The World Health Organization (WHO) describes obesity and overweight as abnormal or excessive fat accumulation. By 2030, it is predicted that more than 40% of the world's population will be affected by obesity.1 This condition is linked to numerous complications. These include type 2 diabetes, cardiovascular diseases, various types of cancer and premature mortality.2,3 The gut microbiota is a complex and rich ecosystem of trillions of microorganisms such as bacteria, viruses, archaea, fungi, and phages.4 Microbial metabolism produces a wide range of metabolites known to have diverse biological activities: energy extraction from food, intestinal permeability, lipid metabolism, gene expression related to fat storage, interaction with bile acids, polysaccharide breakdown, insulin resistance, immune response, endotoxemia and intestinal barrier integrity.5–7 Several studies have indicated that obesity is associated with an imbalance in the composition and functionality of the gut microbiota, leading to a decrease in microbial richness and diversity.5,8 Furthermore, individuals with obesity exhibit a higher relative abundance of Firmicutes, Proteobacteria, Fusobacteria and Lactobacillus reuteri.9,10 Conversely, obesity has been linked to a lower relative abundance of Bacteroidetes and species such as Faecalibacterium prausnitzii, Akkermansia muciniphila, and Bifidobacterium animalis.11–13 A comprehensive systematic review of observational studies that analysed the gut microbiota using next-generation sequencing was conducted. The aim was to compare the composition of the gut microbiota at the taxonomic and functional level in adult patients with obesity compared to normal-weight individuals.

This systematic review was conducted to investigate the composition of the gut microbiota in obesity by taxonomic and functional description. Data were extracted on each bacterial group available at the lowest taxonomic level based on NGS from each included study. Although the heterogeneity in the reported anthropometric variables (e.g., BMI, waist circumference, body weight) may influence the comparability of microbiota associations across studies. This variability must be considered when interpreting the relationships between gut microbiota and body composition. First of all, our findings revealed a decline in alpha diversity among individuals with obesity in comparison to their counterparts without obesity. In particular, the Shannon index showed statistically significant differences in six studies, while the Chao index showed significant differences in seven studies. There is a lack of consensus in the literature regarding the differences in diversity between normal-weight and individuals with obesity. For instance, a meta-analysis by Pinart et al. revealed no statistically significant mean differences in alpha diversity between individuals with obesity and normal weight individuals.9 Otherwise, a recent review conducted by Michels et al.32 synthesized evidence from 87 systematic reviews and meta-analyses on the microbiota metabolic health relationship, reporting consistent findings of reduced alpha diversity in individuals with obesity. Likewise, another meta-analysis using a linear random effects model did identify a statistically significant decrease in richness, evenness and diversity in individuals with obesity.33 Focusing on a taxonomic perspective, at the phylum level, the gut microbiota of individuals with obesity exhibited a predominance of Firmicutes, while Actinobacteria, Verrucomicrobia, and Bacteroidetes were more abundant in individuals with an optimal weight. A high Firmicutes to Bacteroidetes ratio has been associated with the presence of dysbiosis in obesity in both animal models and humans.34 The F/B ratio in human models has shown more inconsistent results, with a recent meta-analysis failing to find statistically significant differences in the F/B ratio between individuals with obesity and lean individuals.35 Indeed, in our review, only two studies observed a higher F/B ratio in individuals with obesity, following the controversial use of this index, as from its first use, it has not achieving the expected general trend in obesity.36–38 In the present review, bacterial taxa that were repeatedly associated with obesity included Blautia, Butyricimonas, Collinsella, Enterobacteriaceae, Gemellaceae, Megamonas, Prevotellaceae, Streptococcaceae, Streptococcus, and Veillonellaceae. Among these, the genus most frequently mentioned was Blautia; however, the precise relationship with obesity remains unclear. Some studies have shown a positive correlation between the genus Blautia and BMI and cholesterol, while others observed an inverse relationship between visceral fat and body weight. Similarly, B. wexlerae has been inversely linked to obesity and type 2 diabetes.39 On the other hand, the family Enterobacteriaceae, and particularly the E. coli species, appear to be enriched in atherosclerotic cardiovascular disease.40E. coli also has been associated with an increased tendency to fat accumulation in mice fed a high-fat diet.41 It has been suggested that Enterobacteriaceae might be a potential marker for inflammatory conditions due to a presumed role in mechanisms driving intestinal dysbiosis.42 On the other hand, it has been observed that patients undergoing Roux-en-Y gastric bypass showed enrichment of the Enterobacteriaceae family, as well as association with the changes observed in the bile acid pool.43 Nevertheless, in this review, only two selected studies presented evidence of E. coli enrichment among individuals with obesity. Likewise, individuals suffering from obesity in our review also showed an enrichment of Prevotella copri and Bacteroides species, such as B. eggerthii, B. fragilis, B. plebeius and B. xylanisolvens.36 Several studies have indicated that Prevotella can proliferate on diets rich in plant nutrients and dietary fibre. However, the role of Prevotella copri in metabolic health remains controversial, given its association with the protein-rich Western diet.44 This has led to conflicting results regarding its impact on insulin resistance and glucose tolerance, with some studies reporting beneficial effects and others indicating adverse results. Some strains have been demonstrated to possess the ability to degrade carbohydrates and fibre; others have the capacity to biosynthesise branched-chain amino acids (BCAAs) from a meat-based diet.44 Moreover, it has been demonstrated that BCAA supplementation can induce insulin resistance in obese mice, but not in normal mice. This has prompted the suggestion that dietary factors may exert an influence on the relationship between P. copri and its host.45 Thus, further research is needed to clarify the role of strains as possible culprits in inconclusive results. In contrast, Bacteroides spp. broad seems to support homeostasis in the gastrointestinal tract. They support the immune system and metabolic health by degrading dietary polysaccharides.46 However, certain species, such as B. fragilis, exert negative metabolic impacts on the host.47 They are involved in lipopolysaccharide synthesis and their presence is associated with the development of non-alcoholic fatty liver disease.48 Individuals with obesity had a lower abundance of Alistipes spp., Bifidobacterium spp., Eubacterium spp., Faecalibacterium, Faecalibacterium prausnitzii, Porphyromonadaceae, Rikenellaceae, Ruminococcus spp., and an unclassified OTU within the Clostridia class in this systematic review. The Porphyromonadaceae and Rikenellaceae families have previously shown a negative association with obesity, as well as a negative association with visceral adipose tissue in older adults with obesity.49 The decrease of Faecalibacterium prausnitzii in the gut microbiota of individuals with obesity is also noteworthy, as it can synthesise butyric acid through fermentation of undigested nutrients and anti-inflammatory effects.11 In addition, the depletion of some taxa such as Akkermansia muciniphila, Lactobacillus species or Bifidobacterium species have been documented in obesity conferring deleterious effects on the host because they contribute to intestinal barrier function, protect against endotoxaemia and even promote weight loss.50–52 However, only one of the studies included in this review reported a decrease in the relative abundance of A. muciniphila.17 The genus Lactobacillus showed inconsistent results across the two cohorts of individuals with obesity.15,29 Two of the selected studies in our systematic review showed a reduction of B. adolescentis in obesity, while Bifidobacterium breve showed mixed results.15 Additionally, positive correlations were found between certain bacterial taxa and BMI, including Acidaminocococcus, Lachnospira, Romboutsia, Ruminococcus, Odoribacteraceae, Clostridium sensu stricto, and Dorea.12,22 In addition, Lachnospira has also demonstrated a positive correlation with hip-to-waist ratio and adiposity. Otherwise, another recent study indicated that Lachnospira was higher in subjects diagnosed with metabolic syndrome or obesity who adhere to a Mediterranean diet and engage in regular physical activity.53 Regarding the second aim of this study, only five of the studies included in this review assessed gut microbiota functionality, with significant variability in both methodology and analytical depth. One of the studies used shotgun metagenomics, the most complete method, while the others used prediction-based methods such as PICRUSt. Reported alterations ranged from 3 to 57 metabolic pathways, most frequently involving carbohydrate and lipid metabolism, SCFA production, and vitamin biosynthesis. For example, Duan et al.19 identified 57 altered pathways suggesting increased energy extraction in obesity. In contrast, de la Cuesta-Zuluaga et al.23 observed a reduction in fermentation-related pathways, including acetogenesis, propionate, and succinate production. A recent meta-analysis of the gut microbiota of individual with obesity and healthy individuals across 17 countries identified 25 bacterial species and 37 metabolic pathways as key predictors of obesity. Of noteworthy interest is the finding that there is a reduction in short-chain fatty acid-producing bacteria and gut barrier protection biomarkers, accompanied by increased activity in amino acid, enzyme cofactor, and peptidoglycan biosynthetic pathways in obese individuals.54 Consequently, there is a harvest theory that the gut microbiota may contribute to obesity through the production of bioactive metabolites, particularly SFCAs, ultimately affecting energy metabolism.55 Although this study has been rigorous in methodology, there are some limitations and discrepancies observed that deserve to be mentioned. The main observed discrepancies among the included studies can be attributed to several methodological factors, such as the sequencing techniques employed, differences in study design, variations in DNA extraction protocols, and inconsistencies across the reference databases used for 16S rRNA gene analysis. These elements have the potential to influence the taxonomic profiles obtained, and consequently restrict the comparability of findings across studies.56 In addition, host-related factors such as age, sex, geographic location and dietary patterns are known to influence the composition of the gut microbiota and may further contribute to the variability in findings.57–59 Therefore, this review also underscores several limitations, which can be attributed to the heterogeneity of the populations included in the studies. For instance, Lara et al.30 included only female participants, while Yasir et al.15 focused exclusively on males, which limits the generalisability of the results across sexes. In the study by Duan et al.19 there were discrepancies in the body composition of the control group, where the mean BMI was 22.3kg/m2, but participants with BMIs as low as 16.5kg/m2 were included, which may affect the comparability of the results. Furthermore, four of the studies incorporated an intermediate overweight category alongside normal weight and obesity, thereby further complicating the comparison of outcomes across trials.17,18,21,27 The included studies also encompassed participants from diverse ethnic and geographic backgrounds, with some even comparing populations from markedly different regions, such as the United States and Ghana in the study conducted by Lara et al.30 Likewise, disparities in age range were evident, with the study by Siniestra et al.27 including participants from 40 up to 70 years of age, thereby introducing an additional layer of variability that may influence gut microbiota composition. Demographic factors are important to consider when studying gut microbiota, as they are inextricably linked to dietary habits. In fact, diet plays a crucial role in determining the composition of the gut microbial ecosystem and may explain much of the variation observed in the results of this review. Diets rich in fiber were more common in less industrialized regions, as observed in the study led by Lara et al.,28 where greater microbial diversity and a higher presence of SCFA-producing bacteria were noted in the population of Ghana. Only a subset of the studies selected for review assessed dietary information by using different methodology, such us collection of dietary data over a 24-hour period, food consumption questionnaires or by recall method.17,18,21,23–25,27,28,31 The most repeated finding among the different studies was the statistically significant differences in recorded fiber intake. Overall, normal-weight individuals showed a higher trend towards fiber intake, while obese individuals showed a higher total calorie intake and a higher carbohydrate intake.21,24,27,28 Specifically, only in the study conducted by Palmas,24 the dietary pattern was evaluated using the Mediterranean Diet Score, which revealed higher adherence among individuals with a normal body mass index compared to those with obesity. Dietary distinctions may offer a partial explanation for the observed enrichment or depletion of specific bacterial strains and functional pathways, notably those associated with SCFA production and energy metabolism. Indeed, an increased adherence to a Mediterranean diet has been demonstrated to be associated with an increased abundance of Bifidobacteria, increased levels of SCFA and increased microbial diversity and richness.59 Thus, a limitation of this review is that study selection was not based on participants’ dietary patterns, which may have influenced the variability in microbiota composition. Future research should therefore stratify participants based on dietary intake or apply statistical adjustments for diet-related variables to more accurately isolate the specific impact of obesity on the gut microbiota from diet-induced alterations.

Despite the heterogeneity of results, this systematic review highlights a consistent association between obesity and reduced gut microbial diversity. It is noteworthy that taxonomic changes remain controversial, particularly regarding the Firmicutes/Bacteroidetes ratio, and findings at the genus and species levels are frequently inconsistent across studies. These discrepancies, when considered in conjunction with the paucity of data concerning gut microbiota functionality, underscore the necessity of shifting the research focus from isolated microbial taxa to a more integrative, ecosystem-based analysis of the gut microbiota. The application of functional assessments has the potential to provide more meaningful insights into host–microbe interactions and to offer more reliable biomarkers for therapeutic strategies.

Specific trends identified in individuals with obesity include an enrichment in certain taxa such as Firmicutes, Blautia, Butyricimonas, Collinsella, Enterobacteriaceae, Gemellaceae, Megamonas, Prevotellaceae, Streptococcaceae, Streptococcus, and Veillonellaceae. From a functional perspective, an upregulation of pathways related to carbohydrate and lipid metabolism, along with a concurrent reduction in those associated with short-chain fatty acid production, appears to be the most consistent microbial signature linked to obesity. In conclusion, although substantial progress has been developed in understanding the relationship between gut microbiota and obesity, further research, particularly focusing on microbial functionality and ecosystem-level analysis, is essential to develop effective and personalised therapeutic interventions.

This study has been funded by the Instituto de Salud Carlos III (ISCIII) through projects (PI18/01160) and (PI21/01677) and co-funded by the European Union. F.J.T. and I.M.-I. also obtained the UMA-FEDERJA-116 project, financed by the Andalusian Regional Government and co-financed with ERDF funds. In addition, C.M.D.-P. was supported by a Rio Hortega postdoctoral contract (CM23/00128) from ISCIII-Madrid (Spain) and D.H.-N. was supported by a Sara Borrell postdoctoral contract (CD23/00111) from ISCIII-Madrid (Spain). A.S.-V. was supported by a predoctoral PFIS (FI22/00193) from ISCIII-Madrid (Spain). V.M. was supported by the ‘Miguel Servet’ programme (CP22/00033) of the ISCIII-Madrid (Spain) and I.M.-I. was supported by the ‘Miguel Servet Type II’ programme (CPII21/00013) of the ISCIII-Madrid (Spain).

The authors declare no conflicts of interest.