Over the last decades, the incidence of diabetes has increased in developed countries and beyond the genetic impact, environmental factors, which can trigger the activation of the gut immune system, seem to affect the induction of the disease process. Since the composition of the gut microbiome might disturb the normal interaction with the immune system and contribute to altered immune responses, the restoration of normal microbiota composition constitutes a new target for the prevention and treatment of diabetes. Thus, the interaction of gut microbiome and diabetes, focusing on mechanisms connecting gut microbiota with the occurrence of the disorder, is discussed in the present review. Finally, the challenge of functional food diet on maintaining intestinal health and microbial flora diversity and functionality, as a potential tool for the onset inhibition and management of the disease, is highlighted by reporting key animal studies and clinical trials. Early onset of the disease in the oral cavity is an important factor for the incorporation of a functional food diet in daily routine.

Building on the first volume of this Research Topic, Volume II was conceived to deepen understanding of the reciprocal interactions between therapeutic interventions, pharmacological agents, and the gut microbiome in experimentally controlled animal models. Its central objective was not only to document treatment-associated shifts in microbial composition, but also to clarify whether these changes participate in therapeutic efficacy, toxicity, drug disposition, and disease modification. The collection therefore encompasses conventional medicines, traditional formulations, botanical and natural bioactive compounds, complementary physical interventions, probiotics, commensal microorganisms, fecal microbiota transplantation, functional foods, and defined microbial metabolites (Bezirtzoglou et al. 2025).Across its 46 contributions, the Research Topic covers a broad spectrum of gastrointestinal and extraintestinal disorders, including inflammatory bowel disease, metabolic and cardiovascular disease, liver and kidney injury, neurological and behavioral conditions, pulmonary disorders, cancer, reproductive dysfunction, and treatment-induced tissue injury. Collectively, these studies extend the field beyond descriptive taxonomic profiling by integrating microbiome analyses with metabolomics, pharmacokinetics, histopathology, intestinal barrier assessment, immune phenotyping, and pathwayspecific validation. They also highlight recurrent mechanisms involving microbial metabolites, epithelial integrity, inflammatory signaling, oxidative stress, and communication along gut-organ axes. The contributions can consequently be synthesized into five interrelated themes: pharmacological treatments and treatment-associated perturbations; traditional, natural, and complementary interventions; direct microbiota-targeted therapies; gastrointestinal inflammation and barrier dysfunction; and extraintestinal microbiome-mediated mechanisms.The relationship between pharmacological treatments and the gut microbiome is bidirectional. Therapeutic agents can alter microbial community structure, microbial metabolic activity, and intestinal barrier function, potentially contributing to their beneficial or adverse effects. Conversely, the composition and functional capacity of the microbiome may influence drug metabolism, systemic exposure, treatment efficacy, and host physiological responses. The studies grouped in this section illustrate these interactions across antidiabetic therapies, experimental microbiota depletion, pharmacokinetic variability, and treatment-associated tissue injury.Several contributions investigated whether established treatments produce effects extending beyond their canonical pharmacological targets. In mice with diabetic kidney disease, He et al. (2026) showed that empagliflozin improved renal outcomes while modifying gut microbial diversity and community composition.Notably, the baseline microbiota, treatment-associated microbial responses, and correlations between selected taxa and renal or metabolic parameters differed between male and female mice. These results identify biological sex as a potentially important source of heterogeneity in microbiome-associated therapeutic responses. However, because the microbial findings were primarily correlational, additional experiments are needed to determine whether these changes contributed directly to renoprotection or accompanied improvements in the underlying disease.Similarly, Chang et al. (2025) reported that sitagliptin partially restored microbial diversity and shifted the microbial profile of diabetic rats toward that observed in healthy controls. Treatment also modified predicted microbial functions, promoted short-chain fatty acid-related activity, increased the expression of the tight-junction protein zonula occludens-1 (ZO-1), and increased the abundance of mucin-secreting goblet cells. These findings connect antidiabetic treatment with a broader microbiotametabolism-intestinal barrier network, although they do not establish whether microbial restoration is a mediator of glycemic improvement or a secondary response to improved metabolic status.A complementary tissue-centered perspective was provided by Silva et al. (2026), who evaluated exogenous melatonin in rats with domperidone-induced hyperprolactinemia. Microscopic, histomorphometric, immunohistochemical, and computational analyses identified structural and proliferative alterations in the stomach, duodenum, and liver. Melatonin modulated body weight and selected duodenal parameters but did not consistently reverse the gastrohepatic alterations associated with hyperprolactinemia. Although this study did not assess the gut microbiome directly, it broadens the collection methodologically by demonstrating the value of organ-level histological and computational analyses when evaluating systemic treatment responses.The reverse influence of the microbiome on pharmacological responses was demonstrated more directly by Xia et al. (2025). Using models of endogenous and ceftriaxone-induced dysbiosis, the authors showed that microbial disruption reduced the oral bioavailability of losartan and its active metabolite.The abundance of Enterococcus faecalis was inversely associated with pharmacokinetic measures of losartan exposure, while complementary in vitro experiments showed that this bacterium could degrade losartan and convert it into E-3179. This study therefore provides direct mechanistic support for pharmacomicrobiomics by showing that specific microbial alterations can contribute to variability in drug disposition.Microbiota-dependent changes in systemic physiology were also examined by Kellenberger et al. (2025). Antibiotic-induced microbiota depletion improved glucose tolerance and increased circulating concentrations of active glucagon-like peptide-1 (GLP-1). The improvement in glucose tolerance was absent in mice lacking the GLP-1 receptor, supporting the involvement of GLP-1...