Microbioma intestinal: influencia en el tratamiento clínico y nutricional de la diabetes mellitus tipo 2 J. Food Sci. Gastron. (January - June 2026) 4(1): 23-41 https://doi.org/10.5281/zenodo.18294243 ISSN 3073-1283 REVIEW ARTICLE Gut microbiome: influence on the clinical and nutritional treatment of type 2 diabetes mellitus  Alberto J. Cevallos alberto.cevallos@iess.gob.ec Received: 12 September 2025 / Accepted: 05 December 2025 / Published online: 23 January 2026 © The Author(s) 2026 Alberto J. Cevallos 1 · Edison H. Arévalo 2 · Mauricio G. Intriago 2 Abstract Type 2 diabetes mellitus (T2DM) is a complex metabolic disease in whose pathophysiology the gut micro- biota plays a key role, inﬂuencing systemic inﬂammation, insulin sensitivity, and glycemic homeostasis, thus condi- tioning the response to clinical and dietary treatments. The objective of this study was to analyze the inﬂuence of the gut microbiota on the pharmacological and dietary treatment of T2DM based on current scientiﬁc evidence. This systematic review, conducted according to the 2020 PRISMA guide- lines, analyzed 27 studies published between 2014 and 2024, identifying that gut dysbiosis, characterized by a reduction in beneﬁcial bacteria and an increase in pro-inﬂammatory species, is associated with poorer metabolic control in pa- tients with T2DM. The most eﬀective interventions included probiotics, prebiotics, synbiotics, high-ﬁber diets, and drugs with microbiota-modulating eﬀects, such as metformin and SGLT2 inhibitors. Evidence suggests that modulation of the gut microbiota represents a promising complementary ther- apeutic strategy; however, methodological limitations still exist, highlighting the need for more robust clinical studies to support its widespread application. Keywords type 2 diabetes mellitus, gut microbiome, prebi- otics, probiotics, emerging therapies. Resumen La diabetes mellitus tipo 2 (DM2) es una enfer- medad metabólica compleja en cuya ﬁsiopatología intervie- ne el microbioma intestinal, el cual inﬂuye en la inﬂamación sistémica, la sensibilidad a la insulina y la homeostasis glu- cémica, condicionando la respuesta a los tratamientos clí- nicos y dietarios. El objetivo fue analizar la inﬂuencia del microbioma intestinal en el tratamiento farmacológico y dietario de la DM2 a partir de la evidencia cientíﬁca actual. Esta revisión sistemática, realizada bajo las directrices PRIS- MA 2020, analizó 27 estudios publicados entre 2014 y 2024, identiﬁcando que la disbiosis intestinal, caracterizada por la disminución de bacterias beneﬁciosas y el aumento de espe- cies proinﬂamatorias, se asocia con un peor control metabó- lico en pacientes con DM2. Las intervenciones más eﬁcaces incluyeron probióticos, prebióticos, simbióticos, dietas ricas en ﬁbra y fármacos con efecto modulador del microbioma, como la metformina y los inhibidores de SGLT2. En conjun- to, la evidencia sugiere que la modulación del microbioma intestinal constituye una estrategia terapéutica complemen- taria prometedora, aunque persisten limitaciones metodoló- gicas que requieren estudios clínicos más robustos para su aplicación generalizada. Palabras clave diabetes mellitus tipo 2, microbioma intesti- nal, prebióticos, probióticos, terapias emergentes. 1 Hospital General Manta, Instituto Ecuatoriano de Seguridad Social, Manta, Ecuador. 2 Universidad Laica Eloy Alfaro de Manabí, Manta, Ecuador. How to cite Cevallos, A. J., Arévalo, E. H., & Intriago, M. G. (2026). Gut microbiome: inﬂuence on the clinical and nutritional treatment of type 2 diabetes mellitus. Journal of Food Science and Gastronomy, 4(1), 23-41. https://doi.org/10.5281/zenodo.18294243

J. Food Sci. Gastron. (January - June 2026) 4(1): 23-41 24 Introduction Type 2 diabetes mellitus (T2DM) is recognized as a chro- nic metabolic syndrome characterized by persistent hyper- glycemia, resulting from insulin resistance and insuﬃcient insulin secretion. Its prevalence and the burden of microvas- cular and macrovascular complications make it one of the major public health problems worldwide (Sikalidis & Ma- ykish, 2020). Traditionally, its management has focused on agricultural treatment, standardized dietary intervention, and the promotion of physical activity; however, recent evidence demonstrates that other biological factors, such as the com- position of the gut microbiome, play a relevant role in me- tabolic regulation and the progression of conﬁnement (Cun- ningham et al., 2021). The gut microbiome, understood as the collection of mi- croorganisms, genes, and metabolites that inhabit the gas- trointestinal tract, has been identiﬁed as a dynamic ecosys- tem with essential digestive, immunological, and endocrine functions. Its alteration, associated with dysbiosis, is linked to the pathophysiology of metabolic disorders, including T2DM (Baars et al., 2024). Several studies have shown that changes in microbial diversity and composition inﬂuence systemic inﬂammation, insulin sensitivity, and glucose ho- meostasis, thus aﬀecting both the progression of diabetes and the response to clinical and dietary interventions (Shar- ma et al., 2022). Advances in technologies such as next-generation sequen- cing, metagenomics, and metabolomics allow for a more precise characterization of the relationship between the gut microbiota and T2DM (Fu et al., 2023). Based on these ﬁn- dings, we identiﬁed microorganisms associated with a favora- ble metabolic proﬁle, such as Akkermansia. muciniphila and Faecalibacterium prausnitzii, as well as pro-inﬂammatory bacteria predominant in patients with poor glucose control (Adeshirlarijaney & Gewirtz, 2020). At the same time, we can resort to therapeutic strategies aimed at modulating the microbiome, including personalized diets enriched with fer- mentable ﬁber, prebiotics, and probiotics, to optimize fatty acid production and reduce systemic inﬂammation (Chiou et al., 20121; Iatcu et al., 2024). Gallardo and García (2024) emphasized that ultra-proces- sed foods or junk food, characterized by high energy density, low nutritional value, and broad social acceptance, negati- vely aﬀect diet quality and risk perception, thereby reinfor- cing the need for comprehensive therapeutic approaches. Within this framework, the study of the gut microbiome emerges as a central element for understanding the interac- tions between diet, metabolism, and clinical response, oﬀe- ring new perspectives for the clinical and nutritional mana- gement of T2DM. Although traditional dietary interventions have proven eﬀective in glucose control and cardiovascular risk reduc- tion, their standardized characteristics do not account for in- terindividual microbial heterogeneity (Sharma et al., 2022). In contrast, microbiome-based personalized diets improve therapy eﬃcacy by tailoring the diet to the patient’s micro- bial proﬁle, but their clinical application is hampered by li- mitations related to cost, standardization, and technological availability (Qin et al., 2025; Murugesan et al., 2025). In this context, it is relevant to systematize the available scienti- ﬁc evidence to understand the role of the gut microbiome in T2DM and compare traditional dietary supplements with those based on microbial personalization. Therefore, the ob- jective of this research was to analyze the inﬂuence of the gut microbiome on the pharmaceutical and dietary treatment of T2DM based on current scientiﬁc evidence. Methodology The systematic review follows the PRISMA 2020 guideli- nes, aiming to ensure transparency, reproducibility, and me- thodological rigor in the identiﬁcation, selection, analysis, and synthesis of scientiﬁc evidence related to the inﬂuence of the gut microbiome on the clinical and nutritional mana- gement of T2DM (Page et al., 2021). The research requi- rement is formulated using the PICO model, deﬁning how patients with T2DM are treated, how interventions are im- plemented in clinical therapies or foods aimed at modulating the gut microbiome, how probiotics, prebiotics, functional diets, or fecal microbiota transplantation are used, compared to standard treatments or placebo, and considering changes in glucose parameters, inﬂammation, gut microbial compo- sition, and associated metabolic complications (Methley et al., 2014). Inclusion criteria include original studies and systematic reviews published between 2014 and 2024, in English or Spanish, that analyze the relationship between the gut mi- crobiome and the treatment of T2DM in humans and animal models. Opinion pieces, editorials, letters to the editor, case reports, studies focused exclusively on type 1 diabetes me- llitus and other metabolic disorders, and studies published without full-text access or with insuﬃcient information for analysis are excluded. The literature search will be conduc- ted between April 1 and 10, 2025, using specialized databa- ses such as PubMed, Scopus, and Web of Science. Science, Embase, and Google Scholar, using a strategy that combines MeSH terms and keywords using booleans, adapted to the speciﬁc criteria of each database and applied with ﬁlters by language, document type, and time range (2014-2024). The study screening and selection process is managed by the Zotero bibliographic management system, where dupli- cate records are initially identiﬁed and removed. Subsequent- ly, studies are selected in consecutive stages: a ﬁrst review of titles and abstracts and a second evaluation of the full text of

J. Food Sci. Gastron. (January - June 2026) 4(1): 23-41 25 the preselected articles, according to established criteria. A matrix is used for data extraction and analysis, which inclu- des information on methodological characteristics, types of intervention, clinical and metabolic variables assessed, main results, and limitations. The results are presented narratively, organized according to the types of intervention and the ob- served metabolic and clinical eﬀects, and are based on the PRISMA 2020 guidelines, including a ﬂowchart of the selec- tion process and summary tables of the analyzed evidence. Results and discussion Search according to the PRISMA 2020 ﬂowchart The search strategy was conducted in ﬁve academic da- tabases (Figure 1). Initially, a total of 5830 records were identiﬁed, distributed as follows: 1200 in PubMed, 1050 in Scopus, 980 in Web of Science, 1100 in Embase, and 1500 in Google Scholar. After removing duplicates, 4500 unique records remained for evaluation. In the selection stage, the titles and abstracts of the 4500 records were examined, excluding 3200 that did not meet the theoretical criteria of interest. Subsequently, in the eli- gibility stage, 1300 full-text message reports were analyzed, of which 1273 were eliminated for various reasons: 392 for irrelevant study design, 312 for including populations unre- lated to T2DM, 221 for gut microbiome data, and 348 for other reasons (such as insuﬃcient methodology or irrelevant results). Finally, 27 studies will be included in the systematic re- view to meet the inclusion criteria. To ensure transparency and methodological rigor in the selection of scientiﬁc evi- dence, this procedure adheres to the PRISMA 2020 guide- lines. Eﬀects of the gut microbiome on the digestive, endocrine, immune, and nervous systems in relation to T2DM Table 1 compiles 27 studies examining the connection between the gut microbiota and T2DM, including book chapters, clinical trials, experimental studies, and systema- tic reviews. These works address therapeutic interventions, pathophysiological mechanisms, and limitations in the re- search. Systematic reviews represent 65% of the studies and focus on mechanisms such as dysbiosis, inﬂammation, and the incidence of bacterial metabolites, as well as die- tary, probiotic, and pharmaceutical therapies. Clinical trials (15%) are primarily pilot studies with small sample sizes (≤ 60 patients). As noted by Palacios et al. (2017), 10% of these studies use murine models of obesity and T2DM to evaluate interventions such as symbiotic or pharmaceutical therapies. The remaining 10% consists of book chapters with theoreti- Figure 1. PRISMA ﬂowchart to represent the item selection process.

J. Food Sci. Gastron. (January - June 2026) 4(1): 22-40 26 Table 1. Synthesis of evidence from the T2DM microbiome Reference Type of study Sample characteristics Type of intervention and duration Microbiome analysis method Clinical and metabolic variables Results major Conclusions Limitations Dzięgielewska- Gęsiak et al. (2022) Cohort comparative 2 T2DM groups (Met vs Met+Ins), 5-10 years of training Pharmacological (Met against Met+Ins) / 5-10 years New sequencing generation Glucose, HbA1c, lipids, and kidney function No diﬀerences in the microbiome, Met+Ins for glucose control Insulin can delay late complications Sample small Stepanova (2024) Revision N/A Review of SGLT2 inhibitors N/A Glucose, weight, blood pressure, microbiota Possible modulating eﬀect of SGLT2i on the microbiota Potential use in personalized treatment Lack of evidence clinic straight Palacios et al. (2017) Rehearsal clinic pilot 60 adults with recent prediabetes/ T2DM Multispecies probiotic vs placebo / 12 weeks Metagenomics + fecal metabolomics Blood glucose, lipid proﬁle, inﬂammation, and intestinal permeability. Improvement of glucose and metabolic parameters with probiotics Probiotics can prevent/control T2DM Study pilot, monitoring short-term Star and others (2024) Comparative clinical trial Prediabetics on metformin Metformin vs Metformin + Linagliptin 16S rRNA in feces Glucose, inﬂammation, metabolic markers Metformin and linagliptin modify bacterial composition and improve their markers Pharmaceutical intervention can modulate the gut microbiota Design is limited by maximum size and a lack of long-term instructions. Baars et al. (2024) Revision N/A Diet and medications Study review Glucose, HbA1c, microbiota, SCFA, LPS Modulation of the microbiota impacts immunity and metabolism. Personalized treatment based on the microbiome High heterogeneity and lack of methodological standardization Fu et al. (2023) Revision N/A Probiotics, prebiotics, pharmaceuticals Metabolomics microbial SCFA, LPS, TMAO, bile acids The microbiota regulates key metabolites in T2DM Therapeutic potential of bacterial metabolites Important evidence in animal models Cunningham et al. (2021) Revision N/A Diet, prebiotics, synbiotics Literature review Glucose, insulin, and intestinal permeability Causal relationship between dysbiosis and T2DM Prediction and therapy of microbiota factors Studies heterogeneous

J. Food Sci. Gastron. (January - June 2026) 4(1): 22-40 27 Reference Type of study Sample characteristics Type of intervention and duration Microbiome analysis method Clinical and metabolic variables Results major Conclusions Limitations Sharma et al. (2022) Revision N/A Bioactive nutritional Studies previous Glucose, inﬂammation, and insulin resistance Bioactives restore eubiosis and improve metabolism Use of polyphenols and prebiotics Evidence clinic limited Chiou et al. (2021) Experimental in animals We are obese because of high- fat diets Symbiotic with Adlay + probiotics / 12 weeks Fecal metagenomics Glucose, insulin, lipid proﬁle, IL-6 Increased obesity, inﬂammation, and microbiota Eﬀective symbiosis in the mouse model Not applicable to humans Majait et al. (2023) Revision N/A Probiotics, antibiotics, fecal transplant Study review Acids biliary microbiota Bile relationship Key acids in T2DM Biliary modulation as a therapeutic strategy High heterogeneity in studies Iatcu and others (2024) Revision N/A Prebiotics (inulin, FOS, GOS, RS) Revision Glucose, insulin, SCFAs Prebiotics improve the microbial and glucose proﬁle Prebiotics are useful in the control of T2DM Further evidence clinic required Sato et al. (2017) Revision N/A Diet, microbiota Revision SCFA, LPS, inﬂammation Dysbiosis alters fatty acids, permeability, and glucose. Normalizing the microbiota to prevent T2DM Diﬀerences in ethnicities/ methods Pizarro and others (2024) Chapter book N/A Diet (hydrated charcoal) Revision Firmicutes/ Bacteroidetes, intestinal permeability Carbohydrates, Modular composition microbial Diet as a cornerstone in microbiota management Lack of controlled trials Murugesan and others (2025) Revision N/A Diet, nutraceuticals, synbiotics Revision LPS, inﬂammation, glucose The disease induces systemic inﬂammation and T2DM Restoring the microbiota reduces inﬂammation and improves metabolism Studies are preliminary in humans

J. Food Sci. Gastron. (January - June 2026) 4(1): 22-40 28 Reference Type of study Sample characteristics Type of intervention and duration Microbiome analysis method Clinical and metabolic variables Results major Conclusions Limitations Sharma et al. (2024) Chapter book/ review N/A Symbiotics Revision Glucose, insulin Synbiotics improve metabolism and bacterial proﬁle Alternative promising in T2DM Clinical evidence in humans is lacking Qin et al. (2025) Revision N/A Probiotics, FMT, natural products Revision HbA1c, insulin, SCFAs Probiotics and FMT modulate the microbiota and glucose parameters Potential therapeutic therapy conﬁrmed in preclinical models Move on to robust clinical studies Negm (2023) Chapter book N/A Microbiota modulation Revision Inﬂammation, permeability, glucose The microbiota inﬂuences T2DM through inﬂammation and endotoxemia Microbiota as a therapeutic target Evidence indirect Ng et al. (2024) Revision N/A Medicine traditional Porcelain Revision Glucose, insulin, and proﬁle bacterial Medicinal plants modulate the microbiota and reduce insulin resistance Integration of traditional medicine in the management of T2DM Studies in humans are limited Adeshirlarijaney and Gewirtz (2020) Revision N/A Diet, prebiotics, fecal transplant Revision Glucose, inﬂammation The disease promotes T2DM during chronic inﬂammation Microbial modulation is useful in prevention Lack of consensus methodological Sikalidis and Maykish (2020) Revision N/A Diet, antibiotics Revision Glucose resistance has insulin Dysbiosis alters metabolism and immunity in T2DM Microbial modulation is key in prevention Lack of trial clinics Oluwaloni et al. (2023) Revision N/A Drugs, diet, prebiotics Revision Glucose, HbA1c, microbiota Dysbiosis associated with T2DM; improved regulatory parameters Necessary to validate interventions dietary Scarcity of studies longitudinal

J. Food Sci. Gastron. (January - June 2026) 4(1): 22-40 29 Reference Type of study Sample characteristics Type of intervention and duration Microbiome analysis method Clinical and metabolic variables Results major Conclusions Limitations Sivadas et al. (2025) Revision N/A Probiotics, FMT Revision Glucose, insulin, SCFAs Probiotherapy and fecal transplantation improved glucose control Potential clinic important Lack of evidence is solid Ebrahimi et al. (2025) Meta- analysis and multivariate analysis 946 samples (9 studies) Without application (comparison between patients with T2DM and controls) 16S rRNA sequencing + data mining + LEfSe N/A (focus on taxonomy) Twenty-three genes and four cell lines were identiﬁed as microbial markers of T2DM (e.g., increased Prevotella, reduced Bacteroides). Computational analysis allows the identiﬁcation of robust microbial biomarkers in T2DM Lack of direct clinical input, purely a bioinformatics approach Martínez-Carrillo et al. (2024) Observatory study Patients with T2DM (n=40) Comparison of carbohydrate consumption Massive sequencing of 16S rRNA Glucose, HbA1c, bacterial diversity Changes in microbial diversity according to the type and amount of carbohydrates A high- carbohydrate diet signiﬁcantly aﬀects the microbiota in T2DM There are no details on durability or control of other variables. Martínez-Carrillo et al. (2024) Multicenter cohort study 8,117 metagenomes from the US, China, Europe, and Israel Observational, cross-sectional Metagenomic shotgun Glucose, HbA1c, bacterial metabolism Functional and taxonomic alterations associated with T2DM; involvement of speciﬁc species such as Enterocloster bolteae Strain analysis oﬀers potential mechanisms involved in T2DM Completion of the interpretation for inter-cohort variability

J. Food Sci. Gastron. (January - June 2026) 4(1): 22-40 30 Reference Type of study Sample characteristics Type of intervention and duration Microbiome analysis method Clinical and metabolic variables Results major Conclusions Limitations Razavi et al. (2024) Case-control studies 36 participants (18 with T2DM and 18 healthy controls) There was no intervention; it was a cross- sectional observational study. Real-time PCR (qPCR) on DNA extracted from feces Do not analyze speciﬁc clinical/ metabolic variables Greater abundance of Bacteroides and Bacteroidetes in T2DM; greater presence of Firmicutes and Actinobacteria in controls; no diﬀerences in other taxa T2DM is associated with intestinal dysbiosis; the use of probiotics/ prebiotics may help control the blockage. Small sample size; cross- sectional design; spurious clinical and metabolic data; limited microbiome analysis Valencia-Castillo et al. (2024) Cohort study 5 mother-infant pairs with and without GDM (Colombia) Cross-sectional observation 16S V3–V4 Sequencing + SILVA Intestinal microbiota and breast milk Maternal dysbiosis associated with gestational diabetes, reduction of Biﬁdobacterium and Sutterella Gestational diabetes aﬀects the microbial composition of both the mother and the child Small sample size, results not generalizable

J. Food Sci. Gastron. (January - June 2026) 4(1): 23-41 31 cal texts lacking original data. Among the interventions evaluated, probiotics and syn- biotics (e.g., Lactobacillus, Biﬁdobacterium) were shown to improve glucose levels, reduce inﬂammation, and increase microbial diversity, according to Sharma et al. (2022) and Palacios et al. (2017). Prebiotics (inulin, FOS, GOS) increa- se the production of short-chain fatty acids (SCFAs), such as butyrate, and reduce LPS levels. Metformin and SGLT2 inhibitors modulate the gut microbiota (increasing Akker- mansia), and metformin can induce resistance. High-ﬁber, low-fat diets restore the Firmicutes/Bacteroidetes balance, although fecal-oral transmission (FMT) beneﬁts the most in preclinical models. 16S rRNA sequencing (70% of clinical studies) and meta- genic/metabolomic techniques to identify bacterial species and metabolites such as SCFAs, TMAO, and LPS. Clinical variables assessed include blood glucose, HbA1c, insulin resistance, lipid proﬁle, and inﬂammatory markers (IL-6, TNF-α, LPS). Regarding the gut microbiota, we analyzed the abundance of Akkermansia, Biﬁdobacterium, and the Firmi- cutes/Bacteroidetes ratio. The results conﬁrm that dysbiosis in T2DM is characte- rized by reduced microbial diversity, an increase in Firmi- cutes, and a decrease in Bacteroidetes (Cunningham et al., 2021). The mechanisms involved in the production of short- chain fatty acids (SCFAs), which improve insulin sensitivi- ty, and the pro-inﬂammatory role of lipoproteins (LPS) are described. The most promising interventions are based on probiotics and high-ﬁber diets, which restore eubiosis and improve glycemic parameters. However, limitations remain, such as the small number of studies (only 20% of clinical trials include more than 100 participants), the lack of stan- dardized methods, and the predominance of preclinical evi- dence (30% in animals). Furthermore, probiotic trials require short periods (≤12 weeks). Advances in the analysis of the gut microbiome and its implication in T2DM Emerging technologies have revolutionized the study of the gut microbiome in T2DM, incorporating next-generation sequencing (NGS), metagenomics, metabolomics, and mul- ti-omics pathways. These tools allow for the characterization of taxonomic composition, the identiﬁcation of functional signatures, and the correlation of microbial proﬁles with glu- cose control and therapies employed (Dzięgielewska-Gęsiak et al., 2022; Valencia-Castillo et al., 2025). As a result, me- tabolism has been shown to be key for bacterial metabolites, such as medium-chain fatty acids (SCFAs), lipopolysac- charides, and trimester N-oxidase, including inﬂammation, insulin resistance, and intestinal barrier dysfunction (Fu et al., 2023). The integration of metagenic, transcriptomic, and metabolomic data has broadened our understanding of the immune mechanisms involved in T2DM and has provided insights for their application in personalized medicine (Baars et al., 2024). However, despite the predominance of in silico infusions, anaerobic culture of speciﬁc bacteria remains es- sential to validate microbial functions and study their direct impact on metabolism and systemic inﬂammation (Pizarro et al., 2024). Regarding microbial composition, evidence indicates that patients with T2DM exhibit a signiﬁcant decrease in gluco- se-producing bacteria, such as Roseburia and Faecalibacte- rium, which are associated with impaired carbohydrate me- tabolism and increased insulin resistance (Iatcu et al., 2024). Simultaneously, we have reported an increase in pro-in- ﬂammatory bacteria, such as Ruminococcus and Prevotella, along with a reduction in Akkermansia, contributing to the microbial imbalance and inﬂammatory state characteristic of the disease (Oluwaloni et al., 2023). Some studies suggest that these changes may constitute microbiota biomarkers of poor glycemic control, and they observe speciﬁc proﬁles as- sociated with metabolic dysfunction in patients with T2DM (Baars et al., 2024). Microbiome-based clinical interventions show very pro- mising results. The use of prebiotics, probiotics, and synbio- tics promotes the proliferation of beneﬁcial short-chain fatty acid (SCFA)-producing bacteria, improves insulin sensitivi- ty, and reduces intestinal inﬂammation (Iatcu et al., 2024). Fecal microbiota transplantation (FMT) is emerging as an innovative strategy to restore microbial balance, with preli- minary results suggesting improvements in glucose metabo- lism, inﬂammation, and lipid proﬁle in experimental models of T2DM, although its clinical application requires further evidence (Singh & Bhadauriya, 2025). Similarly, personali- zed nutrition based on the gut microbial proﬁle is presented as an attractive alternative to optimize glucose control and reduce the risk of glucose entrapment progression, although controlled clinical trials are needed to conﬁrm its eﬃcacy (Meloncelli et al., 2023). Microbial metabolites are fundamental to glucose homeos- tasis. Short-chain fatty acids (SCFAs), especially butyrate, propionate, and acetate, inﬂuence insulin sensitivity, intes- tinal barrier integrity, and the regulation of energy metabo- lism by modulating inﬂammation, the secretion of intestinal hormones such as GLP-1 and PYY, and fatty acid oxidation (Cunningham et al., 2021; Chiou et al., 2021; Sharma et al., 2022; Fu et al., 2023; Baars et al., 2024). Thus, triplet-deri- ved metabolites and bile acids modiﬁed by the microbiota inﬂuence pancreatic β-cell function, immune regulation, and hepatic gluconeogenesis through the activation of receptors such as AhR, FXR, and TGR5 (Majait et al., 2023; Baars et al., 2024; Qin et al., 2025; Murugesan et al., 2025). Eviden-

J. Food Sci. Gastron. (January - June 2026) 4(1): 23-41 32 ce suggests that modulating these metabolites through die- tary, probiotic, and pharmacological interventions, such as metformin use, represents a promising therapeutic approach, reinforcing the relevance of the gut-microbiota-metabolism pathway in the development of innovative and personalized strategies for the comprehensive management of T2DM (Adeshirlarijaney & Gewirtz, 2020; Szymczak-Pajor et al., 2025). Mechanisms of inﬂuence of the intestinal microbiome on T2DM Intestinal dysbiosis is recognized as a central component in the pathology of T2DM, characterized by a reduction in microbial diversity, the predominance of pro-inﬂammatory bacteria, and a reduction in beneﬁcial species that produce short-chain fatty acids (SCFAs), such as Faecalibacterium. prausnitzii and Roseburia spp. (Iatcu et al., 2024; Szymc- zak-Pajor et al., 2025). This microbial imbalance promotes a pro-inﬂammatory intestinal infection that compromises the integrity of the epithelial barrier and facilitates the translo- cation of bacterial endotoxins, particularly lipopolysaccha- rides (LPS), aﬀecting the systemic circulation. Activation of Toll-like receptors, primarily TLR4, triggers a low-grade inﬂammatory response mediated by pro-inﬂammatory mole- cules such as TNF-α, IL-6, and IL-1β, directly contributing to reduced insulin resistance and the progression of T2DM (Sato et al., 2017; Adeshirlarijaney & Gewirtz, 2020). Fur- thermore, other metabolites derived from dysbiosis, inclu- ding some secondary bile acids and protein fermentation products, modulate inﬂammation and metabolism in glucose control, solidifying dysbiosis-inﬂammation as a relevant the- rapeutic target (Sharma et al., 2022; Baars et al., 2024). Microbial metabolites, especially short-chain fatty acids (SCFAs) derived from the fermentation of non-digestible dietary ﬁber, are key to metabolic regulation and glucose homeostasis. Acetate, propionate, and butyrate exert bene- ﬁcial eﬀects on insulin sensitivity, intestinal barrier func- tion, and resistance to inﬂammation (Iatcu et al., 2024; Ng et al., 2024). However, they are produced by bacteria such as Faecalibacterium. prausnitzii and Roseburia Scleroderma spp., constitute an essential energy source for colonocytes and promote the expression of intercellular junction proteins, reduce endotoxin translocation, and decrease metabolic in- ﬂammation (Sato et al., 2017; Szymczak-Pajor et al., 2025). Therefore, propionate and acetate activate G protein-coupled receptors (GPR41 and GPR43), which modulate the secre- tion of incretin hormones such as GLP-1 and PYY, promo- ting post-prandial glucose control and appetite regulation (Baars et al., 2024). Additionally, SCFAs have epigenetic eﬀects through the inhibition of histone deacetylases, regu- lated genes involved in inﬂammation and energy metabolism (Sharma et al., 2022). In patients with T2DM, the increased production of these metabolites is associated with metabo- lic dysfunction and microbial imbalance (Oluwaloni et al., 2023), which negates their relevance as therapeutic drugs (Qin et al., 2025). Bile acid metabolism represents another key mechanism through which the gut microbiota inﬂuences metabolic ho- meostasis in T2DM. Primary bile acids, synthesized in the liver, are transformed into secondary bile acids by intestinal bacterial enzymes, which modify their proﬁle and their abi- lity to activate metabolic receptors such as FXR and TGR5 (Negm, 2023; Baars et al., 2024). Activation of these recep- tors regulates essential processes such as hepatic gluconeo- genesis, lipid metabolism, insulin sensitivity, and GLP-1 se- cretion (Zhang, Zhang et al., 2024). In patients with T2DM, alterations in the gut microbiota are associated with unfa- vorable bile acid proﬁles, resulting in insulin resistance and lipidemia. However, interventions that modulate the micro- biome, such as prebiotics and probiotics, have the capacity to restore beneﬁcial bile acid proﬁles and improve glucose parameters (Ng et al. 2024; Qin et al., 2025). Together, we consolidate the microbiota-bile acid-metabolic receptor re- lationship as a fundamental component in the pathology and therapeutic approach to T2DM (Negm, 2023). Clinical treatment of T2DM based on modulation of the gut microbiome Figure 2 summarizes the role of the gut microbiome in the pathology of T2DM and the proposed intervention stra- tegies. Under conditions of intestinal dysbiosis, an increase in lipopolysaccharides (LPS) and a reduction in short-chain fatty acids (SCFAs) are observed, which contribute to the stability of a state of systemic inﬂammation and the loss of insulin resistance (Fu et al., 2023; Baars et al., 2024). This phenomenon has been documented in both T2DM and gesta- tional diabetes (GDM), including the reduction of propionate and, among other things, the activation of inﬂammatory cells and the polarization of macrophages caused by pro-inﬂam- matory M1 cells (Baars et al., 2024). As therapeutic strategies, we propose interventions aimed at modulating the gut microbiota: the use of probiotics in- creases microbial diversity and promotes immune regula- tion, stimulating the proliferation of beneﬁcial bacteria and the production of SCFAs (Sharma et al., 2024). Therefore, high-ﬁber diets stimulate bacterial fermentation and increase bacterial concentrations of SCFAs, a short-chain fatty acid with recognized anti-inﬂammatory and insulin-sensitizing properties (Iatcu et al., 2024). Similarly, some antidiabetic medications, such as metformin and SGLT2 inhibitors, alter the composition of the gut microbiome and the number of SCFA-producing bacteria. Depending on the patient’s ini- tial microbial proﬁle and clinical context, these changes can have diﬀerent metabolic eﬀects (Dzięgielewska-Gęsiak et

J. Food Sci. Gastron. (January - June 2026) 4(1): 23-41 33 al., 2022; Stepanova, 2024). Personalized treatments based on individual microbial pro- ﬁles, longitudinal studies to evaluate the eﬀects of long-term interventions, and the need for robust clinical trials to vali- date dosage and, speciﬁcally, address the main shortcomings found are all crucial. While promising treatments exist and the gut microbiota plays an important role in T2DM, their immediate clinical application is limited by the mechanisms suggested by the gut microbiota that aﬀect brain and metabo- lic function, as shown in Figure 3. This ﬁgure also illustrates how the various components of the microbiota can aﬀect me- tabolism and the central nervous system. The mechanisms described are based on studies suggesting diﬀerent ways in which the gut microbiota interacts with the brain and me- tabolic system, which may have important implications for brain and metabolic health. The mechanisms proposed by the gut microbiota for mo- dulating brain and metabolic function involve several key processes that connect gut health with neurological and me- tabolic well-being. One of the best-known mechanisms is the gut-brain axis, which refers to the restructuring of the gut microbiota to enhance metabolites related to cognitive func- tion. It is suggested that a balanced microbiota promotes the production of beneﬁcial metabolites that have a positive im- pact on cognition; therefore, maintaining a healthy microbial balance is recommended to optimize brain function (Davari et al., 2013; Pang et al., 2020; Du et al., 2024; Song et al., 2024). Another important mechanism is inﬂammation and immu- nity, which involves reducing pro-inﬂammatory factors and maintaining the integrity of the blood-brain barrier (BBB). A healthy gut microbiota can help reduce systemic inﬂam- mation and protect the BBB, preventing neurological disor- ders such as Alzheimer’s and Parkinson’s. Improved immu- nity and BBB protection are essential for brain health (Lee et al., 2023; Li et al., 2024; Meroni et al., 2025; Bi et al., 2025). Reducing oxidative stress is another key mechanism, as the gut microbiota inﬂuences the increase of antioxidant factors and the reduction of oxidative stress. Preventing cell damage and promoting overall brain health is vital, since oxidative esters are a major cause of various neurodegenerative disea- ses (Davari et al., 2013; Pang et al., 2020; Lee et al., 2023). Furthermore, the metabolic regulation of the gut micro- biota is essential for controlling glucose homeostasis and improving lipid metabolism, which contributes to the pre- vention of metabolic disorders such as T2DM. Maintaining a microbiota that promotes eﬃcient metabolism is fundamen- tal for controlling body weight and preventing metabolic changes (Qu et al., 2024; Li et al., 2024). Neurotransmitter modulation is another interesting mecha- nism, as the gut microbiota has a direct impact on the levels of serotonin, dopamine, and GABA-key neurotransmitters related to the regulation of an animal’s state, response, and cognitive function. This mechanism suggests that the gut mi- crobiota could be used as a therapeutic approach for disor- ders associated with dysregulated neurotransmitters, such as depression and anxiety (Song et al., 2024). In short, synaptic plasticity and neurogenesis describe how the microbiota enhances synaptic transmission and sti- mulates the expression of brain-derived neurotrophic factor (BDNF), which is essential for brain plasticity and neuro- genesis. These processes are fundamental for learning, me- mory, and neuronal regeneration, which explains the impor- tance of the microbiota for maintaining brain health (Pang et Figure 2. Relationship between the gut microbiome, dysbiosis, and interventions in T2DM.

J. Food Sci. Gastron. (January - June 2026) 4(1): 23-41 34 al., 2020; Lee et al., 2023; Li et al., 2024). These mechanisms reﬂect the growing interest in the con- nection between the gut microbiota and various brain and metabolic functions. The inﬂuence of the microbiota on bra- in and metabolic function oﬀers new perspectives for the treatment of neurodegenerative diseases, metabolic disor- ders, and problems related to emotional and cognitive ba- lance. Therefore, manipulating the gut microbiota may be a promising therapeutic strategy for improving brain and me- tabolic health. Figure 4 summarizes the main therapeutic applications of modular gut microbiota in patients with T2DM, presenting representative examples and their metabolic and microbiolo- gical eﬀects. Interventions include probiotics and synbiotics, such as Lactobacillus and Biﬁdobacterium, which improve glucose levels, reduce inﬂammation, and increase microbial diversity (Palacios et al., 2017; Sharma et al., 2022). Pharmacological interventions The pharmacological treatment of T2DM has evolved with a comprehensive approach to glucose control, which is not limited solely to improving metabolic disorders, redu- cing cardiovascular disease, and modulating underlying pa- thophysiological mechanisms, such as chronic inﬂammation and gut dysbiosis. In this context, recent evidence suggests that some antidiabetic drugs have eﬀective modulatory eﬀects on the gut microbiota, which may contribute signiﬁ- cantly to their metabolic and extraglycemic beneﬁts (Negm, 2023; Baars et al., 2024; Qin et al., 2025). Sodium-glucose cotransporter 2 (SGLT2) inhibitors, such as empagliﬂozin, dapagliﬂozin, and canagliﬂozin, are beco- ming established as an eﬀective therapeutic class for T2DM due to their hypoglycemic action, as well as their demons- trated cardiovascular and renal eﬀects (Zhang et al., 2024). Recent studies indicate that these drugs can induce favorable changes in the composition and function of the gut micro- biota, likely as a consequence of modiﬁcations to energy metabolism and substrate availability in the intestinal lumen. Several changes include an increase in short-chain fatty acid (SCFA)-producing bacteria and a reduction in pro-inﬂam- matory microorganisms, which can be explained, at least in Figure 3. Mechanisms underlying the gut microbiota in the modulation of brain and metabolic function.

J. Food Sci. Gastron. (January - June 2026) 4(1): 23-41 35 part, by the eﬀects of weight loss, increased insulin sensiti- vity, and reduced systemic inﬂammation (Ng et al., 2024; Qin et al., 2025). Although the precise mechanisms require further elucidation, the interaction between iSGLT2 and mi- crobiome position is a class of pharmaceutical as a thera- peutic strategy with relevant metabolic and systemic eﬀects (Zhang, Zhang et al., 2024). Metformin, a ﬁrst-line drug in the treatment of T2DM, pri- marily inhibits hepatic gluconeogenesis and improves peri- pheral glucose uptake; however, it has been recognized that part of its clinical eﬃcacy is due to its impact on the gut mi- crobiota (Adeshirlarijaney & Gewirtz, 2020; Szymczak-Pa- jor et al., 2025). Evidence shows that metformin increases the abundance of beneﬁcial bacteria, such as Akkermansia. Muciniphila, Butyrivibrio, and Biﬁdobacterium species are associated with increased insulin sensitivity and reduced inﬂammation, as well as increased short-chain fatty acid (SCFA) production (Sikalidis & Maykish, 2020; Mohamed, 2024; Kim et al., 2024; Szymczak-Pajor et al., 2025). These microbiome-dependent eﬀects contribute to glucose control and the modulation of metabolic and immunological proces- ses involved in T2DM (Zhang et al., 2025). However, the magnitude of these modiﬁcations depends in part on the the- rapeutic context, although combination therapy with insulin does not replicate the microbial changes (Tang et al., 2024; Szymczak-Pajor et al., 2025). Taken together, the recogni- tion of the role of the microbiome in the action of metfor- min presents new opportunities to optimize its clinical eﬀect through dietary strategies or targeted symbiosis (Zhang et al., 2025; Chen et al., 2025). New therapeutic inserts The recognition of the gut microbiota as a central modu- lator in the pathology of T2DM has driven the development of innovative therapeutic strategies that integrate the inte- raction between the human body, diet, pharmaceutical the- rapy, and the microbial ecosystem. In this regard, various interventions targeting microbiome modulation, such as the use of prebiotics, drugs with microbiome-dependent eﬀects, speciﬁc dietary patterns, and fecal microbiota transfer, have the greatest potential to optimize glucose control and reduce variability in therapeutic response (Sharma et al., 2022; Iatcu et al., 2024; Pizarro et al., 2024; Qin et al., 2025). In parti- cular, prebiotics such as inulin, FOS, and GOS promote the production of medium-chain fatty acids (SCFAs) and reduce metabolic endotoxemia, while drugs such as metformin and SGLT2 inhibitors promote the growth of beneﬁcial bacteria such as Akkermansia, with possible contextual eﬀects on mi- crobial resistance (Kim et al., 2024). In this context, personalized medicine emerges as a promi- sing approach for managing T2DM, proposing the adaptation of dietary, pharmacological, and behavioral interventions ac- cording to each patient’s clinical, genetic, and microbiologi- cal characteristics. Analysis of the gut microbiome using the following techniques allows for the identiﬁcation of bacterial proﬁles associated with insulin resistance, poor glucose con- trol, and an increased risk of metabolic complications (Baars et al., 2024; Zhang, Zhang et al., 2024). This information facilitates the identiﬁcation of patient subgroups that could beneﬁt from targeted interventions, such as microbiota mo- dulators or pharmacological adjustments, highlighting the high abundance of Akkermansia muciniphila could predict greater resistance to metformin (Kim et al., 2024; Szymc- zak-Pajor et al., 2025). Its practical application represents Figure 4. Therapeutic strategies modulating the intestinal microbiome in T2DM and their reported eﬀects.

J. Food Sci. Gastron. (January - June 2026) 4(1): 23-41 36 a path towards more precise and eﬀective therapies (Qin et al., 2025). Furthermore, the understanding of the gut-brain axis has ampliﬁed the therapeutic inﬂuence of microbiome modula- tion in T2DM, particularly in relation to the cognitive de- cline associated with conﬁnement. T2DM is caused by neu- rocognitive and neuropsychiatric alterations, while systemic inﬂammation and oxidative stress are not relevant (Sikalidis & Maykish, 2020; Negm, 2023). In this context, probiotics, especially those containing Lactobacillus and Biﬁdobacte- rium, are the most capable of modulating neurotransmitter production, reducing neuroinﬂammation, and improving in- testinal barrier integrity. Preclinical studies and preliminary clinical trials suggest beneﬁts for memory, cognitive func- tion, and inﬂammatory markers, but more extensive research is needed to conﬁrm these ﬁndings (Sharma et al., 2022; Baars et al., 2024; Mohamed, 2024; Qin et al., 2025). On the other hand, diabetic retinopathy, one of the most common and serious microvascular complications of T2DM, has also led to alterations in the gut microbiota. Dysbiosis can contribute to systemic inﬂammation, oxidation, and vascu- lar dysfunction through the production of pro-inﬂammatory metabolites, such as lipopolysaccharides, which are activa- ted when associated with retinal damage (Sato et al., 2017; Adeshirlarijaney & Gewirtz, 2020; Zhang et al., 2025). Con- versely, beneﬁcial SCFA-producing bacteria, such as Biﬁdo- bacterium and Lactobacillus, may have protective eﬀects by reducing inﬂammation and improving intestinal barrier func- tion (Szymczak-Pajor et al., 2025). Modulating the gut microbiota is a cross-cutting thera- peutic challenge in T2DM, with implications not only for metabolism but also for cognitive and microvascular health. Approaches such as the use of prebiotics, probiotics, high-ﬁ- ber and polyphenol-rich diets, and fecal microbiota transfer show promise as complementary therapies to conventional treatments (Kim et al., 2024; Iatcu et al., 2024; Qin et al., 2025; Pizarro et al., 2024). However, the consolidation of these interventions in clinical practice requires longitudinal studies and robust clinical trials to establish their eﬀective- ness, safety, and applicability within a personalized medical model aimed at reducing complications and improving the quality of life of patients with T2DM. Dietary recommendations based on gut microbiome ba- lance for the comprehensive treatment of T2DM Among the 27 studies compiled (Table 1), the dietary strategies from the clinical studies of Palacios et al. (2017) and the systematic reviews of Baars et al. (2024) and Fu et al. (2023) were selected. These studies show that high-ﬁber diets and the inclusion of multispecies probiotics improve metabolic parameters such as fasting glucose, systemic in- ﬂammation, and microbial diversity. A key aspect is the analytical method used. Most studies employ 16S rRNA sequencing and metabolomics tools to identify bacterial species and metabolites such as short-chain fatty acids (SCFAs), since their production is favored by the consumption of fermentable ﬁbers. These techniques allow for the precise correlation of dietary changes with microbio- me composition and clinical indicators of T2DM. In terms of results, it was observed that functional diets based on prebiotic ﬁbers (inulin, FOS, GOS) increased the abundance of beneﬁcial bacteria such as Akkermansia and Biﬁdobacterium, while reducing lipopolysaccharides (LPS), improving glucose homeostasis and reducing inﬂammation. Dietary supplements for the management of T2DM have evolved from generalized strategies based on personalized models that consider the composition of the gut microbio- me. Figure 5 summarizes the main diﬀerences between these paradigms. Dietary interventions based on gut microbiome modula- tion oﬀer therapeutic potential for the comprehensive mana- gement of T2DM according to the patient’s microbial pro- ﬁle, improving insulin sensitivity and glucose control, and reducing mild systemic inﬂammation. However, the predo- minance of pilot studies or small studies necessitates caution in extrapolating results, hence the need for well-designed, longer-term clinical trials. Dietary interventions Dietary interventions aimed at modulating the gut micro- biota are becoming established as a relevant complementary strategy for addressing T2DM, positively inﬂuencing glu- cose homeostasis, insulin sensitivity, and the mild chronic inﬂammation characteristic of this condition. Available evi- dence indicates that manipulating microbial composition and function through prebiotics, probiotics, symbiosis, and high-ﬁber diets allows for the creation of a more favorable intestinal environment, with a direct impact on the metabolic and immunological processes involved in T2DM (Iatcu et al., 2024; Qin et al., 2025). Prebiotics, composed primarily of non-digestible solu- ble ﬁbers such as inulin, fructooligosaccharides (FOS), and galactooligosaccharides (GOS), selectively stimulate the growth of beneﬁcial bacteria that produce medium-chain fa- tty acids (SCFAs), promoting intestinal barrier integrity and modulating the immune response (Iatcu et al., 2024; Sharma et al., 2024). Clinical studies have shown that insulin and FOS supplementation improves glucose tolerance, reduces insulin resistance and inﬂammatory markers, and is associa- ted with an increase in genes such as Biﬁdobacterium and Faecalibacterium prausnitzii (Sivadas et al., 2025; Szymc- zak-Pajor et al., 2025). In a complementary way, probiotics, particularly those of Lactobacillus, Biﬁdobacterium, and

J. Food Sci. Gastron. (January - June 2026) 4(1): 23-41 37 Bacillus, have more eﬀective eﬀects on fasting glucose, in- sulin sensitivity, and the reduction of pro-inﬂammatory cyto- kines, in addition to modulating the release of incretins such as GLP-1, contributing to postprandial glycemic control (Negm, 2023; Ng et al., 2024; Qin et al., 2025). The use of synbiotics, which combine prebiotics and pro- biotics, is emerging as a dietary strategy with synergistic eﬀects on modulating the gut microbiome. In experimental models of T2DM, these interventions have demonstrated improvements in insulin sensitivity, reduced blood glucose levels, and reduced systemic inﬂammation, associated with an increase in short-chain fatty acid (SCFA)-producing bac- teria and a reduction in metabolic endotoxemia (Sivadas et al., 2025; Szymczak-Pajor et al., 2025). As a result, we observed positive modulation of incretin hormones such as GLP-1 and improvements in lipid proﬁle and visceral adipo- sity, positioning them as a promising alternative therapeutic complement, though more robust clinical trials in humans are not required (Sharma et al., 2024; Baars et al., 2024; Qin et al., 2025). Therefore, a high-ﬁber diet is a key nutritional intervention in the management of T2DM, as it has the capacity to increa- se microbial diversity and promote the predominance of be- neﬁcial species through the colonic fermentation of soluble and insoluble ﬁbers (Oluwaloni et al., 2023; Sharma et al., 2024; Ng et al., 2024). The resulting short-chain fatty acid (SCFA) production contributes to improved insulin sensitivi- ty, stimulates incretin secretion, strengthens the intestinal ba- rrier, and reduces systemic inﬂammation (Iatcu et al., 2024; Szymczak-Pajor et al., 2025). This dietary pattern modulates bile acid metabolism and the signaling of receptors such as FXR and TGR5, favorably impacting glucose and lipid me- tabolism (Baars et al., 2024). Evidence shows the incorpo- ration of ﬁber-rich diets as a cornerstone of comprehensive Figure 5. Comparison between traditional diet and microbiome-based personalized diet in T2DM.

J. Food Sci. Gastron. (January - June 2026) 4(1): 23-41 38 therapeutic support for T2DM, due to their eﬀectiveness in modulating the gut microbiome and improving the metabolic proﬁle (Zhang, Zhang et al., 2024). Comparison between traditional and microbiome-based personalized diets in patients with T2DM The dietary management T2DM has historically focused on glucose control and the prevention of micro- and macro- vascular complications. Traditionally, this approach is ba- sed on macronutrient control, calorie reduction, and weight management, prioritizing foods with a low glycemic index, unsaturated fats, and high dietary ﬁber intake (Pizarro et al., 2024; Baars et al., 2024). While this has proven clinically eﬀective in improving glycemic, lipid, and anthropometric proﬁles, its application is only standardized and does not consider individual diﬀerences in the composition and func- tion of the gut microbiome, which is now recognized as a relevant factor in the pathophysiology of T2DM (Ng et al., 2024; Szymczak-Pajor et al., 2025). In response to these limitations, a personalized gut mi- crobiome-based diet plan has emerged, suggesting that the diet be tailored to each patient’s speciﬁc microbial proﬁle. This model helps restore gut homeostasis, reduce dysbiosis, and enhance the production of beneﬁcial metabolites, such as short-chain fatty acids (SCFAs), through the strategic use of prebiotics, probiotics, synbiotics, and the targeted selec- tion of fermentable foods (Sharma et al., 2022; Iatcu et al., 2024). Unlike the traditional model, this approach relies on advanced tools such as next-generation sequencing and me- tabolism, allowing for greater precision in the design of indi- vidualized nutritional interventions (Baars et al., 2024; Qin et al., 2025). A comparison of the two sources shows that, while macro- nutrient control is common to other models, the fundamental diﬀerence lies in the degree of individualization and the ex- plicit consideration of the gut microbiome. Personalized diets adjust nutritional ratios based on individual glucose levels, which are inﬂuenced by the microbiota, and prioritize foods that promote beneﬁcial bacteria, such as Biﬁdobacterium or Akkermansia muciniphila, associated with improvements in metabolic health and reduced inﬂammation (Sharma et al., 2022; Iatcu et al., 2024; Ng et al., 2024; Szymczak-Pajor et al., 2025). For example, these strategies can directly control the production of bacterial metabolites, increase SCFAs, and reduce pro-inﬂammatory compounds such as lipopolysac- charide (LPS) (Adeshirlarijaney & Gewirtz, 2020; Zhang et al., 2025). However, we weigh the promising results in glucose con- trol, insulin sensitivity, and the reduction of inﬂammatory markers (Kim et al., 2024; Zhang et al., 2025), as well as the challenges of clinically implementing personalized diets for major diseases, including high cost, comprehensive diag- nostic testing, and limited standardization and evidence of longitudinal robustness (Zhang et al., 2024; Qin et al., 2025). In this context, some traditional diets continue to be based on extensive scientiﬁc evidence, and microbiome-based perso- nalized diets are emerging as a strategy with high therapeutic potential. Their consolidation will depend on the develop- ment of clinical studies that support their eﬃcacy, applica- bility, and cost-eﬀectiveness in the comprehensive treatment of T2DM (Sharma et al., 2022; Qin et al., 2025). Conclusions Modulating the gut microbiome is emerging as a highly promising therapeutic strategy for optimizing the clinical and nutritional management of T2DM. The evidence analyzed conﬁrmed that the gut microbiota plays a central role in re- gulating energy metabolism, insulin sensitivity, and systemic inﬂammatory processes, positioning it as a strategic target for both the prevention and treatment of this disease. In this context, interventions based on probiotics, prebiotics, syn- biotics, and drugs with microbiome-dependent mechanisms have remarkable potential to improve glucose homeostasis, reduce chronic low-grade inﬂammation, and lower the risk of metabolic and cardiovascular complications. This is achie- ved through modulation of the composition and function of the gut ecosystem, strengthening the intestinal barrier, and activating key physiological genes for the gut-pancreas and gut-brain. However, the clinical translation of these ﬁndings does not present signiﬁcant challenges, but it is subject to the need for controlled, longitudinal, and standardized clinical studies that integrate metagenetic analysis with individuali- zed clinical proﬁles. Moving towards a personalized medici- ne approach is fundamental for designing microbiome-based interventions tailored to each patient’s genetic, dietary, lifes- tyle, and microbiological characteristics, thus enabling the development of more eﬀective, safe, and sustainable com- plementary therapies for the overall management of T2DM. References Adeshirlarijaney, A., & Gewirtz, A. T. (2020). Considering gut microbiota in treatment of type 2 diabetes mellitus. Gut Microbes, 11(3), 253–264. https://doi.org/10.1080/ 19490976.2020.1717719 Baars, D. P., Fondevila, M. F., Meijnikman, A. S., & Nieuw- dorp, M. (2024). The central role of the gut microbiota in the pathophysiology and management of type 2 dia- betes. Cell Host & Microbe, 32(8), 1280–1300. https:// doi.org/10.1016/j.chom.2024.07.017 Bi, T., Feng, R., Ren, W., & Zhan, L. (2025). ZiBu PiYin recipe regulates Aβ metabolism and improves diabe- tes-associated cognitive decline. Journal of Ethnophar- macology, 337(Pt 1), 118808. https://doi.org/10.1016/j.

J. Food Sci. Gastron. (January - June 2026) 4(1): 23-41 39 jep.2024.118808 Chen, M., Peng, Y., Hu, Y., Kang, Z., Chen, T., Zhang, Y., & Zhang, W. (2025). A critical role for Phocaeicola vulgatus in negatively impacting metformin response in diabetes. Acta Pharmaceutica Sinica B. https://doi. org/10.1016/j.apsb.2025.02.008 Chiou, W. C., Chang, B. H., Tien, H. H., Cai, Y. L., Fan, Y. C., Chen, W. J., Chu, H. F., Chen, Y. H., & Huang, C. (2021). Synbiotic intervention with an adlay-based pre- biotic and probiotics improved diet-induced metabolic disturbance in mice by modulation of the gut micro- biota. Nutrients, 13(9), 3161. https://doi.org/10.3390/ nu13093161 Cunningham, A. L., Stephens, J. W., & Harris, D. A. (2021). Gut microbiota inﬂuence in type 2 diabetes mellitus (T2DM). Cardiovascular Diabetology, 13(1), 50. ht- tps://doi.org/10.1186/s13099-021-00446-0 Davari, S., Talaei, S. A., Alaei, H., & Salami, M. (2013). Probiotics treatment improves diabetes-induced impair- ment of synaptic activity. Neuroscience, 240, 287–296. https://doi.org/10.1016/j.neuroscience.2013.02.055 Du, Y., Lu, Y., An, Y., & Zheng, J. (2024). Research prog- ress in mechanisms of gut microbiota in diabetic cog- nitive impairment. Chinese Journal of Gerontology, 44(4), 494–500. https://doi.org/10.3969/j.issn.1674- 8115.2024.04.010 Dzięgielewska-Gęsiak, S., Fatyga, E., Piłot, M., Wierzgoń, A., & Muc-Wierzgoń, M. (2022). Are there diﬀerences in gut microbiome in patients with type 2 diabetes treat- ed by metformin or metformin and insulin? Diabetes, Metabolic Syndrome and Obesity, 15, 3589–3599. ht- tps://doi.org/10.2147/DMSO.S377856 Ebrahimi, S., Rezaei-Tavirani, M., & Areﬁ Oskouie, A. (2025). Identiﬁcation of microbiome-derived bio- markers for type 2 diabetes using a machine learning approach. Scientiﬁc Reports, 15(1), 3164. https://doi. org/10.1038/s41598-024-57477-2 Estrella, A., Martínez-Sandoval, M., Rodríguez-González, I., & Pérez-Mendoza, M. J. (2024). Modulation of gut microbiota in prediabetes with linagliptin and metfor- min. Frontiers in Endocrinology, 15, 1313652. https:// doi.org/10.3389/fendo.2024.1313652 Fu, Y., Li, S., Xiao, Y., Liu, G., & Fang, J. (2023). A metab- olite perspective on the involvement of the gut microbi- ota in type 2 diabetes. International Journal of Molec- ular Sciences, 24(19), 14991. https://doi.org/10.3390/ ijms241914991 Gallardo, W. D., & García, M. A. (2024). Junk food: analy- sis of risks, beneﬁts, and social perception. Journal of Food Science and Gastronomy, 2(1), 26-34. https://doi. org/10.5281/zenodo.13996283 Iatcu, O. C., Hamamah, S., & Covasa, M. (2024). Harnessing prebiotics to improve type 2 diabetes outcomes. Nutri- ents, 16(20), 3447. https://doi.org/10.3390/nu16203447 Kim, H. B., Cho, Y. J., & Choi, S. S. (2024). Metformin increases gut multidrug resistance genes in type 2 di- abetes, potentially linked to Escherichia coli. Scientiﬁc Reports, 14(1), 21480. https://doi.org/10.1038/s41598- 024-72467-z Lee, S., Eom, S., Lee, J., & Lee, J. H. (2023). Probiotics that ameliorate cognitive impairment through anti-inﬂam- mation. Korean Journal for Food Science of Animal Resources, 43(4), 612–624. https://doi.org/10.5851/ kosfa.2023.e22 Li, J., Yang, H., Ruan, N., Lin, Y., & Fang, Z. (2024). Causal relationship between intestinal ﬂora and diabetic neu- ropathy. Chinese Journal of Microbiology and Immu- nology, 36(7), 761–768. https://doi.org/10.13381/j.cnki. cjm.202407003 Majait, S., Nieuwdorp, M., Kemper, M., & Soeters, M. (2023). The black box orchestra of gut bacteria and bile acids: Who is the conductor? International Jour- nal of Molecular Sciences, 24(3), 1816. https://doi. org/10.3390/ijms24031816 Martínez-Carrillo, C., Salazar, A. M., Sánchez-Ortiz, M., Pérez-López, R., Ramírez-González, D., Orozco, A. V., et al. (2024). Global metagenomic proﬁling of gut mi- crobiota in type 2 diabetes. BMC Genomics, 25(1), 112. https://doi.org/10.1186/s12864-024-09983-2 Martínez-Carrillo, C., Sánchez-Ortiz, M., Ramírez- González, D., Ramírez-Vargas, G., García-Pérez, R., & Durán-Padilla, M. A. (2024). Impact of carbohydrate consumption on gut microbiota in patients with type 2 diabetes. Nutrients, 16(2), 435. https://doi.org/10.3390/ nu16020435 Meloncelli, N., Capurso, C., De Giuseppe, R., & De Giro- lamo, G. (2023). Diet, gut microbiota and type 2 dia- betes. Nutrients, 15(13), 2861. https://doi.org/10.3390/ nu15132861 Meroni, M., Longo, M., Paolini, E., & Dongiovanni, P. (2025). Cognitive impairment in metabolic dys- function–associated steatotic liver disease. Journal of Advanced Research, 68, 231–240. https://doi.or- g/10.1016/j.jare.2024.02.007 Methley, A. M., Campbell, S., Chew-Graham, C., McNally, R., & Cheraghi-Sohi, S. (2014). PICO, PICOS and SPI- DER. BMC Health Services Research, 14, 579. https:// doi.org/10.1186/s12913-014-0579-0 Mohamed, S. (2024). Metformin: Diverse molecular mechanisms, gastrointestinal eﬀects and overco- ming intolerance in type 2 diabetes mellitus. Me- dicine, 103(43), e40221. https://doi.org/10.1097/ MD.0000000000040221 Murugesan, R., Kumar, J., Leela, K. V., Meenakshi, S., Srivi- jayan, A., Thiruselvam, S., Satheesan, A., & Chaithanya, V. (2025). The role of gut microbiota and bacterial trans- location in the pathogenesis and management of type 2 diabetes mellitus. Physiology & Behavior, 293, 114838.

J. Food Sci. Gastron. (January - June 2026) 4(1): 23-41 40 https://doi.org/10.1016/j.physbeh.2025.114838 Negm, S. H. (2023). Novel therapeutic strategies targe- ting gut microbiota to treat diseases. En Microbiota and human health (pp. 133–141). Wiley. https://doi. org/10.1002/9781119904786.ch12 Ng, C. Y. J., Zhong, L., Ng, H. S., Goh, K. S., & Zhao, Y. (2024). Managing type 2 diabetes mellitus via the regu- lation of gut microbiota: A Chinese medicine perspec- tive. Nutrients, 16(22), 3935. https://doi.org/10.3390/ nu16223935 Oluwaloni, F. O., Yakubu, O. F., Adebayo, A. H., Koyejo, O. D., & Lawal, A. K. (2023). Review of the gut mi- crobiota dynamics in type-2 diabetes mellitus (T2DM): A focus on human-based studies. Tropical Journal of Natural Product Research, 7(6), 3059–3079. https:// doi.org/10.26538/tjnpr/v7i6.2 PPage, M. J., McKenzie, J. E., Bossuyt, P. M., Boutron, I., Hoﬀmann, T. C., Mulrow, C. D., Shamseer, L., Tetzlaﬀ, J. M., Akl, E. A., Brennan, S. E., Chou, R., Glanville, J., Grimshaw, J. M., Hróbjartsson, A., Lalu, M. M., Li, T., Loder, E. W., Mayo-Wilson, E., McDonald, S., Mc- Guinness, L. A., Stewart, L. A., Thomas, J., Tricco, A. C., Welch, V. A., Whiting, P., & Moher, D. (2021). The PRISMA 2020 statement. BMJ, 372, n71. https://doi. org/10.1136/bmj.n71 Palacios, T., Vitetta, L., Coulson, S., Madigan, C. D., Denyer, G. S., & Caterson, I. D. (2017). The eﬀect of a novel probiotic on metabolic biomarkers in adults with predi- abetes and recently diagnosed type 2 diabetes mellitus: Study protocol for a randomized controlled trial. Trials, 18(1), 7. https://doi.org/10.1186/s13063-016-1762-x Pang, S. Q., Luo, Z., Wang, C. C., & Zhang, J. (2020). Eﬀects of Dioscorea polystachya on cognitive function of dia- betic rats. Journal of Integrative Neuroscience, 19(2), 273–283. https://doi.org/10.31083/j.jin.2020.02.69 Pizarro, R. R., de Guzman, M., Gururagavendiran, S., Mari- ados, S. W., Deb, S., & Vivian Allan, R. B. P. (2024). Human microbiome and diabetes. En Advances in clinical chemistry (pp. 69–76). Elsevier. https://doi. org/10.1016/B978-0-443-15435-5.00006-2 Qin, L., Fan, B., Zhou, Y., Zheng, J., Diao, R., Wang, F., & Liu, J. (2025). Targeted gut microbiome therapy: Appli- cations and prospects of probiotics, fecal microbiota transplantation and natural products in the management of type 2 diabetes. Pharmacological Research, 213, 107625. https://doi.org/10.1016/j.phrs.2025.107625 Qu, Q., He, P., Zhang, Y., & Zeng, P. (2024). The interven- tion of probiotics on type 2 diabetes mellitus in animal models. Molecular Nutrition & Food Research, 68(1), e2200815. https://doi.org/10.1002/mnfr.202200815 Razavi, S., Amirmozafari, N., Zahedi Bialvaei, A., Nav- ab-Moghadam, F., Khamseh, M. E., & Alaei-Shahmiri, F. (2024). Gut microbiota composition and type 2 diabe- tes. Heliyon, 10(20), e39464. https://doi.org/10.1016/j. heliyon.2024.e39464 Sato, J., Kanazawa, A., & Watada, H. (2017). Type 2 dia- betes and bacteremia. Diabetes Therapy, 71(1), 17–22. https://doi.org/10.1159/000479919 Sharma, B. R., Jaiswal, S., & Ravindra, P. V. (2022). Mo- dulation of gut microbiota by bioactive compounds for prevention and management of type 2 diabetes. Biome- dicine & Pharmacotherapy, 152, 113148. https://doi. org/10.1016/j.biopha.2022.113148 Sharma, B., Kumar, A., Sharma, U., Pal, D., & Prashar, S. (2022). The potential role of gut microbiota in the pa- thogenesis of type 2 diabetes mellitus via epigenetics and inﬂammasome. Current Pharmaceutical Biotech- nology, 22(14), 1331–1343. https://doi.org/10.2174/18 71530322666220331152809 Sharma, N., Gupta, P. C., Upadhyay, S., & Pathak, K. (2024). Synbiotics and gut microﬂora: Mechanisms and therapeutic rationality and clinical applications for management of type 2 diabetes. En Synbiotics in he- alth and disease (pp. 55–67). CRC Press. https://doi. org/10.1201/9781032702438-4 Sikalidis, A. K., & Maykish, A. (2020). The gut microbiome and type 2 diabetes mellitus: Discussing a complex rela- tionship. Biomedicines, 8(1), 8. https://doi.org/10.3390/ biomedicines8010008 Singh, S., & Bhadauriya, R. (2025). Gut microbiota modu- lation in diabetes and its associated complications. Eu- ropean Journal of Pharmacology, 960, 175713. https:// doi.org/10.1016/j.ejphar.2024.175713 Sivadas, S., Castelino, R. L., Ajila, V., & Jain, Y. (2025). Gut microﬂora: The unheeded factor in type 2 diabetes mel- litus. Romanian Journal of Diabetes, 32(1), 113–118. https://doi.org/10.46389/rjd-2025-1831 Song, S., Zhang, Q., Zhang, L., Zhou, X., & Yu, J. (2024). A two-sample bidirectional Mendelian randomization analysis investigates associations between gut micro- biota and type 2 diabetes mellitus. Frontiers in Endo- crinology, 15, 1313651. https://doi.org/10.3389/fen- do.2024.1313651 Stepanova, N. (2024). Type 2 diabetes mellitus and the gut microbiota: Charting new territory for sodium-glu- cose co-transporter 2 inhibitors. European Journal of Medical Oncology, 8(1), 1–8. https://doi.org/10.14744/ ejmo.2024.53968 Szymczak-Pajor, I., Drzewoski, J., Kozłowska, M., Krekora, J., & Śliwińska, A. (2025). The gut microbiota-related antihyperglycemic eﬀect of metformin. Pharmaceuti- cals, 18(1), 55. https://doi.org/10.3390/ph18010055 Tang, Y., Yan, M., Fang, Z., Jin, S., & Xu, T. (2024). Eﬀects of metformin, saxagliptin and repaglinide on gut micro- biota in diabetic mice. BMJ Open Diabetes Research & Care, 12(3), e003837. https://doi.org/10.1136/bmj- drc-2023-003837 Valencia-Castillo, S. Y., Hernández-Beza, M. J., Powell-Cer-

J. Food Sci. Gastron. (January - June 2026) 4(1): 23-41 41 da, I., Acosta-Cruz, E., Rodríguez-Castillejos, G. C., Siller-López, F., & Martínez-Montoya, H. (2025). Impact of gestational diabetes mellitus in gut and hu- man breast milk microbiome. Revista Argentina de Microbiología, 57(1), 14–23. https://doi.org/10.1016/j. ram.2024.10.006 Zhang, H., Ma, L., Peng, W., Wang, B., & Sun, Y. (2024). Association between gut microbiota and onset of type 2 diabetes mellitus. Frontiers in Cellular and Infection Microbiology, 14, 1327032. https://doi.org/10.3389/ fcimb.2024.1327032 Zhang, K., Zhang, Q., Qiu, H., Ma, Y., Hou, N., Zhang, J., Kan, C., Han, F., Sun, X., & Shia, J. (2024). The com- plex link between the gut microbiome and obesity-as- sociated metabolic disorders. Heliyon, 10(17), e37609. https://doi.org/10.1016/j.heliyon.2024.e37609 Zhang, Y., Wang, A., Zhao, W., Qin, J., Liu, B., Yao, C., Long, J., Yuan, M., & Yan, D. (2025). Microbial succi- nate promotes the response to metformin by upregulat- ing secretory immunoglobulin A in intestinal immunity. Gut Microbes, 17(1), 2450871. https://doi.org/10.1080/ 19490976.2025.2450871 Conﬂicts of interest The authors declare that they have no conﬂicts of interest. Author contributions Conceptualization: Alberto J. Cevallos. Data curation: Alberto J. Cevallos. Formal analysis: Alberto J. Cevallos. Research: Alberto J. Cevallos, Edison H. Arévalo, Mauricio G. Intriago. Methodology: Alberto J. Cevallos. Supervi- sion: Alberto J. Cevallos. Validation: Alberto J. Cevallos. Visualization: Edison H. Arévalo, Mauricio G. Intriago. Writing-original draft: Alberto J. Cevallos, Edison H. Aré- valo, Mauricio G. Intriago. Writing-review & editing: Al- berto J. Cevallos, Edison H. Arévalo, Mauricio G. Intriago. Data availability statement The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request. Statement on the use of AI The authors acknowledge the use of generative AI and AI-assisted technologies to improve the readability and cla- rity of the article. Disclaimer/Editor’s note The statements, opinions, and data contained in all publi- cations are solely those of the individual authors and contri- butors and not of the Journal of Food Science and Gastro- nomy. Journal of Food Science and Gastronomy and/or the edi- tors disclaim any responsibility for any injury to people or property resulting from any ideas, methods, instructions, or products mentioned in the content.