synthesis of results. Addressing this issue requires the establishment of clear clinical guidelines, robust quality control frameworks, and active regulatory oversight to ensure the reproducibility and reliability of new therapeutic and diagnostic approaches. Equally important is the identification and mitigation of adverse events before widespread adoption. This necessitates an exhaustive safety assessment pipeline, incorporating preclinical toxicology studies and rigorous post-market surveillance systems, to ensure that therapies are safe for long-term use. In addition to safety, a major challenge is to demonstrate sustained therapeutic efficacy. Short-term improvements must be substantiated by evidence of durable benefits, which can only be achieved through long-term follow-up studies tracking patient outcomes, disease recurrence, and the persistence of therapeutic effects. This is particularly important in chronic, multifactorial conditions such as obesity, where treatment success depends on stability over time. In this respect, many studies have relatively short intervention periods, which restricts evaluation of long-term efficacy and safety. Emerging innovations will gradually improve the scalability and reproducibility of microbiome-based therapies. Successful implementation may demonstrate their feasibility and clinical utility. Efforts should prioritize the standardization of methodologies, reductions in costs through technological innovation, and the generation of high-quality, large-scale clinical evidence to support widespread application.

The composition of the GM is altered in obesity and characterized by reduced microbial diversity and inconsistent shifts in dominant bacterial phyla, which collectively contribute to metabolic dysregulation. The GM contributes to obesity pathogenesis through multiple mechanisms, including SCFA-mediated regulation of energy homeostasis and insulin sensitivity, LPS-induced chronic inflammation, modulation of host metabolic and appetite-regulating genes, and alterations in BA signaling via FXR. In addition, GM-driven inhibition of FIAF promotes LPL activity and fat storage in adipose tissue.

Dietary patterns exert a profound influence on GM composition and function, with plant-based diets enhancing SCFA production and conferring protective effects against obesity and its comorbidities. Prebiotics modulate GM composition by promoting beneficial bacteria, such as Bifidobacterium and A. muciniphila, which are linked to improved metabolic outcomes, reduced inflammation, and enhanced insulin sensitivity. In addition, microbiome-based therapeutics, including probiotics, synbiotics, and FMT, have demonstrated potential in modulating key metabolic and inflammatory pathways associated with obesity. However, further research is needed to fully elucidate their mechanisms and optimize clinical applications.

As the scientific understanding of the human GM continues to advance, the integration of microbiome-based therapies into standard clinical practice is poised to become increasingly feasible and therapeutically transformative, particularly for obesity, a complex condition that demands innovative and customized interventions.