Journal of Developing Drugs
Open Access

Effects of a Food-Derived GLP-1 Formula on Endogenous GLP-1 Secretion and Appetite Responses: A Randomized Double-Blind Crossover Study

Yung-Kai Lin¹, Shu-Ting Chan², Tony-T. Wu^2,3, Yung-Hsiang Lin³, Lucas Chang³ and Chi-Fu Chiang^{3* *}Correspondence: Chi-Fu Chiang, Department of Food Science, Research and Design Center, TCI CO., Ltd., Taipei, Taiwan, Email:

Author info »

Introduction

Obesity and overweight have become major global public health concerns, with their prevalence continuing to increase over the past several decades. These conditions are strongly associated with the development of metabolic disorders, including type 2 diabetes mellitus, cardiovascular diseases, non-alcoholic fatty liver disease, metabolic syndrome and other chronic diseases [1]. According to the World Health Organization (WHO), more than one billion individuals worldwide are currently affected by obesity [2]. Along with increasing health awareness and consumer demand for body weight management, the global weight management market has expanded rapidly and encompasses pharmaceutical interventions, dietary supplements, functional foods and lifestyle modifications [3]. However, due to the complexity of physiological mechanisms involved in energy balance and appetite regulation, maintaining long-term weight reduction remains challenging even after successful weight loss through dietary restriction and physical activity. Therefore, developing effective, safe and sustainable strategies for body weight management has become an important area of research [4].

Among the physiological pathways involved in body weight regulation, Glucagon-Like Peptide-1 (GLP-1) has received substantial attention due to its important role in energy metabolism and appetite control [5]. GLP-1 is an incretin hormone secreted by intestinal enteroendocrine L-cells following food intake. It stimulates glucose-dependent insulin secretion, suppresses glucagon release, delays gastric emptying and increases satiety, thereby reducing food intake and regulating body weight [6]. In recent years, GLP-1 Receptor Agonists (GLP-1 RAs), such as semaglutide and tirzepatide, have attracted considerable attention due to their remarkable efficacy in promoting weight loss and have emerged as important therapeutic approaches for obesity management [7]. Despite their favorable effects on body weight reduction, GLP-1-based pharmacological interventions present several limitations in clinical practice. Common adverse effects include nausea, vomiting, diarrhea, constipation and gastrointestinal discomfort. Some individuals may also experience increased fatigue or reductions in muscle mass due to excessive appetite suppression [8]. Furthermore, previous studies have reported body weight regain following treatment discontinuation. Long-term administration is also associated with challenges including high treatment costs, injectable administration and reduced patient compliance [9]. Therefore, the development of food-based interventions that safely promote endogenous GLP-1 secretion and are suitable for long-term consumption has become an emerging area of interest in nutritional and functional food research. Recent studies have suggested that food-derived bioactive ingredients, including probiotics and plant extracts, may enhance GLP-1 secretion through modulation of gut microbiota composition, improvement of the intestinal metabolic environment and stimulation of enteroendocrine cell function [10]. Compared with pharmaceutical interventions, food-derived ingredients generally offer advantages including higher safety profiles, suitability for long-term intake and greater consumer acceptance, making them promising candidates for body weight management applications.

The GLP-1 Formula investigated in this study consists of Bifidobacterium breve, rocket apple extract powder and probio-kombu black tea powder, which were selected to potentially promote endogenous GLP-1 secretion through complementary physiological pathways. Bifidobacterium breve has been reported to modulate gut microbial composition and metabolic function, while promoting the production of Short-Chain Fatty Acids (SCFAs), including acetate and butyrate [11]. These metabolites can activate Free Fatty Acid Receptors (FFAR2/3) expressed on intestinal L-cells, thereby stimulating GLP-1 secretion [12]. In addition, Bifidobacterium breve may contribute to metabolic regulation by improving intestinal barrier integrity and modulating gut signaling pathways [13]. Rocket apple extract powder contains polyphenols and other bioactive phytochemicals, which have been suggested to influence incretin signaling through modulation of glucose metabolism and gut microbial composition [14]. Furthermore, probio-kombu black tea powder, a fermented plant-derived ingredient rich in tea polyphenols, organic acids and microbial metabolites, has been reported to improve the intestinal microbial environment and promote Short-Chain Fatty Acids (SCFA) production, which may contribute to GLP-1 regulation [15,16]. Since these three bioactive ingredients may exert their effects through different physiological mechanisms, their combination is hypothesized to produce synergistic effects in promoting endogenous GLP-1 secretion and satiety regulation.

Therefore, the present study employed a randomized, double-blind, crossover design to evaluate the effects of the GLP-1 formula on plasma GLP-1 and insulin concentrations, as well as subjective appetite responses in adults with elevated body fat levels and to investigate its potential application as a food-based strategy for promoting endogenous GLP-1 secretion in body weight management.

Material and Methods

Clinical trial design

This clinical study was approved by the Ethics Committee of Antai Medical Care Corporation Antai-Tian-Sheng Memorial Hospital (TSMH IRB No. 25-048-A). The study was registered at Clinicaltrials.gov (NCT07097987). All procedures were performed in accordance with the ethical principles outlined in the Declaration of Helsinki (1964) and its subsequent amendments and written informed consent was obtained from all subjects prior to study initiation after a full explanation of the study procedures. This study was designed as a single-center, randomized crossover clinical trial in which each participant served as his or her own control. The primary objective was to evaluate the effects of a weight management formula dietary supplement on endogenous Glucagon-Like Peptide-1 (GLP-1) secretion and appetite regulation in adults with elevated body fat percentage. Eligible participants were adults aged 18 years-65 years who voluntarily signed informed consent before enrollment and met the inclusion criteria of a body fat percentage of 30%-45% for females and 25%-40% for males, with a Body Mass Index (BMI) ranging from 23-34 kg/m². Female participants were required to be non-pregnant and non-lactating and to use acceptable contraceptive methods throughout the study period. Exclusion criteria included use of GLP-1 receptor agonists (e.g., liraglutide, semaglutide, or dulaglutide), glucose-lowering medications, weight-loss-related drugs or functional foods, probiotics, or gastrointestinal health-related supplements within 30 days before study initiation. Participants with a history of chronic gastrointestinal disorders, seizure disorders or epilepsy, hepatic or renal diseases, malignancies, endocrine disorders, prediabetes or diabetes mellitus, psychiatric illnesses, alcohol or drug abuse, or other major organic diseases were also excluded. Additional exclusion criteria included a history of gastrointestinal surgery, organ transplantation, or other major surgery within the previous three months, history of hypoglycemia, lactose intolerance, chronic diarrhea, acute gastroenteritis within two weeks before enrollment, known allergy to any ingredient of the investigational product and employees or immediate family members of TCI Co., Ltd. Participants underwent blood collection, anthropometric assessments including height, body weight, BMI and body composition analysis, as well as questionnaire completion. Each study session lasted approximately 5 h and participants completed two intervention visits separated by a 7-day washout period to minimize potential carryover effects. Participants were instructed to undergo an overnight fast for at least 8 h before each study visit. Blood samples and study assessments were performed at baseline (prior to consumption of the test product or placebo) and subsequently at 15, 30, 45, 60, 90, 120 and 240 min after ingestion.

Supplement formulation

The GLP-1 Formula was provided as a sachet containing three active ingredients: Bifidobacterium breve TCI761, rocket apple extract powder and probio-kombu black tea powder. The placebo sachet, matched in appearance and sensory characteristics, contained microcrystalline cellulose and flavoring agents.

Measurement of GLP-1 secretion

GLP-1 secretion was quantified using a commercial human GLP-1 sandwich Enzyme-Linked Immunosorbent Assay (ELISA) kit (Elabscience®, Houston, TX, USA; Cat. No. E-EL-H6025) according to the manufacturer’s instructions [17]. Briefly, standards or samples (100 μL per well) were added to antibody-precoated 96-well plates and incubated at 37°C for 90 min. After removal of the liquid, 100 μL of biotinylated detection antibody working solution was added to each well and incubated at 37°C for 60 min, followed by washing three times with wash buffer. Subsequently, 100 μL of streptavidin-Horseradish Peroxidase (HRP) conjugate was added and incubated at 37°C for 30 min and the plate was washed five times. Then, 90 μL of TMB substrate was added to each well and incubated at 37°C for 15 min in the dark. The reaction was stopped by adding 50 μL of stop solution and absorbance was measured immediately at 450 nm using a microplate reader. GLP-1 concentrations were calculated from a standard curve. The assay sensitivity was 0.94 pg/mL, with a detection range of 1.56 pg/mL -100 pg/mL. All samples were assayed in duplicate.

Statistical analysis

The comparison of measurement results for parameters among groups and between groups was analyzed by paired t-test or one-way Analysis of Variance (ANOVA) followed by graphpad prism, as p<0.05 was considered statistical significance.

Results

Baseline characteristics of participants

A total of 15 participants completed the randomized crossover study, including 5 females and 10 males, with a mean age of 33.3 years ± 9.3 years. The baseline characteristics of participants are summarized in Table 1. The mean body weight, Body Mass Index (BMI) and body fat percentage were comparable between the placebo and GLP-1 formula intervention periods. Specifically, body weight was 83.8 kg ± 17.4 kg and 83.7 ± 17.5 kg, BMI was 29.5 ± 5.0 and 29.4 kg/m² ± 5.0 kg/m² and body fat percentage was 34.7% ± 6.7% and 35.1% ± 6.6% in the placebo and GLP-1 formula periods, respectively. Similarly, fasting biochemical parameters, including fasting glucose, insulin, liver function markers, (Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT)), renal function markers (Blood Urea Nitrogen (BUN) and creatinine), triglycerides and total cholesterol, were generally comparable between treatment periods. No substantial differences in baseline characteristics were observed between intervention periods, suggesting adequate participant randomization and baseline comparability.

Note: Data are presented as mean ± Standard Deviation (SD); BMI: Body Mass Index; AST: Aspartate Aminotransferase; ALT: Alanine Aminotransferase; BUN: Blood Urea Nitrogen

Table 1: Baseline characteristics of participants.

Effects of food-derived GLP-1 formula on plasma GLP-1 responses

As shown in figure 1A, participants receiving the food-derived GLP-1 formula exhibited positive changes in plasma GLP-1 concentrations across most post-intake time points, whereas the placebo group demonstrated a progressive decline below baseline values throughout the study period. The GLP-1 formula induced an early increase in circulating GLP-1 levels, reaching the highest increase at 15 min after ingestion (+7.92 pg/mL), followed by sustained elevations at 30 min (+3.71 pg/mL), 45 min (+3.43 pg/mL), 60 min (+1.36 pg/mL), 90 min (+2.46 pg/mL) and 240 min (+1.99 pg/mL). Significant differences between the GLP-1 formula and placebo groups were observed at multiple time points, including 15, 45, 90, 120 and 240 min (p<0.05). Similarly, figure 1B illustrates the relative plasma GLP-1 responses normalized to baseline values. Compared with placebo, the food-derived GLP-1 formula consistently demonstrated higher circulating GLP-1 levels throughout the post-intake period. The greatest increase was observed at 15 min, reaching 1.38-fold of baseline and corresponding to a 43% increase compared with placebo. Relative increases of 21%, 36%, 24%, 44%, 23% and 50% were observed at 30, 45, 60, 90, 120 and 240 min, respectively. Notably, elevated GLP-1 responses remained detectable at the late phase (240 min), suggesting a sustained effect of the food-derived GLP-1 formula on endogenous GLP-1 secretion.

Figure 1: Effects of the food-derived GLP-1 formula on plasma GLP-1 levels. (1A): Change in plasma GLP-1 levels from baseline (pg/ mL) following ingestion of the placebo or GLP-1 formula over a 240-min observation period; (1B): Plasma GLP-1 levels expressed as fold changes relative to baseline values following ingestion of the placebo or GLP-1 formula. Data are presented as mean ± SD. Statistical significance versus baseline is indicated as *p<0.05, ** p<0.01, and ***p<0.001. Statistical significance compared with the placebo group is indicated as #p<0.05 and ##p<0.01.

Effects of food-derived GLP-1 formula on plasma insulin responses

As shown in figure 2A, participants receiving the food-derived GLP-1 formula exhibited an early increase in plasma insulin concentrations following intake, whereas insulin levels in the placebo group gradually declined throughout the observation period. The greatest increase from baseline was observed at 15 min after ingestion (+2.01 μU/mL), followed by relatively stable responses at 30 min (+0.72 μU/mL) and 60 min (+0.14 μU/mL). In contrast, placebo administration demonstrated progressively reduced insulin levels below baseline values at later time points. Significant differences between the GLP-1 formula and placebo groups were observed at 240 min (p<0.05).

As illustrated in figure 2B, relative insulin responses normalized to baseline values consistently remained higher in the GLP-1 formula group compared with placebo during the post-intake period. The greatest relative increase was observed at 15 min, reaching 1.21-fold of baseline and corresponding to a 21% increase compared with placebo. Relative increases of 14%, 12%, 19%, 21%, 5% and 14% were observed at 30, 45, 60, 90, 120 and 240 min, respectively. The insulin response pattern generally paralleled the observed increase in plasma GLP-1 concentrations, suggesting that the food-derived GLP-1 formula may influence endogenous insulin responses following intake.

Figure 2: Effects of the food-derived GLP-1 formula on insulin responses. (2A): Change in insulin levels from baseline (uU/mL) following ingestion of the placebo or GLP-1 formula over a 240-min observation period; (2B): Insulin levels expressed as fold changes relative to baseline values following ingestion of the placebo or GLP-1 formula. Data are presented as mean ± SD. Statistical significance versus baseline is indicated as *p<0.05, **p<0.01, and ***p<0.001. Statistical significance compared with the placebo group is indicated as #p<0.05.

Effects of food-derived GLP-1 formula on food craving and appetite responses

As shown in Figure 3A, subjective food craving scores decreased following intake in both groups; however, participants receiving the food-derived GLP-1 formula exhibited a greater reduction compared with placebo. At 120 min, craving scores decreased to 64.1% in the GLP-1 formula group compared with 74.2% in the placebo group, corresponding to a 10.1% greater reduction. At 240 min, craving scores remained lower in the GLP-1 formula group (74.8%) compared with the placebo group (89.9%), representing a 15.1% lower score. These findings suggest that the food-derived GLP-1 formula exerted a sustained effect on reducing food craving responses.

Similarly, figure 3B illustrates the changes in subjective appetite scores following intake. Compared with placebo, participants receiving the food-derived GLP-1 formula demonstrated consistently lower appetite scores throughout the post-intake period. At 120 min, appetite scores decreased to 73.5% in the GLP-1 formula group compared with 78.7% in the placebo group, corresponding to a 5.2% greater reduction. At 240 min, appetite scores remained lower in the GLP-1 formula group (80.4%) than in the placebo group (96.8%), representing a 16.4% reduction. These findings indicate that the food-derived GLP-1 formula may contribute to sustained appetite suppression during the observation period.

Figure 3: Subjective questionnaire-based evaluation of craving and appetite following ingestion of the food-derived GLP-1 formula. (3A): Changes in craving severity (%) assessed using a subjective questionnaire at baseline, 120 min, and 240 min following ingestion of the placebo or GLP-1 formula. Higher scores indicate a stronger desire for specific foods; (3B): Changes in appetite severity (%) assessed using a subjective questionnaire at baseline, 120 min, and 240 min following ingestion of the placebo or GLP-1 formula. Higher scores indicate a greater overall desire to eat. Data are presented as mean ± SD. Statistical significance versus baseline is indicated as *p<0.05 and **p<0.01.

Discussion

The present randomized crossover study demonstrated that consumption of the food-derived GLP-1 formula enhanced endogenous GLP-1 secretion and was accompanied by increased insulin responses and reduced subjective appetite and food craving in adults with elevated body fat levels. Compared with placebo treatment, the GLP-1 formula induced an earlier increase in circulating GLP-1 concentrations and maintained elevated responses throughout the observation period. The parallel changes observed in GLP-1, insulin and appetite-related outcomes suggest that this food-derived formulation may regulate multiple physiological pathways associated with enteroendocrine signaling and energy homeostasis. A notable finding of this study was that increased GLP-1 responses were observed not only during the early post-intake period but also persisted into later time points. Physiologically, GLP-1 secretion after nutrient intake is generally characterized by biphasic regulation [18]. The early phase is largely associated with rapid nutrient sensing and neuroendocrine signaling, whereas sustained or late-phase responses are believed to be associated with intestinal fermentation processes, gut microbial metabolites and prolonged stimulation of enteroendocrine cells [19]. Therefore, the sustained elevation observed in this study may indicate that the GLP-1 formula simultaneously influences both rapid and delayed regulatory mechanisms. From a comparative market perspective, currently available food-derived GLP-1-support products generally rely on ingredients such as dietary fibers, probiotic blends, polyphenol-rich plant extracts, or appetite-control ingredients [20]. Most commercially available ingredients primarily report indirect outcomes, including reductions in hunger scores, calorie intake, or body weight changes, whereas relatively few have demonstrated direct increases in circulating GLP-1 concentrations in human studies [21]. Reported food-based interventions commonly show modest changes in appetite parameters or short-term satiety responses; however, direct endocrine responses are frequently inconsistent and often transient [22]. In contrast, the present food-derived GLP-1 formula demonstrated an increase in circulating GLP-1 responses of approximately 50% compared with placebo, accompanied by an approximately 21% increase in insulin responses and reductions of approximately 15%-16% in appetite- and craving-related scores. Notably, elevated GLP-1 responses remained detectable at 240 min after intake, suggesting a sustained endocrine effect rather than a short-lived response. The ability to simultaneously induce endocrine changes and subjective appetite modulation may provide a distinct advantage over many currently available foodgrade GLP-1-support products, which frequently focus on a single physiological endpoint.

The enhanced GLP-1 secretion observed in this study may involve several complementary mechanisms associated with Bifidobacterium breve, rocket apple extract powder and probio-kombu black tea powder. Beyond Short-Chain Fatty Acid (SCFA)-mediated pathways, Bifidobacterium breve may influence bile acid metabolism and thereby regulate GLP-1 secretion [23]. Gut microbiota can convert primary bile acids into secondary bile acids, which subsequently activate Takeda G-protein-coupled Receptor 5 (TGR5) expressed on intestinal L-cells. Activation of TGR5 increases intracellular Cyclic Adenosine Monophosphate (cAMP) levels and stimulates GLP-1 release [24]. Additionally, B. breve may improve intestinal barrier integrity and reduce circulating Lipopolysaccharide (LPS) exposure [25]. Since chronic low-grade inflammation has been associated with impaired enteroendocrine function, reducing intestinal inflammatory burden may indirectly improve L-cell responsiveness [26]. Rocket apple extract powder may contribute through mechanisms beyond antioxidant effects. Apple-derived polyphenols have been reported to influence intestinal glucose handling by modulating Sodium-Glucose Cotransporter-1 (SGLT1) and Glucose Transporter-2 (GLUT2) activity [27,28]. Altered glucose transport dynamics within the intestinal lumen may prolong nutrient exposure and stimulation of enteroendocrine cells. Furthermore, polyphenol-derived metabolites may activate AMP-Activated Protein Kinase (AMPK), which plays a central role in cellular energy sensing and metabolic regulation [6,29]. Activation of AMPK has been associated with improved metabolic function and may indirectly support incretin secretion and nutrientresponsive signaling pathways [30]. Probio-kombu black tea powder may further contribute through modulation of the intestinal metabolic environment [31]. Fermentation-derived metabolites, tea polyphenols and organic acids have been reported to alter gut microbial activity and enhance intestinal fermentation capacity [32]. Such alterations may increase the production of bioactive metabolites and improve communication between the intestine and neuroendocrine systems. Previous evidence suggests that microbial metabolites may activate vagal afferent pathways and influence satiety signaling through the gut-brain axis [33]. Therefore, the sustained GLP-1 responses observed in this study may result from synergistic interactions among microbial regulation, nutrient sensing and neuroendocrine communication.

The increase in insulin responses observed in the present study may be explained by activation of the enteroinsular axis following increased endogenous GLP-1 secretion. Upon binding to GLP-1 receptors on pancreatic β-cells, intracellular cAMP signaling is activated and subsequently stimulates Protein Kinase A (PKA) and exchange protein directly activated by cAMP [34]. These signaling cascades promote closure of ATP-sensitive potassium channels, membrane depolarization, calcium influx and insulin granule exocytosis. In addition to GLP-1-mediated signaling, microbial metabolites and polyphenol-derived compounds may also improve insulin sensitivity through reduction of oxidative stress and modulation of PI3K/Akt signaling pathways [35,36]. Therefore, the increased insulin responses observed in this study may result from both direct incretin effects and broader metabolic improvements. The reduction in appetite and food craving observed in this study may also be associated with multiple mechanisms beyond increased GLP-1 secretion alone [37]. GLP-1 is known to delay gastric emptying and prolong gastric distension, thereby enhancing peripheral satiety signaling [38]. In addition, GLP-1 receptors are highly expressed in appetite-regulating brain regions, including the hypothalamus, where GLP-1 signaling can increase Proopiomelanocortin/Cocaine- and Amphetamine-Regulated Transcript (POMC/CART) neuronal activity and suppress Neuropeptide Y/Agouti-Related Peptide (NPY/AgRP) pathways [39]. Gut microbiota-derived metabolites may additionally influence secretion of appetite-related hormones such as Peptide YY (PYY) and ghrelin, further contributing to appetite regulation through gut-brain communication [40].

Limitations

Several limitations should be acknowledged in this study. First, the relatively small sample size may limit generalizability to larger populations. Second, the present study evaluated acute responses over a relatively short observation period; therefore, long-term effects on body weight reduction, body composition changes and metabolic outcomes remain uncertain. Third, biomarkers related to appetite and metabolic regulation, including PYY, ghrelin, leptin, gastric emptying parameters, bile acid profiles and gut microbiota alterations, were not measured. Finally, because this study evaluated a multi-component formulation, the relative contribution of each ingredient to the observed effects could not be determined. Future studies incorporating longer intervention periods, larger populations and mechanistic analyses involving gut microbiota and additional endocrine biomarkers are warranted to further elucidate the physiological effects and clinical relevance of this food-derived GLP-1 formula.

Conclusion

The present study demonstrated that the food-derived GLP-1 formula promoted endogenous GLP-1 secretion and was associated with increased insulin responses and reduced appetite-related outcomes in adults with elevated body fat levels. These effects may involve multiple physiological mechanisms related to intestinal metabolic signaling, enteroendocrine regulation and gut–brain communication. Given the rapidly growing consumer demand for weight management and metabolic health solutions, particularly in the post-GLP-1 era, foodderived approaches that support endogenous GLP-1 secretion may offer advantages including improved safety, convenience and suitability for long-term use. Therefore, the food-derived GLP-1 formula may have potential applications in functional foods, dietary supplements and personalized nutrition products targeting appetite management and metabolic wellness.

Declaration of Competing Interests

The authors disclose no potential conflicts of interest related to the research, authorship and publication of this article.

Acknowledgments

Thanks to all the subjects and related assistants who participated in the trial.

References

1. Ahmed SK, Mohammed RA. Obesity: Prevalence, causes, consequences, management, preventive strategies and future research directions. Metabol Open. 2025;27:100375.

   [Crossref] [Google Scholar] [PubMed]

2. Ahmed SK, Mohammed RA. Obesity: Prevalence, causes, consequences, management, preventive strategies and future research directions. Metabolism Open. 2025;27:100375.

   [Crossref] [Google Scholar] [PubMed]

3. Djaoudene O, Romano A, Bradai YD, Zebiri F, Ouchene A, Yousfi Y, et al. A global overview of dietary supplements: regulation, market trends, usage during the covid-19 pandemic and health effects. Nutrients. 2023;15(15):3320.

   [Crossref] [Google Scholar] [PubMed]

4. Adeola OL, Haglin JM, Khan M, Bhat A, Hussain N, Shahid S, et al. The effectiveness of nutritional strategies in the treatment and management of obesity: A systematic review. Cureus. 2023;15(9):45518.

   [Crossref] [Google Scholar] [PubMed]

5. Zheng Z, Yang Y, Zhang Y, Wang C, Wang Y, Li X, et al. Glucagon-like peptide-1 receptor: Mechanisms and advances in therapy. Signal Transduct Target Ther. 2024;9(1):234.

   [Crossref] [Google Scholar] [PubMed]

6. Müller TD, Finan B, Bloom SR, D'Alessio D, Drucker DJ, Flatt PR, et al. Glucagon-like peptide 1 (GLP-1). Mol metab. 2019;30:72-130.

   [Crossref] [Google Scholar [PubMed]

7. Hammad BF, Al Khairi I, Al-Hakim M, Alhajri N, Al-Mulla F, Abubaker J, et al. Exploring the multifaceted roles of GLP-1 receptor agonists: A comprehensive review. Front Clin Diabetes Healthc. 2025;6:1590530.

   [Crossref] [Google Scholar] [PubMed]

8. Takrori E, Peshin S, Singal S. Gastrointestinal adverse effects of anti-obesity medications in non-diabetic adults: A systematic review. Medicina (Kaunas). 2025;61(11):1922.

   [Crossref] [Google Scholar] [PubMed]

9. Kolli RT, Shah K, Kakkera K, Reddy N, Pabbathi S, Gopireddy D, et al. Rebound or retention: A meta-analysis of weight regain after the discontinuation of glucagon-like peptide-1 (glp-1) receptor agonists and other anti-obesity drugs. Cureus. 2025;17(10):94926.

   [Crossref] [Google Scholar] [PubMed]

10. Kanbay M, Demiray A, Afsar B, Covic A, Ortiz A, Kalantar-Zadeh K, et al. Gut microbiota modulation in GLP-1RA and SGLT-2i therapy: Clinical implications and mechanistic insights in type 2 diabetes. Clin Kidney J. 2025;18(12):351.

    [Crossref] [Google Scholar] [PubMed]

11. Rivière A, Selak M, Lantin D, Leroy F, De Vuyst L. Bifidobacteria and butyrate-producing colon bacteria: Importance and strategies for their stimulation in the human gut. Front Microbiol. 2016;7:979.

    [Crossref] [Google Scholar] [PubMed]

12. Mishra SP, Karunakar P, Taraphder S, Yadav H. Free fatty acid receptors 2 and 3 as microbial metabolite sensors to shape host health: Pharmacophysiological view. Biomedicines. 2020;8(6):154.

    [Crossref] [Google Scholar] [PubMed]

13. Gavzy SJ, Hsiao EY, Tseng CH. Bifidobacterium mechanisms of immune modulation and tolerance. Gut Microbes. 2023;15(2):2291164.

    [Crossref] [Google Scholar] [PubMed]

14. Cano R, Marín-García PJ, González-Muniesa P, Milagro FI, Martínez JA. Dietary polyphenols and gut microbiota cross-talk: molecular and therapeutic perspectives for cardio metabolic disease: A narrative review. Int J Mol Sci. 2024;25(16):8863.

    [Crossref] [Google Scholar] [PubMed]

15. Zhang R, Wang Y, Li Y, Chen X, Zhao J, Liu Z, et al. Harnessing the power of fermented tea to improve gut microbiota and combat obesity epidemic. Biology (Basel). 2024;13(10):801.

    [Crossref] [Google Scholar] [PubMed]

16. Zhang JM, Sun YS, Zhao LQ, Chen TT, Fan MN, Jiao HC, et al. Scfas-induced glp-1 secretion links the regulation of gut microbiome on hepatic lipogenesis in chickens. Front Microbiol. 2019;10:2176.

    [Crossref] [PubMed]

17. Baran O, Gundogdu R, Akbaş A, Çelik F, Arslan A, Turgut M, et al. The association between calreticulin and glucagon-like peptide-1 expressions with prognostic factors in high-grade gliomas. J Cancer Res Ther. 2024;20(1):25-32.

    [Crossref] [Google Scholar] [PubMed]

18. Lim GE, Brubaker PL. Glucagon-Like Peptide 1 secretion by the L-cell: The view from within. Diabetes. 2006;55(2):70-77.

    [Crossref] [Google Scholar]

19. Su Khin KL, Yeo GS, Khoo CM, et al. Emerging role of taste receptors, entero-endocrine cells in type 2 diabetes and metabolic disorders. Nutrients. 2026;18(5).

    [Crossref] [Google Scholar] [PubMed]

20. Mozaffarian D, Kushner RF, Stanford FC, Apovian CM, Hand RK, Fitch AK, et al. Nutritional priorities to support glp-1 therapy for obesity: A joint advisory from the american college of lifestyle medicine, the american society for nutrition, the obesity medicine association and the obesity society. Am J Lifestyle Med. 2025:15598276251344827.

    [Crossref] [Google Scholar] [PubMed]

21. Mozaffarian D, Kushner RF, Stanford FC, Apovian CM, Hand RK, Fitch AK, et al. Nutritional priorities to support glp-1 therapy for obesity: A joint advisory from the american college of lifestyle medicine, the american society for nutrition, the obesity medicine association, and the obesity society. Obes Pillars. 2025;15:100181.

    [Crossref] [Google Scholar] [PubMed]

22. Holliday A, Ronn PF, Wewer Albrechtsen NJ, Holst JJ, Rehfeld JF, Hansen M, et al. Appetite-related gut hormone responses to feeding across the life course. J Endocr Soc. 2025;9(2):223.

    [Crossref] [Google Scholar] [PubMed]

23. Chen K, Wang X, Liu Y, Zhang H, Li J, Zhao Y, et al. Common mechanisms of gut microbe-based strategies for the treatment of intestine-related diseases: Based on multi-target interactions with the intestinal barrier. Cell Commun Signal. 2025;23(1):288.

    [Crossref] [Google Scholar] [PubMed]

24. Lin X, Zhang Y, Wang H, Liu J, Chen Z, Li Y, et al. Crosstalk between bile acids and intestinal epithelium: Multidimensional roles of farnesoid x receptor and takeda G protein receptor 5. Int J Mol Sci. 2025;26(9).

    [Crossref] [Google Scholar] [PubMed]

25. Li J, Zhang Y, Zhang X, Wang Y, Liu H, Chen Y, et al. Bifidobacterium: A probiotic for the prevention and treatment of depression. Front Microbiol. 2023;14:1174800.

    [Crossref] [Google Scholar] [PubMed]

26. Peuhkuri K, Vapaatalo H, Korpela R. Even low-grade inflammation impacts on small intestinal function. World J Gastroenterol. 2010;16(9):1057-1062.

    [Crossref] [Google Scholar] [PubMed]

27. Prpa E, Corpe C, Hall W. Acute effects of apple extracts with different polyphenol compositions on glucose transport in human intestinal cell line Caco-2/TC7. Proc Nutr Soc. 2020;79.

    [Crossref] [Google Scholar]

28. Schulze C, Bangert A, Kottra G, Geillinger KE, Schwanck B, Vollert H, et al. Inhibition of the intestinal Sodium-Coupled Glucose Transporter 1 (SGLT1) by extracts and polyphenols from apple reduces postprandial blood glucose levels in mice and humans. Mol Nutr Food Res. 2014;58(9):1795-1808.

    [Crossref] [Google Scholar] [PubMed]

29. Liang Q, Wang Y, Zhang Y, Li J, Liu X, Chen Z, et al. Targeting the AMP-activated protein kinase pathway: The active metabolites of botanical drugs represent potential strategies for treating metabolic-associated fatty liver disease. Front Pharmacol. 2025;16:1681880.

    [Crossref] [Google Scholar] [PubMed]

30. Viollet B, Andreelli F. AMP-activated protein kinase and metabolic control. Handb Exp Pharmacol. 2011;(203):303-330.

    [Crossref] [Google Scholar] [PubMed]

31. Costa MAC, Mota JF, Silva FM, Bressan J, Alfenas RCG, Volp ACP, et al. Regular consumption of black tea kombucha modulates the gut microbiota in individuals with and without obesity. J Nutr. 2025;155(5):1331-1349.

    [Crossref] [Google Scholar] [PubMed]

32. Luo C, Zou L, Sun H, Peng J, Gao C, Bao L, et al. Interactions between gut microbiota and polyphenols: New insights into the treatment of fatigue. Molecules. 2022;27(21):7387.

    [Crossref] [Google Scholar] [PubMed]

33. Wang SZ, Yu YJ, Adeli K. Role of gut microbiota in neuroendocrine regulation of carbohydrate and lipid metabolism via the microbiota-gut-brain-liver axis. Microorganisms. 2020;8(4):527.

    [Crossref] [Google Scholar] [PubMed]

34. Austin G, Tomas A. Signaling architecture of the glucagon-like peptide-1 receptor. J Clin Invest. 2026;136(2).

    [Crossref] [Google Scholar] [PubMed]

35. Al-Noshokaty TM, El-Mesallamy HO, El-Ashmawy NE, Abdel-Moneim A, El-Hawary SS, Abdallah HM, et al. Unlocking the multifaceted roles of GLP-1: Physiological functions and therapeutic potential. Toxicol Rep. 2025;14:101895.

    [Crossref] [Google Scholar] [PubMed]

36. Williamson G, Sheedy K. Effects of polyphenols on insulin resistance. Nutrients. 2020;12(10):3135.

    [Crossref] [Google Scholar] [PubMed]

37. Krug I, Treasure J, Hibbs R, Hart S, Bryant E, Brown A, et al. Beyond weight loss: GLP-1 usage and appetite regulation in the context of eating disorders and psychosocial processes. Nutrients. 2025;17(23).

    [Crossref] [Google Scholar] [PubMed]

38. Shankar A, Nwafor IA, Mikhail GW, Patel N, Kharbanda RK, Channon KM, et al. GLP-1 receptor agonists and delayed gastric emptying: Implications for invasive cardiac interventions and surgery. Cardiovasc Endocrinol Metab. 2025;14(1):00321.

    [Crossref] [Google Scholar] [PubMed]

39. Geloneze B, de Lima-Junior JC, Velloso LA. Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RAs) in the brain-adipocyte axis. Drugs. 2017;77(5):493-503.

    [Crossref] [Google Scholar] [PubMed]

40. Yu M, Yu B, Chen D. The effects of gut microbiota on appetite regulation and the underlying mechanisms. Gut Microbes. 2024;16(1):2414796.

    [Crossref] [Google Scholar] [PubMed]