Interactions between Glucagon-Like Peptide-1 and the Gut Microbiota in Metabolic Disorders

AUTHOR: Sara Kralj, MSc, Master in Nutrition

The gut-endocrine system represents a key link between diet, metabolism, and the microbiota. Enteroendocrine L-cells of the gut respond to the presence of nutrients and microbial metabolites by secreting hormones that influence glucose homeostasis, appetite, and energy metabolism¹. Among these hormones, glucagon-like peptides (GLP-1 and GLP-2) play a central role in communication between the gut and other organ systems. These hormones act via specific G-protein-coupled receptors (GLP-1R and GLP-2R), which are differentially distributed across tissues, determining their physiological function².

GLP-1 – role in metabolic regulation

Glucagon-like peptide-1 (GLP-1) is a 30-amino-acid hormone secreted from enteroendocrine L-cells in response to nutrient intake, especially glucose. Two bioactive forms exist (GLP-1₇₋₃₇ and GLP-1₇₋₃₆ amide), and their secretion is stimulated by dietary components in the proximal gut as well as by microbial metabolites in distal gut regions, such as short-chain fatty acids (SCFAs), indoles, and bile acids^3,4. In this way, the microbiota participates in the regulation and prolonged secretion of GLP-1 and peptide YY (PYY) after meals, maintaining postprandial homeostasis¹.

GLP-1 exerts multiple metabolic effects. It stimulates insulin synthesis and secretion in pancreatic β-cells while simultaneously inhibiting glucagon secretion, contributing to improved glucose homeostasis. By acting on the gastrointestinal tract, it slows gastric emptying and reduces gastric acid secretion, thereby lowering postprandial glycemia and enhancing satiety^1,5.

GLP-1 actions are mediated through specific GLP-1 receptors (GLP-1R) located in the pancreas, central nervous system (hypothalamus, brainstem, mesolimbic system), and peripheral tissues such as muscle and adipose tissue. Activation of GLP-1R in the brain reduces appetite, while in muscle and adipose tissue, GLP-1R agonists promote glucose uptake via AMP-activated protein kinase (AMPK) activation and GLUT-4 translocation, mimicking insulin effects. GLP-1R agonists (e.g., exenatide, liraglutide) also exert cytoprotective effects, promoting proliferation and reducing apoptosis of pancreatic β-cells, thereby preserving their function and improving insulin sensitivity¹.

Endogenous GLP-1 is rapidly degraded by dipeptidyl peptidase-4 (DPP-4), but part of its effect is mediated via vagal afferent nerves. Vagus nerve activation (n. vagus) is critical for GLP-1’s anorectic and incretin effects, as vagotomy abolishes GLP-1-induced appetite suppression. This connection, known as the neuroendocrine-incretin effect, links peripheral and central GLP-1 actions in regulating food intake and glucose metabolism^1,6.

In conclusion, GLP-1 represents a central regulator of glycemic control and appetite, with its actions arising from a complex interplay between the gut, microbiota, endocrine cells, and nervous system.

GLP-2 – role in maintaining gut integrity

GLP-2, secreted concurrently with GLP-1 in approximately equal ratios, acts primarily locally in the gut via GLP-2 receptors (GLP-2R). Its main functions include stimulating crypt cell proliferation, promoting intestinal mucosal growth, and epithelial regeneration^7,8,9,10,11. Through these effects, GLP-2 contributes to the maintenance of gut barrier integrity and reduced intestinal permeability, indirectly supporting systemic metabolic balance and immune homeostasis².

Impact of the gut microbiota on GLP-1

The gut microbiota significantly influences the secretion and activity of GLP-1. Microbial metabolites such as short-chain fatty acids (SCFAs), indoles, and secondary bile acids stimulate L-cells to secrete GLP-1 while simultaneously improving the sensitivity of target tissues to insulin and insulin signaling. Dysbiosis, defined as an imbalance in the microbiota composition, is associated with altered GLP-1 responses, reduced secretion, and the development of metabolic disorders such as insulin resistance, fatty liver, and obesity^1,5.

At the level of the gut barrier, GLP-1 reduces intestinal permeability and bacterial translocation, thereby contributing to gut integrity preservation and reduction of systemic inflammation associated with metabolic disorders. In energy metabolism, GLP-1 promotes lipolysis and energy expenditure, enhances glycogen storage in the liver, and reduces hepatic glucose output. Its effects on the central nervous system manifest as appetite suppression in the hypothalamus and increased satiety, contributing to decreased food intake and body weight regulation⁵.

Microbial metabolites in GLP-1 secretion control

The secretion of GLP-1 from enteroendocrine L-cells results from a complex network of interactions between dietary components, microbial metabolites, and endocrine signaling. The gut microbiota produces numerous bioactive molecules that directly or indirectly regulate L-cell function, thereby influencing glucose homeostasis, appetite, and body weight⁵.

Short-chain fatty acids (SCFAs), such as acetate, propionate, and butyrate, are key microbial metabolites generated through the fermentation of indigestible dietary fibers in the colon. Since the human genome encodes fewer than 20 enzymes capable of digesting complex carbohydrates, a significant portion of polysaccharides reaches the colon undigested, where the microbiota degrades them via carbohydrate-active enzymes¹². This process results in high SCFA concentrations precisely in gut regions abundant in L-cells, highlighting the physiological significance of this local interaction. Over 90% of SCFAs are absorbed by the intestinal epithelium or further metabolized by the microbiota, while the remainder acts locally on L-cells through free fatty acid receptors GPR43 (FFAR2) and GPR41 (FFAR3)^5,13. Activation of these receptors increases intracellular calcium, promoting GLP-1 and peptide YY (PYY) secretion. Notably, reduced SCFA production or fermentation capacity is linked to metabolic diseases, including type 2 diabetes, further underscoring their role in metabolic regulation^5,14,15.

Secondary bile acids (BAs) also act as important signaling molecules in GLP-1 regulation. Primary bile acids, cholic acid (CA) and chenodeoxycholic acid (CDCA), synthesized in the liver, undergo microbial conversion into secondary forms – lithocholic acid (LCA) and deoxycholic acid (DCA). Since these transformations depend on bacterial activity, changes in gut microbiota composition can significantly affect the quantity and ratio of secondary BAs. Secondary BAs exhibit dual regulatory effects on GLP-1 secretion: they activate the Takeda G-protein-coupled receptor 5 (TGR5) on L-cell surfaces, stimulating GLP-1 release^16,17, but can also exert inhibitory effects via farnesoid X receptor (FXR) activation, reducing hormone synthesis and secretion^18,19. This establishes a fine balance between stimulatory and inhibitory signals depending on bile acid type and concentration.

In addition to SCFAs and bile acids, other microbial metabolites modulate GLP-1 secretion. 2-Oleoyl glycerol (2-OG), derived from dietary fat digestion, activates GPR119 receptors on L-cells, while indoles, products of bacterial tryptophan metabolism, also stimulate GLP-1 secretion. Lipopolysaccharides (LPS), components of gram-negative bacterial cell walls, can further activate GLP-1 secretion via Toll-like receptor 4 (TLR4), linking microbial signaling to metabolic and inflammatory processes⁵.

Overall, these complex mechanisms demonstrate that GLP-1 secretion is closely associated with gut microbiota activity. Metabolites such as SCFAs and secondary bile acids serve as key signaling molecules in the microbiota-host communication, mediating interactions between nutrient intake, microbial fermentation, and endocrine responses. Maintaining a balanced gut microbiota and optimal metabolite production is therefore a fundamental factor in preventing and managing metabolic disorders associated with impaired GLP-1 signaling⁵.

Impact of prebiotics and probiotics on GLP-1 Secretion

Prebiotics and probiotics play an important role in modulating the gut microbiota and stimulating the secretion of intestinal peptides, including glucagon-like peptide-1 (GLP-1) and peptide YY (PYY). Their effects are based on improving gut barrier integrity, modulating immune responses, and influencing microbial metabolites such as short-chain fatty acids (SCFAs) and bile acids, which directly stimulate enteroendocrine cells⁵.

Prebiotics

Prebiotics, including oligofructose, fructans, resistant starch, and arabinoxylan-oligosaccharides, are fermented by the gut microbiota, increasing SCFA production (acetate, propionate, and butyrate). These metabolites activate GPR41 and GPR43 receptors on L-cells, promoting the secretion of GLP-1 and PYY^5,20.

Although the role of prebiotics in modulating intestinal peptide secretion is well documented in experimental models, clinical results in humans remain inconsistent⁵. Some studies reported that oligofructose supplementation increased PYY concentration but not GLP-1^21,22. Conversely, arabinoxylan-oligosaccharide supplementation reduced early postprandial GLP-1 secretion, accompanied by decreased gut microbiota alpha diversity and increased relative abundance of the genera Bifidobacterium, Akkermansia, and Lactobacillus²³. In hyperinsulinemic subjects, increased dietary fiber intake stimulated SCFA production, particularly acetate and butyrate, leading to elevated plasma GLP-1 levels and higher fasting and postprandial insulin concentrations, although without significant changes in body weight²⁴. Furthermore, a low-carbohydrate almond-based diet significantly increased the relative abundance of Roseburia and Ruminococcus, known SCFA producers, along with increased GLP-1 concentrations^25,26. Overall, clinical prebiotic interventions show heterogeneous effects on GLP-1 secretion, indicating the need for further standardized research to clarify their specific mechanisms and interindividual response variability.

Animal studies highlight significant variability in prebiotic effects on GLP-1 secretion. In animal models, prebiotics promoted the growth of butyrate-producing bacteria²⁷, increased GLP-1 secretion, and improved glucose homeostasis⁵. For example, Dendrobium polysaccharides increased the abundance of Akkermansia and Parabacteroides, as well as SCFA, tryptophan, and indole concentrations, stimulating GLP-1 secretion²⁸. Similarly, resveratrol and tetrahydrocurcumin enhanced GLP-1 release alongside changes in microbiota composition^29,30. Prebiotics such as oligofructose, fructo-oligosaccharides, fructans, and inulin increased GLP-1, PYY, and SCFA levels, although microbiota structural changes were not always consistent⁵. In type 2 diabetes models, fiber supplementation increased the abundance of Akkermansia muciniphila and Bacteroidetes, decreased Firmicutes and Proteobacteria, resulting in higher GLP-1 levels and improved metabolic parameters³¹.Additionally, flavonoids from Lycium barbarum and polysaccharides from adlay seeds modulated the microbiota and inflammatory processes while increasing GLP-1 and producing hypoglycemic effects^32,33. Overall, prebiotics can beneficially affect GLP-1 secretion via gut microbiota modulation and enhanced SCFA production.

Probiotics

Probiotics also show potential in modulating GLP-1 secretion through changes in gut microbiota composition and activity. Supplementation with Anaerobutyricum soehngenii increased secondary bile acids and postprandial GLP-1, improving glucose metabolism³⁴. Administration of Lactobacillus reuteri increased GLP-1 and insulin secretion in individuals with impaired glucose tolerance, while the probiotic mixture VSL#3 (containing eight strains including Streptococcus thermophilus, Bifidobacterium [B. breve, B. infantis, B. longum], Lactobacillus acidophilus, L. plantarum, L. paracasei, and L. delbrueckii subsp. bulgaricus)elevated GLP-1 levels and reduced BMI in children with non-alcoholic fatty liver disease over four months^35,36.

A study in type 2 diabetic mice consuming Kombucha (a source of polyphenols and organic acids) showed improved inflammation and gut barrier integrity, with reduced LPS levels and increased expression of zonula occludens-1, claudin-1, occludin, and mucin. Simultaneously, SCFA-producing bacterial abundance increased, resulting in higher SCFA levels and elevated GLP-1 and PYY concentrations³⁷. Exopolysaccharides from Bacillus amyloliquefaciens also increased GLP-1 levels through gut tissue interaction³⁸. VSL#3 supplementation for eight weeks increased butyrate-producing bacteria, butyrate levels, and GLP-1, improving glucose tolerance in diabetic and obese mice³⁹.

A recombinant Lactobacillus paracasei NFBC 338 strain expressing a long-acting GLP-1 analog improved glucose and lipid metabolism in diet-induced obese rats without significant cecal microbiota changes⁴⁰. Similarly, composite probiotic supplementation enhanced GLP-1 and PYY secretion via microbiota modulation and increased SCFA production, improving glucose and lipid metabolism and pancreatic function in diabetic mice⁴¹. Oral administration of Lactobacillus casei increased the abundance of Bacteroidetes, Bifidobacterium, and Lactobacillus, resulting in enhanced butyrate production and GLP-1stimulation⁴². Clostridium butyricum CGMCC0313.1 reduced the Firmicutes/Bacteroidetes ratio, increased SCFA-producing bacteria and FFAR2/FFAR3 receptor expression, and raised GLP-1 levels in serum and ileum, although this effect was absent in db/db mice with leptin receptor defects⁴³. Supplementation with L. fermentum MCC2759/MCC2760 reduced pathogenic bacteria, increased Lactobacillus spp., and promoted GLP-1 production^44,45. Furthermore, L. rhamnosus LGG increased beneficial bacterial abundance and GLP-1 levels, with elevated acetate and propionate concentrations⁴⁶. In piglets, L. plantarum supplementation decreased Bacteroides and Parabacteroides abundance and lithocholic acid (LCA) levels, resulting in improved glucose metabolism⁴⁷.

Impact of the gut microbiota on GLP-1 function

Incretin-based drugs have proven highly effective in treating type 2 diabetes. Numerous studies indicate that the incretin effect is impaired in individuals with obesity, impaired glucose tolerance (IGT), and type 2 diabetes. However, in some cases, reduced therapeutic efficacy of GLP-1 receptor agonists (GLP-1 RA) occurs, leading to treatment discontinuation. This phenomenon, known as GLP-1 resistance, may be associated with gut microbiota dysbiosis⁵.

Clinical research shows that gut microbiota composition can influence the efficacy of GLP-1 receptor agonist therapy. In a study of patients receiving liraglutide or dulaglutide, only a subset exhibited reductions in HbA1c and BMI. Microbiota analysis revealed significant differences in beta diversity between these groups, including the presence of bacterial species such as Bacteroides dorei and Roseburia inulinivorans, suggesting that microbiota profiles may predicttherapeutic response^5,48.

Experimental models further confirm the link between dysbiosis and GLP-1 resistance. A 2017 study developed two mouse models of type 2 diabetes – diabetic obesity and diabetic leanness. Following an oral glucose tolerance test (OGTT), glucose levels were similar across groups, but lean diabetic mice had higher plasma GLP-1 concentrations and lower insulin levels, indicating the development of GLP-1 resistance. Transplantation of the ileal microbiota from these mice into germ-free animals resulted in impaired incretin response, confirming that GLP-1 function depends on gut microbiota balance. Dysbiosis can therefore directly weaken the GLP-1 response^48,49.

Impact of the gut microbiota on the circadian rhythm of GLP-1 secretion

Circadian rhythms are endogenous, approximately 24-hour cycles that regulate numerous physiological processes in the body, including metabolism and hormone secretion. In addition to the central nervous system, the biological clock is present in peripheral tissues such as the pancreas and gastrointestinal tract, where genes like CLOCK and BMAL1 coordinate metabolic functions^50,51. Dysfunction of these genes has been associated with the development of metabolic disorders, including diabetes mellitus⁵.

GLP-1 secretion also follows a circadian pattern. Studies in humans and animal models have shown that GLP-1 secretion is higher in the morning, while the lowest levels are observed in the evening or early morning hours⁵². These oscillations reflect the rhythmic activity of intestinal L cells, whose GLP-1 release depends on the expression of clock genes, particularly BMAL1, PER1/2/3, DBP, and TEF⁵.

The gut microbiota plays a key role in regulating the circadian rhythm of GLP-1 secretion. Studies in germ-free mice have shown that the absence of gut bacteria disrupts the rhythmic secretion of insulin and GLP-1, whereas their rhythm is restored after microbiota transplantation from healthy animals⁵³. Furthermore, the biological rhythms of L cells, especially the expression of clock genes such as Bmal1, Per1/2/3, Dbp, and Tef, regulate GLP-1 release. Reduced expression of Bmal1 leads to disturbances in circadian GLP-1 secretion^54,55. Therefore, gut microbiota balance and proper L cell function jointly maintain the physiological rhythm of GLP-1 secretion.

Impact of GLP-1 on the gut microbiota

GLP-1 analogs and microbiota modulation

Recent research shows that drugs acting through the incretin system, particularly GLP-1 receptor agonists (GLP-1 RA), can influence the composition and functionality of the gut microbiota, extending beyond their primary pharmacological effects. Liraglutide is an example of a GLP-1 analog that, in experimental animal studies, increases the proportion of short-chain fatty acid (SCFA)-producing bacteria, including Bacteroides and members of the Lachnospiraceae family, as well as probiotic genera such as Bifidobacterium⁵⁶. Notably, an increase in Akkermansia muciniphila, a bacterium associated with intestinal homeostasis and metabolic health, has been observed^57,58,59.

In human studies, liraglutide administration increased microbiota diversity and richness, with a notable rise in the relative abundance of Bacteroidetes, Proteobacteria, and Bacilli⁶⁰. However, results have not always been consistent. Combined therapy with metformin or sulfonylureas sometimes masked the effects of liraglutide on the microbiota, while in older populations with type 2 diabetes, no significant changes in gut microbiota diversity were observed⁶¹. Additionally, liraglutide may act via activation of the gut sympathetic nervous system, representing an alternative mechanism for microbiota modulation⁶². Overall, GLP-1 analogs demonstrate the capacity to positively modulate the gut microbiota, although the extent of this effect depends on the therapeutic context and study population⁵.

DPP-4 inhibitors and microbiota

Dipeptidyl peptidase-4 (DPP-4) inhibitors improve oral glucose tolerance and elevate plasma GLP-1 concentrations, with concomitant changes in gut microbiota composition. Clinical studies using vildagliptin monotherapy in type 2 diabetes patients have shown a reduction in Bacteroidetes abundance⁸⁹, whereas in animal models, linagliptin and sitagliptin increasedthe proportion of Bacteroidetes and succinate concentration, an important metabolite for energy metabolism^63,64.

Vildagliptin additionally reduced Oscillibacter spp. and increased Lactobacillus spp. and propionate levels in animals fed a Western diet^65,66. Furthermore, DPP-4 inhibitors, such as PKF-275-055 and vildagliptin, decreased the Firmicutes/Bacteroidetes ratio and increased SCFA-producing bacteria, effects comparable to metformin^67,68. Overall, DPP-4 inhibitors moderately correct gut microbiota dysbiosis in obesity and type 2 diabetes.

Bidirectional communication between GLP-1 and the microbiota

Disruption of the gut microbiota can promote endotoxemia and the development of insulin resistance. In type 2 diabetes, there is an increased proportion of gram-negative Enterobacteriaceae and a reduced number of acetate-producing bacteria, such as Bifidobacterium, resulting in elevated LPS release and decreased acetate production⁶⁹. LPSbinds to Toll-like receptor 4 (TLR4), disrupting the gut barrier⁶⁹ and increasing serum LPS levels, contributing to inflammation in prediabetes^70,71.

As compensation, enteroendocrine cells increase GLP-1 secretion in response to LPS exposure, and the cytokine IL-6 further stimulates its release^5,72. GLP-1 promotes insulin synthesis, enhances satiety, and reduces food intake through GLP-1 receptors⁷³, whose agonist, exendin-4, exhibits anti-inflammatory effects by inhibiting cytokine production and macrophage infiltration⁷⁴. Therapeutic interventions that elevate GLP-1 levels have shown beneficial effects on the intestinal inflammatory response, confirming the immunomodulatory role of this hormone.

Gut hormones as regulators of the microbiota

The gut microbiota operates in symbiosis with enteroendocrine cells (EECs), which are distributed among the epithelial cells of the intestinal mucosa and secrete various hormones. L cells, which produce GLP-1 and PYY, are predominantly located in the distal intestine and colon⁵. These peptides influence appetite, satiety, and food intake, while changes in the gut microbiota can reciprocally affect eating behavior^75,76. Intestinal peptides also regulate gut motility and permeability⁷⁷ and may possess antimicrobial and protective properties⁷⁸. For example, peptide D3 increases the abundance of Akkermansia muciniphila and reduces appetite, whereas milk-derived peptides improve gut barrier integrity⁷⁹. Overall, intestinal peptides serve as key mediators of communication between the gut microbiota and the host.

Conclusion

The interaction between GLP-1 and the gut microbiota represents a complex bidirectional system that regulates host metabolism, appetite, and immune responses. The gut microbiota, through the production of metabolites such as short-chain fatty acids (SCFAs), indoles, and secondary bile acids, stimulates GLP-1 secretion, while GLP-1 modulates gut microbiota function and metabolic responses in the brain, intestines, and pancreas. Interventions such as prebiotics, probiotics, GLP-1 analogs, DPP-4 inhibitors, or bariatric surgery alter microbiota composition and activity, improving host metabolism and potentially enhancing therapeutic responses. Although study results remain heterogeneous, evidence suggests that modulation of the gut microbiota can indirectly enhance GLP-1 secretion and the production of key microbial metabolites, opening the way for personalized strategies in the prevention and treatment of metabolic disorders, including obesity and type 2 diabetes. Future application of multi-omic technologies may further clarify these relationships and support individualized therapeutic approaches based on GLP-1 and gut microbiota interactions.

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