Crosstalk between glucagon-like peptide 1 and gut microbiota in metabolic diseases
ABSTRACT
INTRODUCTION
MECHANISMS BY WHICH GUT MICROBIOTA METABOLITES STIMULATE GLP-1 SECRETION
SCFAs stimulate GLP-1 secretion
Secondary bile acids stimulate GLP-1 secretion
INTERVENTIONS THAT AFFECT GUT MICROBIOTA TO PROMOTE GUT PEPTIDE SECRETION, SUCH AS GLP-1
Prebiotics promoted GLP-1 secretion
Study design and references | Subject state or condition | BMI (kg/m2) | Intervention | Gut microbiota | Gut microbiota metabolites | Gut peptide | Outcomes |
---|---|---|---|---|---|---|---|
Crossover (76) | GERD (n = 9) | N/A | Oligofructose (20 g/d) for a week | N/A | N/A | GLP-1↑; PYY (-) | Breath H2↑; the rate of TLESRs↑ |
Double blind, R, parallel, PC (75) | Healthy (n = 10) | 21.6 ± 0.99 | Fructan (16 g/d) for 2 weeks | N/A | N/A | GLP-1↑; PYY↑ | PBG↓; breath H2↑; hunger↓ |
Single blind, R, crossover (80) | T2D (n = 17) | 31.0 ± 1.3 | RS (40 g/d) for 12 weeks | N/A | Fasting serum propionate and butyrate↓ | Fasting GLP-1↓; GLP-1↑ | PBG↓; TAG↓; TNF-α↓; fasting NEFA↓; leptin or adiponectin (-) |
R, crossover (42) | Healthy (n = 20) | 23.6 ± 2.3 | RS (17.0 g/d) and NSP (20.6 g/d) for 3 days | N/A | Fasting s-SCFA↑, (especially acetate↑) | Fasting GLP-1↑; PYY and GLP-2↑; OXM and ghrelin (-) | Breath H2↑; insulin sensitivity↑; blood glucose ↓; hunger, NEFA, and adiponectin (-) |
Double blind, R, PC, P, trial (81) | Slow GI transit (n = 48) | 24.7 ± 3.1 | Axos (15 g/d) for 12 weeks | Alpha diversity↓; fecal Bifidobacterium↑, Akkermansia↑, Lactobacillus↑ | Fecal and serum SCFA (-) | Early postprandial GLP-1↓; PYY (-) | Stool consistency↓; gut permeability/inflammation (-); glucose, insulin, FFA, TAG, glycerol; and appetite, hunger, satiety, and fullness ratings (-) |
Double blind, R, placebo-controlled trial (77) | Overweight/obese (n = 39) | 30.4 ± 3.4 | FOS (21 g/d) for 12 weeks | N/A | N/A | GLP-1 (-), PYY↑; ghrelin↓; | Postprandial insulin↓; fat mass↓; energy intake↓; postprandial glucose (-); lipids (-); |
Single blind, R, P, C study (78) | Healthy (n = 22) | 29.7 ± 1.0 | FOS (30 g/d) for 6 weeks | N/A | s-SCFA↑; acetate↑ | GLP-1 (-); plasma PYY↑ | Breath H2↑; appetite↓; hunger↓; fullness ↑; PBG, insulin (-); lipids, body fat (-); AST, ALT (-); |
Double blind, R, crossover (79) | Healthy (n = 31) | 24.8 ± 0.3 | FOS (16 g/d) for 13 days | N/A | N/A | GLP-1↑; PYY↑ | Energy intake↓ |
RCT (43) | FPI ≥40 pmol/L (n = 40) | 25·7 ± 1.1 | 24 g fiber /d for a year | N/A | Acetate and butyrate↑ | Plasma GLP-1↑ | Body weight (-); fasting and postprandial insulin (-); NEFA (-) |
Double blind, RCT (85) | NAFLD children (n = 44) | 27.3 (24.7–28.6) | VSL#3 for 4 months | N/A | N/A | GLP-1 and activated GLP-1↑ | BMI↓ |
Double blind, R trial (86) | Glucose tolerant (n = 21) | 23.6 ± 1.7 | L. reuteri (2 × 1010 cells b.i.d.) for 4 weeks | a-Diversity, overall composition, and total lactobacilli (-); | N/A | GLP-1↑; GLP-2↑ | Insulin↑; C-peptide↑; PBG (-); IL-8, and MIP-1b (-); TNF-α↑; oxidative stress (-) |
Double blind, R, PC crossover study (57) | MetS (n = 12) | 35.9 (32.3–37.9) | Duodenal infusion A. soehngenii L2-7 treatment | Microbiota richness and diversity (-); fecal SCFA (-) | Plasma secondary BA (TDCA, TLCA, GDCA); butyrate↑ | GLP-1↑ | GPR43, TGR5, FXR5, and REG1B↑ |
Single blind, R, crossover (44) | Hyperinsulinemic female (n = 6) | 31·0 (SEM 1.0) | Rectal or intravenous acetate infusions | N/A | Plasma acetate↑; Cecal SCFA (-) | GLP-1↑; PYY↑ ghrelin (-) | Plasma glucose or insulin (-); TNF-α and NEFA (-) |
Clinical trial (87) | T2D (n = 14) | 30.0 ± 3.3 | Stopping metformin | Firmicutes↑; Bacteroidetes↓ | Cholic acid and conjugates↑ | GLP-1↓ | Plasma glucose levels↑ |
RCT (88) | T2D (n = 19) | 33.3 ± 4.1 | Metformin 1,000 mg twice daily | N/A | N/A | GLP-1R; PYY↑ | PBG↓; fasting glusocse levels↓ |
R, open-labeled, two-arm trial (89) | Treatment-naive T2D (n = 92) | 26.83 ± 1.81 | Acarbose or vildagliptin for 6 months | Bacteroidetes species↓ | N/A | Fasting GLP-1↑ | HbA1c↓; visceral fat areas |
Clinical trial (45) | Diagnosed-naive diabetes (n = 50) | 25.82 ± 2.88 | Metformin 1,500 mg/d for 12 weeks | Phascolarctobacterium, Intestinimonas, and Clostridium III↑ | Acetic acid and propanoic acid in feces↑ | Total GLP-1↑ | Food intake↓; glucose control↑ |
Observational study (90) | Morbidly obese (n = 3) | 40.6 ± 5.4 | RYGB surgery | Firmicutes↓; Gammaproteobacteria↑; Archaea↓ | N/A | N/A | N/A |
Animal model and references | Invention | Gut microbiota | Gut microbiota metabolites | Gut peptide | Metabolism | Putative outcomes |
---|---|---|---|---|---|---|
Male C57Bl/6J diabetic mice (94) | Resveratrol diet (60 mg RSV/Kg/day) for 5 weeks | Modified cecal bacterial composition | N/A | Active GLP-1 in the colon↑; portal vein GLP-1↑ | Insulin; proglucagon mRNA↑ | N/A |
db/db Mice (95) | THC for 8 weeks | Proteobacteria, Actinobacteria, and F/B ratio↓ | N/A | GLP-1 in the pancreas↑; | FBG↓; insulin↑ | Islet injury↓ |
T2D male Kunming mice (47) | Kombucha for 4 weeks | SCFAs-producing bacteria↑; Gram-negative bacteria and pathogenic bacteria↓; Firmicutes↑; Proteobacteria↓ | SCFAs↑, especially butyric acid and acetic acid | GLP-1↑; PYY↑; GPR41 and GPR43↑; | FBG↓; food intake↓; BW↑; HOMA-IR↓; glycogen synthesis↑; AST, ALT, and the liver coefficient↓ | LPS↓; islet cells↑; the pancreatic index↓; IL-1β, IL-6, and TFN-α↓; colonic injury recovered; tight junction proteins and mucin↑ |
T2D male C57BL/6 J mice (46) | Modified DFs for 4 weeks | Akkermansia muciniphila↑; Verrucomicrobia and Bacteroidetes↑; Firmicutes, Proteobacteria, and Actinobacteria↓; F/B ratio↓ | SCFAs↑, especially acetic acid, propionic acid, and butyric acid | GLP-1↑; PYY↑ | FBG↓; insulin and leptin↑; liver to body ratio↓; TC, TG, and LDL-C↓; HDL-C↑; pancreatic islets↑; liver injury↓ | Glut2 and insulin receptor in the liver↓; G6Pase↑ |
Diabetic mice (98) | LBFs | N/A | N/A | GLP-1↑; TLR-4↓ | FBG↓; HOMA-IR, HOMA-IS, and HbA1c↓; OGTT↓; TC and TG↓ | LPS, TLR-4, TNF-4, IL-6, IL-10↓ |
T2D ICR male mice (99) | PAS | Altered the diversity and composition of the microbiota | N/A | GLP-1↑ | BG↓; HbA1c↓; TC and TG↓; AC1-42↓; STZ-lesioned pancreatic cells↓ | N/A |
Goto-Kakizaki rat (48) | An RS diet for 10 weeks | Butyrate-producing bacteria in cecal contents↑ | SCFAs↑ in cecal contents | Total GLP-1↑ | FBG↓; fasting insulin↓; pancreatic β cell mass↑; insulin sensitivity↑; pancreatic insulin content↑; fat weight↓ | N/A |
Male Wistar rats (49) | Oligofructose (10 g/100 g diet) for 4 weeks | N/A | Butyrate↑ in the cecum and proximal colon | Portal serum GLP-1↑ | Food intake, energy intake, and body weight gain↓ | Enteroendocrine L-cells↑; neurogenin 3 and NeuroD↑; total cecum weight↑ |
C57J/B6 male mice and Lep receptor-deficiency ob/ob mice (50) | VSL#3 for 8 weeks | Butyrate-producing bacteria↑ | Butyrate in the fecal and serum samples↑ | GLP-1↑; FFAR3↑ | FBG↓; glucose tolerance and insulin tolerance↑ | Genes involved in GLP-1 synthesis (Gcg and Pcsk1) and secretion (Slc5a1) ↑ |
HFD-fed male C57BL/6 J mice (91) | FOS for 4 weeks | N/A | N/A | GLP-1↑ | Glucose tolerance↑, FBG↓; Insulin↑, and body weight gain↓ | Hepatic phosphorylation of IKK-beta and NF-B↓ |
Male Wistar rats (51) | Fructo-oligosaccharide (16 g/day) for 28 days | N/A | SCFA in colon and terminal ileum↑, especially acetate and butyrate | GLP-1↑ | Densities of FFA2- and GLP-1-IR cells↑; | The weights of the cecal tissues and contents↑ |
Male Wistar rats (96) | Fructans (100 g) for 3 weeks | N/A | N/A | Portal vein serum GLP-1↑; ghrelin↓ | Epididymal fat mass↓ | N/A |
WT (97) | Inulin (for 2 or 14 weeks) | N/A | SCFAs↑ | PYY↑ | BW gain↓; IR↓; food intake↓; glucose tolerance↑ | N/A |
DIO rats (100) | L. paracasei intervention for 3 or 12 weeks | Composition of the cecum microbiome (-) | N/A | GLP-1↑ | Serum LDL-C↓; TG↓; insulin secretion↑; IR index (-); weight gain (-); TRL-C↓; BG↓; fasting cholesterol↓; MAT↓; EAT↓; | GLP-1 intervention; serum molecular signature changed; microbiome mediated |
Male db/db diabetic mice (52) | 10 Lactobacillus strains and 4 Saccharomycetes strains composite probiotics (6 wks) | Bacteroidetes/Bifidobacterium/Lactobacillus/Clostridium leptum/Roseburia, and Prevotella↑; Firmicutes/ Actinobacteria/Enterococcus faecium/Gram-negative bacteria/Escherichia coli and Bacteroides thetaiotaomicron↓ | Propionate and butyrate↑; acetate↓ | GLP-1↑; PYY↑ GPR43↑; GPR41↑ | PBG↓; C-peptide↑; TG, TC, and LDL-C↓; insulin↑ | Improved pancreas function, immune state, and the intestinal barrier function |
Male C57BL/6J diabetic mice (53) | L. casei CCFM419 | Bacteroidetes/Bifidobacterium/Lactobacillus/ SCFA-producing bacteria↑; Firmicutes↓ | Acetic acid, butyric acid, and total SCFAs in the feces↑ | GLP-1↑ | PBG↓; HbA1C↓; leptin↓; LDL-C↓; HDL-C↑; | TNF-α↓; IL-6↓ |
Leptin receptor-deficiency db/db mice (54) | Oral gavage CB0313.1 daily (5 weeks) | N/A | N/A | N/A | Insulin sensitivity↑; improved glucose tolerance | Inflammatory tone in adipose tissue↓ |
C57BL/6J diabetic mice (54) | Oral gavage CB0313.1 daily (13 weeks) | Butyrate-producing bacteria↑ | SCFA↑; SCFA receptor↑ | GLP-1↑ | Insulin sensitivity↑; glucose tolerance↑; HOMA-β↑ | Inflammatory tone in adipose tissue↓; TNF-α↓; MCP-1↓ |
Female Wistar diabetic rats (101) | Oral L. fermentum MCC2759/2760 (4 weeks) | Pathogenic bacteria such as Escherichia coli, Staphylococcus aureus, and Campylobacter spp. ↓ | N/A | GLP-1↑; TLR4 receptor↓ | Glucose tolerance↑; plasma insulin↓; BG↓; adiponectin↑; GLUT4↑ | Tight junction protein ZO-1↑; endocannabinoid receptor CB2↑; |
Male albino Wistar T2D rats (55) | L. rhamnosus NCDC 17 (9.5 to 10 log cfu/mL) (6 weeks) | Bacteria abundance and numbers↑; Eubacterium rectale-Clostridium coccoides, Bacteroides, Lactobacilli, and Bifidobacteria↑ (cecal contents) | Acetate↑ | GLP-1↑ | Glucose tolerance↑; FBG↓; HDL-C↑; TG↓; VLDL-C↑; adiponectin↑ | Activity of catalase and GPx↑; activity of SOD↑;TNF-v↓ and IL-6↓; |
Male albino Wistar T2D rats (55) | L. rhamnosus LGG (8 to 8.5 log cfu/mL) (6 weeks) | Bacteria abundance and numbers↑; Bacteroides↓ (cecal contents) | Propionate↑ | GLP-1↑ | Glucose tolerance↓; FBG↓; HDL-C↑; | Activity of catalase and GPx↑;activity of SOD↑ |
ICR mice (102) | Oral EPSs (800 mg/kg) | N/A | N/A | GLP-1↑ | BG↓; glucose consumption of the FL83B cells↑ | Activation of Akt↑ |
HCD-fed C57BL6 mice (103) | Oral L. fermentum MCC2760 (10.95 log CFU/mL) (8 weeks) | Lactobacillus spp. count↑; pathogen count (like Staphylococcus and Campylobacter)↓ | N/A | GLP-1↑ | BG↓; body weight↓; serum CHOL, TG, LDL-C, AST, and ALT↓ | Bacterial translocation count↓; LPS, TNF-α, IL-6, IL-12↓. and IL-10; GSH-Px, GSH-Tr, CAT, and SOD↑; CB1↓, CB2↑; ZO-1↑ |
Piglets (104) | Lactobacillus plantarum (50 mg) (3.5 × 1010 CFU/g) daily (2 weeks) | Alpha diversity (-); Tenericutes phylum/ Bacteroides/Parabacteroide/Clostridium_sensu_stricto_1/Ruminococcus_1/Desulfovibrio↓; Lactobacillus/Megasphaera/Collinsella↑ | G-LCA↓; T-LCA↓; CA↑; TBA (-) (in ileum tissue) | Postprandial plasma GLP-1↓ | PBG↑; genes associated with BA metabolism (-) | Genes related to inflammation and glucose transport (-); GLUT2 and SGLT1 (-) |
Pig (105) | Cecal propionate infusions (0, 5, 20, and 100 mmol/L) | N/A | Exogenous propionate↑ | GLP-1↑; PYY↑; FFAR2/FFAR3 expression↑ | Acute feed intake↓; | AgRP expression↓ |
FFAR2 (−/−) mice (56) | Colonic propionate infusions (180 mmol/L) | N/A | Exogenous propionate↑ | Portal vein plasma GLP-1 and PYY (-) | N/A | N/A |
Wistar rats and C57BL6 mice (56) | Colonic propionate infusions (180 mmol/L) | N/A | Exogenous propionate↑ | Portal vein plasma GLP-1 and PYY↑ | N/A | N/A |
FFAR2−/− and FFAR3−/− mice (39) | Receptor knockout (3 to 4 months) | N/A | SCFAs↑ | GLP-1↓ | N/A | N/A |
Male HFD-fed C57BL/6 J mice (106) | FMT | Akkermansia, Bacteroides, and Butyricimonas (-) | N/A | GLP-1↑; TLR1 and TLR4↑ | BG↑; body weight (-); TC (-); | IL-18↓; TLR2, TLR5, and TLR6 (-); |
Male HFD-fed C57BL/6 J mice (107) | Metformin (250 mg/kg) for 16 weeks | Genera Akkermansia, Bacteroides, Butyricimonas, and Parabacteroides↑ | N/A | N/A | BG↓; BW↓; TC and LDL↓ | IL-1β and IL-6 in epididymal fat↓ |
DIO male C57Bl/6 J mice (11) | SG | Clostridiales (-) | LCA in portal veins↑ | GLP-1↑ | Expression levels of mSult2A1 and Vdr in liver↑; CA7S↑ | LCA-VDR-SULT2A1-CA7S pathway |
Male C57BL/6 J mice, SD rats, and Zucker diabetic fatty rats (108) | Canagliflozin (0.3–30 mg/kg) and sitagliptin (10 mg/kg) | N/A | N/A | Plasma active GLP-1↑ | Insulin↑; BG↓ | Transient intestinal SGLT1↓ |
Male C57BL/6 renal failure mice (109) | Canagliflozin (10 mg/kg for 2 weeks) | Bifidobacterium↓ | Colonic SCFAs↑ | N/A | p-Cresyl sulfate and indoxyl sulfate↓; BG (-) | Intestinal SGLT1↓ |
Probiotics promoted GLP-1 secretion
EFFECT OF GUT MICROBIOTA ON GLP-1 FUNCTION
EFFECT OF GUT MICROBIOTA ON GLP-1 RHYTHM
EFFECT OF GLP-1 ON GUT MICROBIOTA
GLP-1 analogs and DPP-4 inhibitor changed the composition and abundance of gut microbiota
Effect of GLP-1 on the gut microbiota is involved in the inflammatory response
Gut hormones affect the composition and function of gut microbiota
INTERVENTIONS THAT MAY AFFECT GUT MICROBIOTA PROMOTE GUT PEPTIDE SECRETION, SUCH AS GLP-1
Oral antidiabetic drugs promoted the GLP-1 secretion
Bariatric surgery promoted the GLP-1 secretion
CONCLUSION AND PROSPECTS
ACKNOWLEDGMENTS
REFERENCES
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