Crosstalk between glucagon-like peptide 1 and gut microbiota in metabolic diseases

ABSTRACT Gut microbiota exert influence on gastrointestinal mucosal permeability, bile acid metabolism, short-chain fatty acid synthesis, dietary fiber fermentation, and farnesoid X receptor/Takeda G protein-coupled receptor 5 (TGR5) signal transduction. The incretin glucagon-like peptide 1 (GLP-1) is mainly produced by L cells in the gut and regulates postprandial blood glucose. Changes in gut microbiota composition and function have been observed in obesity and type 2 diabetes (T2D). Meanwhile, the function and rhythm of GLP-1 have also been affected in subjects with obesity or T2D. Therefore, it is necessary to discuss the link between the gut microbiome and GLP-1. In this review, we describe the interaction between GLP-1 and the gut microbiota in metabolic diseases. On the one hand, gut microbiota metabolites stimulate GLP-1 secretion, and gut microbiota affect GLP-1 function and rhythm. On the other hand, the mechanism of action of GLP-1 on gut microbiota involves the inflammatory response. Additionally, we discuss the effects and mechanism of various interventions, such as prebiotics, probiotics, antidiabetic drugs, and bariatric surgery, on the crosstalk between gut microbiota and GLP-1. Finally, we stress that gut microbiota can be used as a target for metabolic diseases, and the clinical application of GLP-1 receptor agonists should be individualized.

a long history of shared ancestry (14).In the human body, the ratio of bacteria to human cells is close to 1:1 (15).Almost 65% of the human genome comes from microorganisms (16).
The human gut, or gastrointestinal tract, is the body's largest digestive and immune organ.Each part of the gut has distinct characteristics.For example, the distal colon has the densest and the most diverse bacteria (17,18).Gut microbiota has approximately 1,000 microbial species.The human gut microbiome comprises almost 10 million genes, which are more than 150 times the size of the human genome, and includes many metabolic genes (19).Human gut microbiota are mostly dominated by phylum of the phyla Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria, and Verrucomicrobia (18).Gut microbiota is highly involved in fighting against disease-causing microbes (e.g., promote IgA secretion) and energy metabolism (e.g., produce monosaccharides).The composition and proportion of gut microbiota are affected by genes [FXR (20)], lifestyle [diet (21)], drugs [antibiotics (22)], aging (23), etc.In addition, the gut microbiome is affected by the host feeding pattern (24), regulating circadian rhythms and metabolism in the host [reviewed in references (25,26)].In summary, gut microbiota plays an important role in human health and disease, such as T2D [reviewed in references (27,28)].
The gut microbiota is increasingly involved in the pathogenesis of diabetes.Meanwhile, both the composition and proportion of the gut microbiota are affected in patients with diabetes (Fig. 1).Patients with T2D had gut microbial dysbiosis and an increase in various opportunistic pathogens (29).Specifically, the abundance of some butyrate-producing bacteria (such as the phylum Firmicutes and genus Bifidobac terium) was reduced, while Gram-negative bacteria were relatively enriched such as the phyla Bacteroidetes and Proteobacteria (30,31).However, alterations in certain gut microbiota by drugs or dietary fibers [such as decreased abundance of Firmicutes and Bacteroidetes (32)] contributed to the elevation of GLP-1 levels and the improvement hormones.Microbial metabolites can be divided into three categories.The first type, such as short-chain fatty acids and 2-oleoyl glycerol (2-OG, derived from dietary fats), is produced by intestinal microorganisms directly digesting or fermenting food components.The second category is metabolites produced by the host and modified by intestinal microorganisms, such as secondary BAs.Secondary BAs are dissociated and transformed from primary BAs by intestinal 7-α/β dehydroxylation bacteria and contribute to the establishment of intestinal homeostasis in hosts.The third type is the metabolites synthesized by intestinal microorganisms, such as LPS.Gut microbiota metabolites such as SCFAs (42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55)(56) and secondary BAs (11,57) can stimulate GLP-1 secretion.In addition, microbial metabolites such as 2-OG (58) and indole (59) directly activate GLP-1 secretion from L cells.Therefore, prebiotics and probiotics may amelio rate obesity and T2D through the gut microbiota-SCFA-inflammation/GLP-1 mechanism.Bariatric surgery may improve body weight, glucose metabolism, and inflammation by the gut microbiota-secondary BA-GLP-1 mechanism (11).

SCFAs stimulate GLP-1 secretion
SCFAs are involved in maintaining health and the development of disease and have attracted considerable attention.In fact, decreased SCFA production or production potential is associated with metabolic diseases, such as T2D (60,61).The human genome encodes fewer than 20 enzymes to digest complex carbohydrates (62), so some carbohydrate polymers (dietary fibers) that are neither digested nor absorbed in the small intestine will be fermented to SCFAs by gut microbiota through carbohydrateactive enzymes in the gastrointestinal tract [reviewed in reference (63)].Interestingly, the colon produces high levels of SCFAs and contains many L cells (64).More than 90% of SCFAs are absorbed by the gut or used by the microbiota (65).SCFA receptors are the G-protein-coupled free fatty acid receptors GPR43 (FFAR2) and GPR41 (FFAR3) (66).GPR43 and GPR41 are relatively conserved and highly expressed in enteroendocrine L cells in rats and humans and differ in their intracellular signals [reviewed in reference (67)].In the human and rat colon and terminal ileum, the increase in SCFAs after adding fermenting dietary fiber may activate GPR43 and lead to increased GLP-1 secretion (51).Additionally, intravenous or rectal SCFA infusion was shown to increase GLP-1 secretion in humans (44).However, when SCFAs are given to GPR43 knockout mice, GLP-1 secretion cannot be stimulated (39).The mechanism involves GPR43 and GPR41 activation leading to increased intracellular calcium in L cells (39,56,68).Thus, these results suggest that gut microbiota can influence the production of SCFAs and the secretion of anorexic intestinal hormones, such as GLP-1, from rodent (39,56) and human (44) enteroendocrine L cells via the receptor GPR43, but further studies are needed to elucidate the underlying mechanisms.However, GPR43 activation by increased SCFAs increased the number of the PYY-producing cells and PYY expression, which might be an effective therapeutic target for obesity but not T2D (69).Therefore, the increase in GLP-1 might occur through the receptor GPR41 (Fig. 3).

Secondary bile acids stimulate GLP-1 secretion
Secondary BAs occur under the action of the gut microbiota, which means that alterations in the gut microbiota may change the composition of the BA pool.BAs as metabolites regulate signaling and glucose homeostasis.For example, secondary BAs have dual regulatory effects on GLP-1 secretion.On the one hand, secondary BAs activate Takeda G protein-coupled receptor 5 (TGR5) on intestinal L cells to stimulate GLP-1 secretion (70,71).On the other hand, secondary BAs activate the farnesoid X receptor (FXR) to inhibit GLP-1 secretion (40,72).
The effects of prebiotics on GLP-1 secretion are also inconsistent.In mice, inges tion of prebiotics increased butyrate-producing bacteria (48), enhanced GLP-1 release (91), and improved diabetes symptoms (92).For example, dendrobium polysaccharides upregulated the abundance of Akkermansia and Parabacteroides, thereby increasing gut microbiota metabolites such as SCFAs, tryptophan, and indole to stimulate GLP-1 secretion [reviewed in reference (93)].In diabetic mice, ingestion of resveratrol enhanced GLP-1 release and modified cecal bacterial composition (94).In db/db mice, tetrahy drocurcumin supplementation decreased the ratio of Firmicutes to Bacteroidetes and increased the volume of GLP-1 in the pancreas (95).Oligofructose (49), fructo-oligo saccharide (51), fructans (96), and inulin (97) caused an increase in GLP-1, PYY, and SCFAs, but the change in gut microbiota was not applicable.In T2D mice, the supple mentation of modified dietary fibers increased the relative abundance of Akkermansia muciniphila, Verrucomicrobia, and Bacteroidetes, decreased the relative abundance of Firmicutes, Proteobacteria, and Actinobacteria, and increased the production of SCFAs.It also increased the levels of GLP-1 and PYY and then improved the metabolism of blood glucose and lipids (46).Additionally, flavonoids from Lycium barbarum regulate the gut microbiota and reduce pro-inflammatory cytokines to ameliorate the symptoms of T2D mice, accompanied by the elevation of GLP-1 (98).Polysaccharides from adlay seeds (PAS) increased Simpson's diversity index and GLP-1 concentrations, indicating that PAS altered the diversity and composition of the microbiota and had hypoglycemic effects in T2D mice (99) (Table 2).In conclusion, one of the mechanisms by which prebiotics regulates host health is to promote GLP-1 secretion by regulating changes in gut microbiota.

Probiotics promoted GLP-1 secretion
Probiotics are live microorganisms that bring many benefits to the host (110).Probiotic interventions have strain-specific anti-inflammatory effects on healthy adults (111).While the effects of probiotics on the host are not necessarily related to their interactions with the protoflora, their use is often associated with claims about beneficial regulation of probiotics and the normalization of disturbed flora, either as a favorable outcome of the probiotics themselves or as a mechanism by which the probiotics protect the host against disease (73).However, the effect of probiotic intake on intestinal mucosa is not necessarily fixed and is related to the host and its microbiome characteristics (112).The beneficial effects of probiotics on diabetes have been studied, and the mechanism may be related to enhancing immunity, increasing the production of anti-inflammatory cytokines, reducing intestinal permeability, and reducing oxidative stress.
In subjects with metabolic syndrome, a single duodenal Anaerobutyricum soehngenii bacteria infusion increased the levels of plasma secondary BAs and postprandial GLP-1 and thereby improved glucose metabolism (57).Moreover, no adverse events were observed when live Anaerobutyricum soehngeni was orally administered (113).Intake of Lactobacillus reuteri improved GLP-1 and insulin secretion in people with glucose       (85).In T2D mice, Kombucha (polyphenols and organic acid active substances) administra tion improved the inflammation state and intestinal tight conjunction, such as decreas ing the levels of LPS and pancreatic index and increasing the protein zona occludens 1, claudin-1, occludin, and mucin (47).At the same time, the abundance of SCFA-producing bacteria was increased, thereby increasing SCFAs and elevating the concentrations of GLP-1 and PYY (47).Exopolysaccharides from Bacillus amyloliquefaciens could increase GLP-1 levels by interacting with intestinal tissues (102).Supplementation with VSL#3 for 8 weeks increased the abundance of butyrate-producing bacteria, butyrate, and GLP-1 and improved fasting blood glucose, glucose, and insulin tolerance in both C57J/B6 male mice and Lep ob/ob mice (50).A recombinant microbe Lactobacillus paracasei NFBC 338 was successfully transformed to express a long-acting analog of GLP-1.The short-term or long-term administration of L. paracasei NFBC 338 did not change the composition of the cecum microbiome but improved glucose or lipid metabolism in diet-induced obese (DIO) rats (100).Supplementation with composite probiotics stimulated the secretion of GLP-1 and PYY by changing the composition of the gut microbiota and the produc tion of SCFAs.At the same time, the metabolism of blood glucose and lipids, immune state, and pancreas function were improved in db/db diabetic mice (52).In T2D mice, oral administration of Lactobacillus casei increased the abundance of Bacteroidetes, Bifidobacterium, and Lactobacillus, and butyrate production increased, which stimulated GLP-1 secretion (53).Daily administration of Clostridium butyricum CGMCC0313.1 for 13 weeks decreased Firmicutes/Bacteroidetes ratios and increased SCFA-producing bacteria and SCFA receptors FFAR2 and FFAR3 in T2D mice.Moreover, serum and ileal GLP-1 levels increased, but this improvement has not been observed in leptin receptor-deficient db/db mice (54).This may be related to the time of administration and the different mouse models.Supplementation with L. fermentum MCC2759/L.fermentum MCC2760 orally or intragastrically decreased the count of pathogenic bacteria and increased the production of GLP-1 and Lactobacillus spp.count (101,103).Two different concentrations of L. rhamnosus LGG increased the bacterial abundance, number, and GLP-1 levels.However, the increased types of SCFAs were acetate or propionate (55).In piglets, the supplementation with L. plantarum reduced the abundance of Bacteroides and Parabacteroides, and also decreased the levels of lithocholic acid (LCA), eventually increasing BG (104).In conclusion, probiotics regulate host health by regulating changes in gut microbiota.

EFFECT OF GUT MICROBIOTA ON GLP-1 FUNCTION
Incretin-based drugs are effective in treating individuals with diabetes.Many studies have demonstrated that the incretin effect is impaired in obesity, IGT (impaired glucose tolerance), and T2D patients.However, sometimes it is necessary for patients to stop their treatment with GLP-1 RA due to a lack of efficacy.This phenomenon is a state of GLP-1 resistance (114).This state could be caused by gut microbiota dysbiosis (115).
In a human study, different gut microbiota compositions have different responses to GLP-1 RA (116).T2D patients on a treatment with GLP-1 RA (liraglutide or dulaglutide) for 12 weeks were divided into GLP-1 RA responders (n = 34) and non-responders (n = 18).The former had both decreased levels of HbA1c and BMI, and the latter had no change in these two variables.The beta diversity of gut microbiota was significantly differed between these two groups, as well as some bacteria, such as Bacteroides dorei and Roseburia inulinivorans.So, the signature of gut microbiota may predict the GLP-1 RA efficacy.In 2017, how gut microbiota dysbiosis induces GLP-1 resistance was well exhibited in mice (117).In this study, two T2D mouse models were created: a diabetic obese model and a diabetic lean model.At 15 min after OGTT (oral glucose tolerance test) experiments, glycemia was almost similar between these two diabetic groups and normal control mice.However, in the diabetic lean model, the plasma GLP-1 concentra tion was higher, but the plasma insulin concentration was lower than that in the diabetic obese model and normal model.This suggested that GLP-1 resistance existed in the diabetic lean model.Then, the ileum microbiota was transplanted from the two diabetic groups and the normal control group to germ-free mice.The results demonstrated that the incretin effect was impaired, while GLP-1R expression was slightly higher in germfree mice after fecal transplantation from diabetic lean mice compared to other groups.This result suggested that the function of GLP-1 was dependent on the normal gut microbiota.Gut microbiota dysbiosis impaired GLP-1 responsiveness (117).Therefore, the gut microbiota is closely responsible for GLP-1 function (89).

EFFECT OF GUT MICROBIOTA ON GLP-1 RHYTHM
Circadian rhythms refer to physiological changes in an organism's activities that occur almost every 24 hours, also known as the biological clock (118).This biological clock exists not only in the brain but also in peripheral organs, such as the pancreas and gastrointestinal tract.It has been proven that pancreatic islets have circadian genes such as CLOCK and BMAL1 in Homo sapiens and rodents (119,120), and disruption of circadian genes leads to diabetes (121).Moreover, the secretion of insulin abides by a circadian clock pattern (122).In humans, it was revealed that GLP-1 secretion has temporal differences because early GLP-1 release was more prominent in the morning than in the afternoon (123).A significant circadian rhythm in GLP-1 secretion by intestinal L cells (124) or GLP-1 responsiveness (125) was found in animal experiments.In mice, the peak time of GLP-1 release was 8 p.m. (ZT14).The bottom time of GLP-1 secretion was 8 a.m.(ZT2).Taken together, there is clear evidence that GLP-1 secretion has a circadian rhythm.The composition and function of the gut microbiota also exhibit some oscillations that follow the host dietary pattern.In return, gut microbiota regulate host circadian rhythms and metabolism [reviewed in reference (26)].
The regulation of GLP-1 secretion rhythm by gut microbiota is essential.First, gut microbiota disorders can affect the rhythmic secretion of GLP-1.In germ-free mice without gut microbiota, there was no circadian rhythm of insulin secretion.However, after fecal transplantation from normal diet-fed mice, the insulin rhythm reappeared (126).Therefore, the homeostasis of the gut microbiota environment was significant for the rhythmic secretion of GLP-1 (126).Second, the same team demonstrated that the biological rhythms of L cells regulated GLP-1 release.The core biological clock gene Bmal1 in intestinal L cells regulates the rhythm of GLP-1 secretion (127), as do Per1/2/3, Dbp, and Tef (126).Knockdown of Bmal1 in L cells impaired GLP-1 circadian secretion (128).In summary, the circadian rhythm of GLP-1 release is mediated by L cells and regulated by the gut microbiota (Fig. 4).

GLP-1 analogs and DPP-4 inhibitor changed the composition and abundance of gut microbiota
The GLP-1 RA liraglutide, but not saxagliptin (129), changed the overall structure of the gut microbiota, especially some bacteria related to glucolipid metabolism and intestinal inflammation (130,131).For example, liraglutide treatment of diabetic male rats changed the gut microbiota, such as increasing SCFA-producing bacteria (Bacteroides and Lachnospiraceae) and probiotics (Bifidobacterium) (132).In addition, liraglutide treatment in wild-type mice and db/db mice significantly increased the abundance of intestinal Akkermansia muciniphila (130,133,134).In humans, liraglutide significantly increased the diversity and richness of the gut microbiota, especially Bacteroidetes, Proteobacteria, and Bacilli (135).However, a recent randomized controlled trial suggested that liraglutide and sitagliptin did not change the alpha or beta diversity of the gut microbiota, when they were used as add-on therapies with metformin or sulfonylureas (136).Additionally, a fixed combination of liraglutide and degludec for 6 months did not change the micro biome biodiversity or community among a group of very old T2D subjects (mean age 82 years) (137).The possible reason was that the combination of drugs masked the effect.In addition, liraglutide can activate the sympathetic nervous system of the gut (138).In conclusion, the GLP-1 analog liraglutide modulated the gut microbiota structure.
DPP-4 inhibitors could improve oral glucose intolerance and raise plasma GLP-1 concentrations.Additionally, they impacted on the composition and function of the gut microbiota.Vildagliptin monotherapy reduced the Bacteroidetes species in treatmentnaive T2D patients, similar to acarbose (89).However, DPP-4 inhibitors [linagliptin (139) and sitagliptin (140)] increased the abundance of Bacteroidetes and succinate in mice.Moreover, vildagliptin mainly decreased Oscillibacter spp.and increased Lactobacillus spp.and propionate in Western diet-fed mice (141) and Zucker diabetic fatty rats (142).Similarly, DPP-4 inhibitor (PKF-275-055 or vildagliptin) treatment was reported to significantly decrease Firmicutes/Bacteroidetes ratios and increase butyrate-producing bacteria in diabetic and obese mice, similar to metformin (143,144).Overall, treatment with a DPP-4 inhibitor moderately corrected the dysbiosis of the microbiota in obese and T2D mice.

Effect of GLP-1 on the gut microbiota is involved in the inflammatory response
Disturbance of the gut microbiota can promote endotoxemia and insulin resistance.Increased Gram-negative Enterobacteriaceae and decreased acetic acid-producing bacteria (such as Bifidobacteria) associated with T2D resulted in increased LPS release and decreased acetic acid, respectively.Then, LPS from the gut lumen binds Toll-like receptor 4 (TLR4) to damage the intestinal barrier (145), and serum LPS moderately increases, which is an inflammatory state of prediabetes (146,147).However, EECs increased the incretion of GLP-1 after sensing LPS as compensation (41).Similarly, inflammatory cytokine IL-6 (148) also acts on gut endocrine L cells to promote GLP-1 secretion.GLP-1 exerts a variety of physiological functions, such as promoting insulin synthesis and secretion, increasing satiety, and reducing food intake by binding to GLP-1R (149).GLP-1R is expressed in intestinal intraepithelial lymphocytes, and the GLP-1R agonist exendin-4 significantly inhibits inflammatory cytokines and macrophage infiltration (59).Many interventions that increase GLP-1 levels improve the intestinal inflammatory response (Tables 1 and 2).These findings suggested that the mechanism of GLP-1 action on gut microbiota involved inflammatory responses.

Gut hormones affect the composition and function of gut microbiota
The gut microbiota is symbiotic with EECs.Distinct EEC subtypes are scattered among the epithelial cells of the gut mucosa and secrete different hormones.L cells that produce GLP-1 and PYY are distributed toward the distal intestine and are finally high in the colon (64,150).These gut peptides can influence appetite, satiety, and food types.In return, alterations in gut microbiota could also affect eating behaviors (151,152).In addition, gut peptides could regulate intestinal motility and intestinal permeability (153).Drosophila peptides have antimicrobial effects (154) and then regulate gut microbiota composition and abundance.Food peptides are multifunctional and can prevent gut dysbiosis (155).For example, a novel peptide, D3, increased the abundance of Akkerman sia muciniphila and also suppressed appetite to improve DIO (156).Some milk-derived short peptides can enhance intestinal barrier function (157).In conclusion, gut peptides mediate the crosstalk between the gut microbiota and the host.

Oral antidiabetic drugs promoted the GLP-1 secretion
In addition to dietary factors, nonantibiotic drugs also affect the microbiota composition and function.In turn, the gut microbiota can influence the effects of drugs.A wellknown example is that Nature published an article providing support for the microbiota variation associated with the oral antidiabetic drug metformin in 2015.Treatment with metformin in T2D patients increased Escherichia spp.and decreased Intestinibacter spp.compared to untreated patients (158).In addition, a recent meta-analysis indicated that antidiabetic drugs (metformin) have a strong association with the relative abundance of microbiota (159).
In T2D patients, oral metformin increased the abundance of Phascolarctobacterium, Intestinimonas, and Clostridium III and the levels of GLP-1 and PYY (45,88).However, stopping metformin decreased the Bacteroidetes abundance and the GLP-1 concen trations (87).Treatment with acarbose or vildagliptin in treatment-naive T2D patients decreased the abundance of Bacteroidetes and increased GLP-1 levels.
In DIO mice, the abundance of Akkermansia muciniphila, Bacteroides, Butyricimonas, and Parabacteroides was significantly increased by metformin treatment (107,160).However, fecal transplantation from metformin-treated 16-week-old mice increased the GLP-1 concentration without changing the composition of gut microbiota and body weight (106).In hyperglycemic rats, SGLT2 inhibitor, canagliflozin, can also inhibit intestinal SGLT1, which is the primary transporter for glucose and galactose, to elevate plasma active GLP-1 level and reduce post-prandial glucose (108).Moreover, canagliflozin increased cecal SCFA production and changed the intestinal microbiota in renal failure mice (109).Dual SGLT1/2 inhibitors, sotagliflozin and licogliflozin, exert more selectivity for SGLT1 than canagliflozin, which may give dual SGLT1/2 inhibitors specific anti-hyperglycemia efficacy and cardiovascular and renal safety characteristics (161).So, although SGLT2 inhibitors are considered to act mainly through the kidneys, their effects on the microbiome deserve further evaluation.Therefore, the relationship between increased GLP-1 concentrations and gut microbiota after antidiabetic drug administra tion needs to be further confirmed.

Bariatric surgery promoted the GLP-1 secretion
Bariatric surgery, which alters gut microbiota ecology, improved obesity and T2D well (11,162).After Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) surgery, significant weight loss was exhibited along with the improved glycemia and changed gut microbiota.One of the main mechanisms is increased endogenous GLP-1 signaling (163).For example, RYGB surgery decreased Firmicutes and Archaea and increased Gammapro teobacteria (90).Therefore, in bariatric surgery, what is the exact relationship between gut microbiota and GLP-1 is still not clear.
Increased GLP-1 after bariatric surgery may be the result of rapid gastrointestinal nutrient input and increased plasma BAs (164).In healthy subjects, postprandial plasma BA concentrations were positively correlated with GLP-1 and PYY (165).In DIO mice, SG increased the LCA levels in portal veins without changing the abundance of Clostridiales to stimulate the GLP-1 production (11).Therefore, future studies of the crosstalk between gut microbiota and GLP-1 in bariatric surgery should start with BAs.

CONCLUSION AND PROSPECTS
The interaction between GLP-1 and gut microbiota influences the host metabolism and health.Hosts in different metabolic states or with specific preferences will consume in different kinds and contents of the diet.Food can be derived into metabolites of the gut microbiota under the action of the gut, such as SCFAs.Some gut microbiota metabolites promote the secretion of GLP-1.GLP-1 exerts an influence on the brain, intestine, and pancreas to improve host metabolism.In addition, some interventions, such as prebiotics, probiotics, antidiabetic drugs, and bariatric surgery, changed the composition and function of the gut microbiota and then exerted benefits on the body, suggesting that gut microbiota is a target for diseases, such as obesity and T2D.
However, the relationship between gut microbiota, GLP-1 secretion, and the host still has many black boxes to uncover.In the future, the development of multiomics technology will help to interpret the relationship between GLP-1 and gut microbiota.In the clinical application of GLP-1RA, the effects of gut microbiota should be considered, and individualized programs should be given.

FIG 4
FIG 4 The circadian rhythm of GLP-1 release mediated by L cells and regulated by gut microbiota.GLP-1 secretion in normal mice showed a circadian rhythm, with the peak of 8 p.m. (ZT14) and the bottom line of 8 a.m.(ZT2).The abundance of Akkermansia muciniphila which was closely related to the secretion of GLP-1 was higher at ZT14 than at ZT2.While in germ-free mice and antibiotic-induced microbial depleted model, the GLP-1 rhythm was not exhibited.And the biological rhythms of L cells regulated GLP-1 release.The clock gene Bmal1 was significantly increased at ZT2.While Per1/2/3, Dbp, and Tef increased at ZT14.

TABLE 1
Clinical studies on the interaction between gut microbiota therapy

TABLE 2
Animal studies on the interaction between gut microbiota modification therapy and gut peptides a

TABLE 2
Animal studies on the interaction between gut microbiota modification therapy and gut peptides a