Direct and Indirect Evidence of Effects of Bacteroides spp. on Obesity and Inflammation

Metabolic disorders present a significant public health challenge globally. The intricate relationship between the gut microbiome, particularly Bacteroides spp. (BAC), and obesity, including their specific metabolic functions, remains partly unresolved. This review consolidates current research on BAC’s role in obesity and lipid metabolism, with three objectives: (1) To summarize the gut microbiota’s impact on obesity; (2) To assess BAC’s efficacy in obesity intervention; (3) To explore BAC’s mechanisms in obesity and lipid metabolism management. This review critically examines the role of BAC in obesity, integrating findings from clinical and preclinical studies. We highlight the changes in BAC diversity and concentration following successful obesity treatment and discuss the notable differences in BAC characteristics among individuals with varying obesity levels. Furthermore, we review recent preclinical studies demonstrating the potential of BAC in ameliorating obesity and related inflammatory conditions, providing detailed insights into the methodologies of these in vivo experiments. Additionally, certain BAC-derived metabolites have been shown to be involved in the regulation of host lipid metabolism-related pathways. The enhanced TNF production by dendritic cells following BAC administration, in response to LPS, also positions BAC as a potential adjunctive therapy in obesity management.


Introduction
The human gastrointestinal tract is a dense microbial habitat hosting approximately 4 × 10 13 bacteria, predominantly Firmicutes, Bacteroidetes, Proteobacteria, Actinobacteria, and Verrucomicrobia [1,2].Firmicutes and Bacteroidetes are dominant constituents of the gut microbiota [3].Bacteroides (BAC), a prominent genus within the Bacteroidetes phylum, is characterized by anaerobic, bile-resistant, non-spore-forming, Gram-negative rods [4].Significant taxonomic revisions in recent decades have expanded the genus to encompass over 20 distinct species [5,6].Prominent members of BAC in the colon include B. vulgatus, B. distasonis, and B. thetaiotaomicron (at levels of 10 10 per g dry weight of feces); species such as B. fragilis, B. ovatus, B. eggerthii, B. uniforms, and B. "B5-21" are less abundant but still present in substantial concentrations (10 9 per g dry weight of feces).BAC are integral to the ecological balance of the colon [7,8].Their robust adaptability within the host and potential benefits have garnered significant attention from researchers, positioning them as valuable models or communities for studies in the realm of gut microbiology.
Recent studies have highlighted the potential of prebiotic and probiotic supplementation for weight management, with negligible adverse effects [9].For instance, supplementation with Lactobacilli (phylum Firmicutes) has exhibited favorable effects on blood glucose levels, lipid profiles, weight, and body fat in overweight adults and those with obesity, as corroborated by several clinical studies [10,11].Bifidobacterium spp.has also effectively reduced fat and body weight in preclinical and clinical studies of obesity and type 2 diabetes [12,13].Furthermore, BAC have been shown to activate fat oxidation in adipose tissue via the bile acid-TGR5-PPARα axis, thus increasing energy consumption [14].A previous review also emphasized the ability of BAC to mitigate various diseases, such as Helicobacter hepaticus infection, oxazolone-induced experimental colitis, Vibrio parahaemolyticus infection, antibiotic-associated diarrhea, high-fat diet-induced cardiovascular disease, and cancer [15].BAC-derived compounds and metabolites interact with various immune cells and contribute to immune response activation.Notably, Polysaccharide A (PSA), derived from the human commensal B. fragilis NCTC9343, is a symbiotic factor that stimulates immune development in mammalian hosts, stimulates dendritic cell maturation and T-cell proliferation, in addition to possessing abscess-inducing properties [16,17].
BAC engage in both competitive and symbiotic interactions with adjacent bacterial species, thereby markedly influencing gut microbiota dynamics.BAC employ two distinct strategies for polysaccharide breakdown: they either prevent other bacteria from accessing the products of polysaccharide degradation or make these products available to other species.For example, B. thetaiotaomicron exhibits limited degradation of the yeast cell wall polysaccharide α-mannan outside the cell, transporting the relatively large α-mannan polysaccharides into the periplasm for further breakdown into manno-oligosaccharides and mannose [18].This strategy discourages the utilization of partially degraded α-mannan by bacterial species lacking the requisite transporter for this unique polysaccharide, thereby favoring the proliferation of species equipped to utilize it [19].However, previous research records show that BAC is identical to some commercial conventional probiotics [20][21][22].The health-promoting properties also depend on the strain.Although the PSA produced by non-enterotoxigenic B. fragilis attenuates infections and aids colonization, it also serves as a symbiont for bacterial growth [23,24].Despite the diversity of research directions, there is a common thread among numerous previous studies that have focused on BAC, with most findings supporting their beneficial effects against obesity, metabolic disorders, and inflammation.
Recent investigations have elucidated that BAC exhibited anti-inflammatory properties within the body [25].Notably, the interplay between obesity and inflammation is well-documented, with both conditions often presenting concurrently [26].Despite these findings, the direct impact of BAC in mitigating obesity in humans has not been thoroughly explored, underscoring the need for comprehensive research in this area.
In our analysis, we primarily referenced both direct and indirect experiments in previous studies that explored the effects of BAC on weight loss, encompassing animal models and human clinical trials.Given the absence of clinical trials that directly elucidate the mechanisms whereby BAC supplementation modulates obesity in humans, we aimed to extrapolate the potential mechanisms by summarizing the outcomes of preclinical and clinical studies associated with increased concentration of BAC in the gut.Our review included an exploration of the efficacy and potential mechanisms of BAC related to its antiobesity and lipid-reducing properties, encompassing the impact of BAC on the structure and diversity of the host gut microbiota as well as the potential involvement of BACderived metabolites in the regulation of host metabolic signaling pathways.This analysis is pivotal for advancing targeted obesity interventions.

Data Source and Search Strategy
We conducted a comprehensive literature search in November 2022 using the PubMed, Google Scholar, Cochrane, Scopus, and Web of Science databases within a restricted time period between 1 January 2000 and 30 November 2022.We employed specific search strings combining terms and Boolean operators, such as "Bacteroides AND obesity AND trial".These terms were adapted for each literature database and combined with database-specific filters for human clinical trials and preclinical trials in animals.

Inclusion and Exclusion Criteria
We searched for studies demonstrating that BAC effectively treated obesity, metabolic diseases, and inflammation.Because of the lack of studies that focused on the efficacy of BAC for obesity, the searched articles included both clinical trials and preclinical studies using animal models.However, the screening and selection were conducted separately, according to the below criteria.There were no language restrictions, and only the literature with abstracts was reviewed.In addition, studies with incorrect BAC descriptions or those without statistical analyses were excluded.
The inclusion criteria for clinical trials with indirect evidence were as follows: (1) human studies wherein participants were clearly defined as being overweight or obese at baseline; (2) participants who were overweight or obese and had a significant reduction in body weight, body fat, and other relevant body metrics after treatment; and (3) the richness, diversity, abundance, and diversity of BAC changed as the body metrics gradually normalized.The exclusion criteria were as follows: (1) unavailability of the full text; (2) no weight loss with treatment; (3) animal models; and (4) failure to provide results related to BAC.For the article type, it was not limited to randomized controlled trials.Observational studies, which compared the obese characteristics to healthy subjects' characteristics, were also included.In the case of intervention, any reasonable treatments for obesity were included, and there was no limitation for the comparator.The before-after studies for a single group were also included; however, reviews, case series, or case reports were excluded.
The inclusion criteria for preclinical trials with direct certification were as follows: (1) animal model; (2) involvement of a control group; and (3) treatment or intervention with BAC supplementation.The following exclusion criteria were used: (1) not an original paper; (2) lack of comparison; and (3) not using animal models such as human studies; no direct results demonstrated that BAC exhibited anti-obesity effects.The key data for inclusion are summarized in Figure 1.

Data Extraction and Data Analysis
In the initial phase of our research, we amalgamated the search results sourced from various databases to compile a comprehensive dataset.Subsequently, this dataset underwent a rigorous process of de-duplication, ensuring the removal of any redundant entries.
The task of evaluating and determining the relevance of the collated data was undertaken collaboratively by a trio of researchers.In cases where differing viewpoints emerged, these discrepancies were diligently addressed through in-depth discussions, leading to a consensus.This methodical approach not only ensured the accuracy and reliability of our data selection but also underscored the collaborative integrity of our research methodology.
From each selected publication, data extraction was performed separately based on the characteristics of the studies.
For the clinical trials used for indirect proof, the following data were extracted: information about sex; age; physical data related to obesity; and the changes caused by BAC were obtained for human participants.For the preclinical studies, information on study design, interventions, comparisons, strains and doses, intervention periods, and primary outcomes were extracted.
The primary outcome indicator for indirect evidence in clinical trials was a change in the abundance of BAC, whereas the primary outcome indicators for direct evidence in preclinical studies were body weight, liver weight, body fat, blood lipids, liver injury, steatosis, hepatic lipid metabolism, and insulin levels.
For studies utilizing BAC in combination therapies, a sub-analysis was conducted to isolate the effects attributable to BAC alone based on available data.Studies that indicated improved health markers without weight loss were subjected to a separate analytical process to determine the potential role of BAC in metabolic health.
Given the established anti-inflammatory properties of BAC in human subjects, this study aimed to explore the broader implications of BAC on obesity management.The data analysis is, therefore, organized into four distinct sections: The first part comprises studies that indirectly demonstrated changes in BAC after treatment with probiotics, herbs, dietary supplements, and synthetic probiotic supplements, either alone or in combination with other treatments, resulting in weight loss in overweight human participants and patients with obesity using medical subject terms (Bacteroides spp.).The second section explores the differences in the abundance of BAC in the gut microbiota of individuals with obesity and healthy individuals using medical subject headings (Bacteroides spp., gut microbiota, clinical trials, overweight, obesity, and 16S rRNA gene sequencing).Because there are no clinical trials of BAC directly treating obesity, the third part comprises information regarding preclinical studies demonstrating that BAC can treat obesity using medical subject headings (Bacteroides spp., mice, preclinical studies, overweight, obesity, weight loss).The fourth section comprises preclinical wherein BAC were found to directly affect inflammation (Bacteroides spp., mice, preclinical studies, inflammation).

Quality Assessment
We adapted the Downs and Black checklist to suit the nuances of the reviewed studies, focusing on parameters critical for assessing the reliability and applicability of obesity and microbe-related research [27].The checklist contained 27 items across the following five domains: reporting; external validity; internal validity (bias); internal validity (confounding); and efficacy.After assessment, the studies were categorized according to their scores as excellent (25)(26)(27), good (20)(21)(22)(23)(24), fair (15)(16)(17)(18)(19), or poor (<14).If no patients were lost to follow-up, the ninth analyzed indicator was deleted, and an extra point was added to the scoring results.The quality of the included studies was presented using Review Manager version 5.3.(Copenhagen, the Nordic Cochrane Centre, the Cochrane Collaboration, 2014).

Study Description
The primary objective of our study was to investigate the impact of BAC on human obesity.Our research commenced with a systematic search for clinical trials specifically addressing the direct treatment of obesity using BAC strains.Regrettably, no relevant clinical trials were identified.However, we identified pertinent preclinical trials and collected clinical trials for indirect evidence.We curated clinical trials where BAC strains indirectly influenced obesity treatment.Of the 31 relevant studies, 19 reported that interventions leading to weight loss in human participants resulted in increased BAC abundance.These findings imply a correlation between BAC and weight management, although the directionality of this relationship requires further investigation.Interestingly, two studies documented weight loss concurrent with a decrease in BAC abundance, suggesting that other unidentified factors might influence the interaction between the gut microbiota and weight regulation or that different BAC strains might have varying effects.The ten comparative microbiota analyses across individuals with different demographic backgrounds and body compositions further improved our understanding of the role of BAC.Although they did not provide direct evidence of weight loss, they contributed significant insights into the natural variance of BAC in the human gut and its correlation with obesity, underscoring the need for personalized approaches to microbiota-targeted treatments.The key data for inclusion are summarized in Tables 1-3.
The direct evidence analysis identified 142 potentially relevant articles, of which 12 met the inclusion criteria.Six of these studies, wherein BAC were directly administered via gavage, reported a consistent decrease in body weight, suggesting the potential anti-obesity effect of these bacterial strains.The more details are presented in Table 4.
The data summarized in Table 5 from relevant studies indicate that BAC, in combination with various pharmacological agents, contribute to reducing the inflammatory response in experimental animal models.This section always reflects the mechanisms by which obesity, inflammation, and BAC may be related.In this section, only clinical weight loss trials after pharmacological interventions evaluate the specific drug of the intervention, the number of patients involved in the problem, the type of intervention, and the duration.The second part of the review considers only articles reporting fat reduction upon direct gavage of BAC strains were considered, and the types of interventions considered included specific strains, types of experimental animals, types of interventions, and duration of interventions.
A clinical trial conducted on Italian patients with obesity, wherein most of the included patients had metabolic dysfunction, showed a statistically significant reduction in body weight and adiposity after the administration of a healthy diet based on caloric intake, macronutrient composition, and fiber intake.There was a statistically significant increase in the abundance of BAC spp., especially B. uniformis (p = 0.005) [35].In another study, nine healthy volunteers were selected to fast for approximately 17 h per day for 29 days; at the end of the trial, there were no significant changes in obesity-related values, but a significant increase in the abundance of both A. muciniphila (p = 0.0039) and B. fragilis (p = 0.0078) was observed [45].Notably, an increase in the abundance of BAC spp. was reported in all these studies (Table 1).
However, a few clinical trials have yielded conflicting results in that obesity improved while BAC spp.abundance decreased.Furthermore, two clinical trials in children and women with obesity showed a decrease in B. vulgatus abundance after the administration of probiotics [46,47] (Table 2).BAC levels are positively correlated with other beneficial bacteria levels.[45] The results presented in the table demonstrate statistical significance.IPE: Inulin-propionate ester; TC: Total cholesterol; BMI: Body Mass Index; T2D: Type 2 diabetes; PREDIM: Predicted clamp-derived insulin sensitivity index from a standard meal test; IL-1β: Interleukin 1 beta; FBG: Fasting blood glucose; LBP: Lipopolysaccharide-binding protein; IL-8: Interleukin-8; IgG: Immunoglobulin G; SCFAs: Short-chain fatty acids; BW: Body weight.An upward arrow (↑) signifies an increase in the abundance of the specified gut microbe, while a downward arrow (↓) indicates a decrease in the abundance of the specified gut microbe.[47] BMI: Body mass index; IL-6: Interleukin 6.An upward arrow (↑) signifies an increase in the abundance of the specified gut microbe, while a downward arrow (↓) indicates a decrease in the abundance of the specified gut microbe.

Comparison of Gut Microbiota between Individuals with Obesity and Healthy Individuals Demonstrates an Association between BAC and Obesity
To further demonstrate the relationship between BAC and obesity, we included nine clinical trials that analyzed the differences in gut microbiota between populations with and without obesity.Seven of these were studies on adults; two were on children and adolescents; seven studies, while not directly stating their significance, reported lower BAC abundance and diversity in obese populations than in non-obese populations, and three studies directly indicated significance.
The results of a survey of the gut microbiota of 46 pairs of twins and their mothers were revealed.The obese gut microbiota was significantly different (p = 0.003) and less diverse than the lean core gut microbiome [48].In a study by Kasai et al., (2015), a comparison of gut microbiota composition between individuals with and without obesity in a Japanese population showed that B. faecichinchillae and B. thetaiotaomicron were virtually undetectable in the feces of individuals with obesity and that the proportion of these BAC was significantly higher in individuals without obesity [49].Additional details are provided in Table 3.The results presented in the table demonstrate statistical significance.BMI: Body mass index; hs-CRP: Highsensitivity C-reactive protein; SCFAs: Short-chain fatty acids; TC: Total cholesterol; TG: Total triglyceride; T-RFLP: Terminal restriction fragment length polymorphism.An upward arrow (↑) signifies an increase in the abundance of the specified gut microbe, while a downward arrow (↓) indicates a decrease in the abundance of the specified gut microbe.

In Vivo Direct Evidence of the Anti-Obesity Effects of BAC
Animal experiments published in 2021 had a high frequency of publications; five were conducted on C57BL/6J mice, and only one on rats; >90% of the studies used male animals.The duration of the intervention ranged from 7 to 18 weeks.Consistent evidence from various animal studies indicates that certain BAC strains can significantly reduce key obesity-related metrics, including body weight, fat accumulation, and adverse serum profiles.

Studies on Direct Anti-Inflammatory Therapy with BAC
Recent studies have shown that white adipose tissue in patients with obesity develops low-grade chronic inflammation, which induces insulin resistance [61].Due to the close relationship between obesity and inflammation, we included six preclinical studies in which BAC were directly gavaged.All experiments were conducted with mice; the minimum duration of the experiment was five days, and the maximum was 21 days.Only three experiments clearly labeled the gavaged BAC concentration, which ranged from 1 × 10 9 CFU/mL to 7 × 10 9 CFU/mL.In these studies, BAC significantly upregulated the expression of anti-inflammatory cytokines and downregulated the expression of proinflammatory cytokines.These studies suggest that BAC have therapeutic potential for preventing intestinal inflammatory diseases in animal models (Table 5).[67] The results presented in the table demonstrate statistical significance.SCFAs: Short-chain fatty acids; IL-6: Interleukin-6; TNF: Tumor necrosis factor α; IL-10: Interleukin-10; IFNγ: Interferon-γ; FITC-Dextran: Fluorescein isothiocyanate; NF-κB: Nuclear factor κB; TLR2: Toll-like receptor 2; CCR5: C-C chemokine receptor 5; LPS: Lipopolysaccharide; PSA: Polysaccharide A; WT: Wild type.

Quality Assessment and Scores
After a quality assessment of the selected studies using the modified Downs and Black checklist, only 9 of the 17 investigational trials on humans scored a superior grade [28,29,[31][32][33][34]38,40,44].Six studies were assessed as high quality [30, 35,39,[41][42][43].Eight experiments provided sufficient details on withdrawal and exit [28,[31][32][33][34]38,40,44].We also considered participant empowerment, and all experiments mentioned having gone through an ethical approval process and obtained informed consent from the participants (Table 6).We present our quality assessment for all included studies.This assessment highlights that all selected articles achieved 100% compliance with reporting standards, and 50% of these studies met the criteria for adequate statistical power (Figure 2).

Q1
Hypothesis/aim/objective clearly described Q8 All adverse events of intervention reported 0 0

Q11
Subjects Study participants asked to participate were representative of the source population

Q12
Subjects Study participants prepared to participate were representative of the source population

Q13
Location and delivery of study treatment were representative of the source population The '-' symbol indicates that this clinical laboratory course can be used without analyzing this question.Count one point.

Discussion
Bacteroides spp.(BAC) constitute a significant proportion of the human gut microbiota and play a pivotal role in maintaining host metabolic homeostasis and immune regulation.These microbes aid in lipid metabolism, potentially influencing obesity outcomes and systemic inflammation [68].This review represents the first thorough examination of BAC in obesity, detailing their correlation with body weight and prevalence in diverse populations across multiple countries.It also includes an analysis of preclinical studies on obesity and inflammation, shedding light on the potential mechanisms of action.
There is a recent study demonstrating the ability of BAC to degrade a wide range of polysaccharides and summarizing the utilization of BAC and their beneficial effects on intestinal health that supports our review [69].This study demonstrated the BAC catabolism of polysaccharides to oligosaccharides or short-chain fatty acids (SCFAs).Fermentation of oligosaccharides and monosaccharides by SCFA-producing bacteria increases the luminal concentrations of acetate, butyrate, and propionate, which are beneficial effects of SCFAs on intestinal inflammation and immunity.
Furthermore, our review summarized clinical studies and randomized controlled trials of human anti-obesity treatments and focused on differences and relationships between body weight and BAC.In our review, all included preclinical studies presented positive improved results.In 70% of the clinical trials, weight loss in humans after treatment was accompanied by increased BAC richness.However, some studies have shown opposite results, of which two examples are provided in this review.We speculate that BAC richness is highly susceptible to changes caused by other drugs or foods, and we suspect an inhibitory relationship between probiotics and BAC.However, we still need to shed light on the actual evidence for this conjecture, and more experimental evidence is required.In addition, a study on microbial enterotypes reported that enterotypes may influence an individual's ability to lose weight when following a specific diet [6].We previously speculated that the difference in each individual characteristic affects the amount of BAC in the body.This study suggests that stratifying individuals according to two microbial enterotypes (dominance of either Prevotella or BAC) may help predict the response to diet and medication.It is a challenging point that individual differences can influence our judgment and conclusions regarding the results.Although preclinical studies have predominantly indicated a consistent anti-obesity effect of BAC, human trials present more heterogeneous outcomes.There are also studies that show that human dietary preferences in animal husbandry practices may influence domesticated animals [70].Dietary homogenization among different species may lead to convergence of microbial characteristics.This discrepancy underscores the complexity of translating

Discussion
Bacteroides spp.(BAC) constitute a significant proportion of the human gut microbiota and play a pivotal role in maintaining host metabolic homeostasis and immune regulation.These microbes aid in lipid metabolism, potentially influencing obesity outcomes and systemic inflammation [68].This review represents the first thorough examination of BAC in obesity, detailing their correlation with body weight and prevalence in diverse populations across multiple countries.It also includes an analysis of preclinical studies on obesity and inflammation, shedding light on the potential mechanisms of action.
There is a recent study demonstrating the ability of BAC to degrade a wide range of polysaccharides and summarizing the utilization of BAC and their beneficial effects on intestinal health that supports our review [69].This study demonstrated the BAC catabolism of polysaccharides to oligosaccharides or short-chain fatty acids (SCFAs).Fermentation of oligosaccharides and monosaccharides by SCFA-producing bacteria increases the luminal concentrations of acetate, butyrate, and propionate, which are beneficial effects of SCFAs on intestinal inflammation and immunity.
Furthermore, our review summarized clinical studies and randomized controlled trials of human anti-obesity treatments and focused on differences and relationships between body weight and BAC.In our review, all included preclinical studies presented positive improved results.In 70% of the clinical trials, weight loss in humans after treatment was accompanied by increased BAC richness.However, some studies have shown opposite results, of which two examples are provided in this review.We speculate that BAC richness is highly susceptible to changes caused by other drugs or foods, and we suspect an inhibitory relationship between probiotics and BAC.However, we still need to shed light on the actual evidence for this conjecture, and more experimental evidence is required.In addition, a study on microbial enterotypes reported that enterotypes may influence an individual's ability to lose weight when following a specific diet [6].We previously speculated that the difference in each individual characteristic affects the amount of BAC in the body.This study suggests that stratifying individuals according to two microbial enterotypes (dominance of either Prevotella or BAC) may help predict the response to diet and medication.It is a challenging point that individual differences can influence our judgment and conclusions regarding the results.Although preclinical studies have predominantly indicated a consistent anti-obesity effect of BAC, human trials present more heterogeneous outcomes.There are also studies that show that human dietary preferences in animal husbandry practices may influence domesticated animals [70].Dietary homogenization among different species may lead to convergence of microbial characteristics.This discrepancy underscores the complexity of translating microbial interventions from animal models to humans, influenced by factors such as individual microbiome composition, diet, and lifestyle.
Because there are no sufficient clinical trials used to demonstrate the anti-obesity effect of BAC, the preclinical studies were reviewed to overcome this lack of studies.After a review of the preclinical studies focused on the mechanism of BAC in obesity was conducted, we concluded that BAC significantly prevents obesity in the animal model, particularly in mice.Our analysis underscores the potential of certain BAC, such as B. uniformis and B. vulgatus, in mitigating obesity-related parameters.For example, B. uniformis has been shown to reduce lipid accumulation and modulate adipose tissue inflammation, whereas B. vulgatus appears to influence body weight regulation, possibly through interactions with gut mucin dynamics.In our analyses, the BAC measure had to be at least 1 × 10 6 CFU/day and lasted at least 7 weeks to present validity in the body weight results.We also found that BAC improved immune dysfunction, promoted the growth of Akkermansia by utilizing metabolites from mucin degradation, increased serum insulin levels, and prevented obesity by promoting the catabolism of circulating branched-chain amino acids in the brown adipose tissue.Notably, Agustí et al., administered B. uniformis CECT 7771 to rats for 18 days and found that it affected the brain's reward response, improved overeating, and reduced anxiety behavior.These effects are produced, at least in part, by altering the levels of dopamine, 5-hydroxytryptamine, and norepinephrine in the nucleus ambiguous, as well as the expression of dopamine D1 and D2 receptors in the prefrontal cortex and gut [57].Furthermore, certain BAC can modulate systemic and local inflammation.B. vulgatus FTJS7K1 have been observed to downregulate pro-inflammatory cytokines and potentially contribute to maintaining gut barrier integrity, thereby potentially reducing low-grade systemic inflammation often observed in obesity scenarios [67].The mechanisms underlying these effects are not entirely clear and may involve complex interactions between gut microbiota, host metabolism, and systemic inflammation.Further research is needed to clarify these mechanisms and determine whether similar effects occur in humans.
This study had some limitations.First, this review was constrained by the scarcity of long-term human trials and inconsistencies in the study design, particularly concerning probiotic strains, dosages, and participant demographics.These variations complicate the interpretation of the therapeutic potential of BAC in obesity management.Second, attempts were made to identify all randomized controlled trials on the increase in BAC following treatment efficacy, but potential incompleteness of citation tracking may have resulted in some relevant randomized controlled studies being overlooked.In addition, despite clear eligibility criteria, these studies need to be more consistent regarding this study's design, probiotic strain, form and duration of application, sample population, and outcomes.Data are often not reported because many studies have not reported positive results for BAC after pharmacological interventions.
The quality assessment of the current studies indicated variability in the quality of the available research.While many studies were conducted, some lacked sufficient rigor, highlighting the need for more high-quality, consistent, and replicable research in this field.Most studies have been short-term, ranging from 4 to 24 weeks.Considering that obesity-related inflammation is a chronic disease, long-term evaluation of treatment is recommended.An apparent strength of this study is that our search included combinations of obesity and BAC and combinations of BAC alone or combinations where it was determined that BAC produced an effect, if available.
This review provides direct and indirect evidence of the effectiveness of BAC supplementation in treating obesity.In conclusion, BAC offers a promising avenue for treating obesity and inflammation, with certain BAC strains having specific therapeutic potential.However, the existing body of research is characterized by variability, necessitating more comprehensive, standardized, and long-term clinical trials.Future investigations are needed to elucidate the mechanistic pathways underlying the anti-obesity effects of BAC, assess the feasibility and acceptance of interventions, such as fecal microbiota transplant (FMT), and establish protocols for overcoming challenges in post-administration microbial colonization.Through this, we can progress toward targeted obesity therapies that harness the beneficial capacities of the gut microbiota.
Intriguingly, these anti-obesity properties appear to be species-and strain-specific, underscoring the biological complexity and the necessity for precision when considering probiotic interventions.Despite promising indications from preclinical studies, there is a lack of human clinical trials that directly examine the effects of BAC supplementation on obesity.This gap highlights an unresolved dichotomy in the field, wherein empirical support is burgeoning, yet a definitive clinical consensus remains elusive.
Therefore, the therapeutic potential of BAC in managing obesity requires further targeted longitudinal human studies.Future research should prioritize identifying and validating the most efficient BAC strains for obesity mitigation and investigate their mechanistic pathways, optimal dosages, and administration protocols.Moreover, exploring synergistic or antagonistic interactions between different BAC strains and broader microbiome-host dynamics will be instrumental in harnessing the full therapeutic arsenal of these microbes.

Figure 1 .
Figure 1.Flowchart of the process for screening articles on systematic reviews that directly and indirectly demonstrate the effects of Bacteroides spp. on human obesity.

Figure 2 .
Figure 2. Quality assessment.(A) presents quality assessment summary: review authors' judgments about each risk of bias item for each included studies low risk (+: green), high risk (-: red), or unclear risk (?: yellow); (B) indicates quality assessment graph: review authors' judgments about each assessment item presented as percentages across all included studies.

Table 1 .
Indirect evidence of the anti-obesity effect of BAC.

Table 2 .
Indirect evidence that BAC do not have an anti-obesity effect.

Table 3 .
Comparison of gut microbiota between individuals with obesity and healthy individuals demonstrating the indirect metabolism-modulation function of BAC.

Table 4 .
In vivo evidence of anti-obesity effect of BAC.

Table 5 .
Study of direct anti-inflammation treatments with BAC.

Table 6 .
Quality assessment and scores of included studies using Downs and Black quality checklist.