Sucralose can improve glucose tolerance and upregulate expression of sweet taste receptors and glucose transporters in an obese rat model.

OBJECTIVES: Non-nutritive sweeteners (NNS) are widely used as replacements for table sugar in beverages and dessert. However, the metabolic effects of NNS remain controversial. This study aimed to investigate the effects of various sucralose loads on glucose metabolism and expression of sweet taste receptors (STR) and glucose transporters in a high-fat diet (HFD) rats. METHODS: Four-week-old male Sprague Dawley rats were fed a HFD for 8 weeks, then randomly divided into eight groups (6 in each group). All were gavaged with either saline, sucralose (0.54 mM or 0.78 mM), or sucrose (324 mM) with/without gurmarin, a sweet taste inhibitor, for 4 weeks, followed by an intragastric glucose tolerance test (IGGTT) with blood glucose, and plasma insulin, GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) measurements. In the following week, the rats were sacrificed and the small intestine was removed for measurement of sweet taste receptor and glucose transporter expression by quantitative Reverse Transcription-Polymerase Chain Reaction. RESULTS: In HFD rats, blood glucose levels were decreased at 30, 60, and 120 min during the IGGTT after 4 weeks supplementation with 0.78 mM sucralose. TIR3 expression was increased in the duodenum and TIR2 was increased in the ileum after 324 mM sucrose supplementation. T1R3 expression was increased after 0.54 mM and 0.78 mM sucralose in the ileum, but there was no change in the expression of TIRs in the duodenum after sucralose treatments. SGLT-1 expression was increased after both 0.78 mM sucralose and 324 mM sucrose in the ileum, and only increased in the duodenum after 324 mM sucrose supplementation. CONCLUSIONS: The effects of sucralose on glucose metabolism in HFD rats are dose-dependent and related to enhanced expression of sweet taste receptors and glucose transporters. Further studies are needed to clarify the molecular mechanisms involved.

Effects of Metformin and Sitagliptin Monotherapy on Expression of Intestinal and Renal Sweet Taste Receptors and Glucose Transporters in a Rat Model of Type 2 Diabetes.

Disordered intestinal sweet taste receptors (STRs) are implicated in glucose homeostasis by involving in incretin secretion and glucose absorption. However, the effects of antidiabetic medications on STRs, downstream molecules, and glucose transporters expression are unknown. In our study, ZDF rats (n=24) were randomly treated by metformin (MET, 215.15 mg/kg), sitagliptin (SIT, 10.76 mg/kg), or saline for 4 weeks. Fasting blood glucose and insulin levels were measured, and HOMA-IR and QUICKI index were calculated. One week later, we detected relative mRNA expression of T1R2/T1R3, α-gustducin, TRPM5 and glucose transporters including SGLT1, SGLT2, and GLUT2 in the small intestine and kidney. We found that though both metformin and sitagliptin effectively decreased fasting blood glucose, only metformin improved HOMA-IR and QUICKI (p<0.05). MRNA levels of STRs and sweet taste molecules in duodenum and jejunum were not different among three groups, but those in ileum were dramatically upregulated after SIT (vs. MET p<0.05; vs. CON p<0.01). SGLT1 and GLUT2 in ileum were markedly increased after SIT (p<0.01). In the kidney, expression of SGLT2 and GLUT2 were downregulated in both SIT and MET group (p<0.05). In conclusion, metformin and sitagliptin exerted different effects on expression of STRs and glucose transporters in the gut and kidney. STRs, downstream molecules, and glucose transporters in distal small intestinal were sensitively increased in response to sitagliptin than metformin treatment. Renal glucose transporters were downregulated after metformin and sitagliptin treatment.

Bacteroides methylmalonyl-CoA mutase produces propionate that promotes intestinal goblet cell differentiation and homeostasis.

Propionate is a short-chain fatty acid that is generated upon microbiome-mediated fiber fermentation in the intestine. By modulating immune and metabolic pathways, propionate exerts many health benefits. Key bacterial species, such as Bacteroides thetaiotaomicron, generate propionate, but the biochemical pathways and specific functions remain undetermined. We identified a gene operon-encoding methylmalonyl-CoA mutase (MCM) that contributes to propionate biosynthesis in B. thetaiotaomicron. Colonization of germ-free mice with wild-type or MCM-deficient strains as well as in vitro examination demonstrated that MCM-mediated propionate production promotes goblet cell differentiation and mucus-related gene expression. Intestinal organoids lacking the propionate receptor, GPR41, showed reduced goblet cell differentiation upon MCM-mediated propionate production. Furthermore, although wild-type B. thetaiotaomicron alleviated DSS-induced intestinal inflammation, this effect was abolished in mice receiving the MCM-deficient strain but restored upon propionate supplementation. These data emphasize the critical role of MCM-mediated propionate biosynthesis in goblet cell differentiation, offering potential pathways to ameliorate colitis.

Cushing Syndrome Is Associated With Gut Microbial Dysbiosis and Cortisol-Degrading Bacteria.

CONTEXT: Cushing syndrome (CS) is a severe endocrine disease characterized by excessive secretion of cortisol with multiple metabolic disorders. While gut microbial dysbiosis plays a vital role in metabolic disorders, the role of gut microbiota in CS remains unclear. OBJECTIVE: The objective of this work is to examine the alteration of gut microbiota in patients with CS. METHODS: We performed shotgun metagenomic sequencing of fecal samples from 78 patients with CS and 78 healthy controls matched for age and body mass index. Furthermore, we verify the cortisol degradation capacity of Ruminococcus gnavus in vitro and identify the potential metabolite by LC-MC/MS. RESULTS: We observed significant differences in microbial composition between CS and controls in both sexes, with CS showing reduced Bacteroidetes (Bacteroides vulgatus) and elevated Firmicutes (Erysipelotrichaceae_bacterium_6_1_45) and Proteobacteria (Enterobacter cloacae). Despite distinct causes of hypercortisolism in ACTH-dependent and ACTH-independent CS, we found no significant differences in metabolic profiles or gut microbiota between the 2 subgroups. Furthermore, we identified a group of gut species, including R. gnavus, that were positively correlated with cortisol levels in CS. These bacteria were found to harbor cortisol-degrading desAB genes and were consistently enriched in CS. Moreover, we demonstrated the efficient capacity of R. gnavus to degrade cortisol to 11-oxygenated androgens in vitro. CONCLUSION: This study provides evidence of gut microbial dysbiosis in patients with CS and identifies a group of CS-enriched bacteria capable of degrading cortisol. These findings highlight the potential role of gut microbiota in regulating host steroid hormone levels, and consequently host health.

Obesity-enriched gut microbe degrades myo-inositol and promotes lipid absorption.

Numerous studies have reported critical roles for the gut microbiota in obesity. However, the specific microbes that causally contribute to obesity and the underlying mechanisms remain undetermined. Here, we conducted shotgun metagenomic sequencing in a Chinese cohort of 631 obese subjects and 374 normal-weight controls and identified a Megamonas-dominated, enterotype-like cluster enriched in obese subjects. Among this cohort, the presence of Megamonas and polygenic risk exhibited an additive impact on obesity. Megamonas rupellensis possessed genes for myo-inositol degradation, as demonstrated in vitro and in vivo, and the addition of myo-inositol effectively inhibited fatty acid absorption in intestinal organoids. Furthermore, mice colonized with M. rupellensis or E. coli heterologously expressing the myo-inositol-degrading iolG gene exhibited enhanced intestinal lipid absorption, thereby leading to obesity. Altogether, our findings uncover roles for M. rupellensis as a myo-inositol degrader that enhances lipid absorption and obesity, suggesting potential strategies for future obesity management.

Gut microbiota regulates postprandial GLP-1 response via ileal bile acid-TGR5 signaling.

The gut microbiota interacts with intestinal epithelial cells through microbial metabolites to regulate the release of gut hormones. We investigated whether the gut microbiota affects the postprandial glucagon-like peptide-1 (GLP-1) response using antibiotic-treated mice and germ-free mice. Gut microbiome depletion completely abolished postprandial GLP-1 response in the circulation and ileum in a lipid tolerance test. Microbiome depletion did not influence the GLP-1 secretory function of primary ileal cells in response to stimulators in vitro, but dramatically changed the postprandial dynamics of endogenous bile acids, particularly ω-muricholic acid (ωMCA) and hyocholic acid (HCA). The bile acid receptor Takeda G protein-coupled receptor 5 (TGR5) but not farnesoid X receptor (FXR), participated in the regulation of postprandial GLP-1 response in the circulation and ileum, and ωMCA or HCA stimulated GLP-1 secretion via TGR5. Finally, fecal microbiota transplantation or ωMCA and HCA supplementation restored postprandial GLP-1 response. In conclusion, gut microbiota is indispensable for maintaining the postprandial GLP-1 response specifically in the ileum, and bile acid (ωMCA and HCA)-TGR5 signaling is involved in this process. This study helps to understand the essential interplay between the gut microbiota and host in regulating postprandial GLP-1 response and opens the foundation for new therapeutic targets.

Low Doses of Sucralose Alter Fecal Microbiota in High-Fat Diet-Induced Obese Rats.

Artificial sweeteners (AS) have been widely used as sugar substitutes to reduce calorie intake. However, it was reported that high doses of AS induced glucose intolerance via modulating gut microbiota. The objective of this study was to investigate the effects of lower doses of sucralose on fecal microbiota in obesity. Eight weeks after high-fat diet (HFD), the male Sprague Dawley rats were randomly divided into four groups (6 in each group) and administrated by a daily gavage of 2 ml normal saline (CON), 0.54 mM sucralose (N054), 0.78 mM sucralose (N078), and 324 mM sucrose (S324), respectively. After 4 weeks, fecal samples were obtained and analyzed by 16S ribosomal RNA gene sequencing. The richness and diversity of fecal microbiota were not changed by sucralose or sucrose. Both 0.54 mM (0.43 mg) and 0.78 mM (0.62 mg) sucralose tended to reduce the beneficial bacteria, Lactobacillaceae and Akkermansiaceae. The relative abundance of family Acidaminoccaceae and its genus Phascolarctobacteriam were increased after 0.54 mM sucralose. In functional prediction, 0.54 mM sucralose increased profiles of carbohydrate metabolism, whereas 0.78 mM sucralose enhanced those of amino acid metabolism. The lower doses of sucralose might alter the compositions of fecal microbiota. The effects of sucralose in different dosages should be considered in the future study.

Dapagliflozin Modulates the Fecal Microbiota in a Type 2 Diabetic Rat Model.

Background: The gut microbiota is recognized as a major modulator of metabolic disorders such as type 2 diabetes. Dapagliflozin, sodium glucose cotransporter 2 inhibitors (SGLT2i), enhances renal glucose excretion, and lowers blood glucose levels. The study aimed to determine the effects of dapagliflozin on fecal microbiota in a type 2 diabetic rat model. Methods: Four-week-old male Sprague Dawley rats (n = 24) were fed a high-fat diet (HFD) for 8 weeks and then given a single dose of STZ injection (30 mg/kg, i.p). They were randomly divided into three groups (n = 8). Each group received intragastric infusion of normal saline (2 ml, 0.9%) or metformin (215.15 mg/kg/day) or dapagliflozin (1 mg/kg/day) for 4 weeks. Blood glucose levels and plasma insulin levels were detected during intragastric glucose tolerance. Fecal samples were collected to access microbiome by 16S ribosomal RNA gene sequencing. Results: Dapagliflozin significantly decreased fasting and postprandial blood glucose levels as metformin in type 2 diabetic rats (P < 0.001). Enterotype was composed of Ruminococcaceae after treatment of dapagliflozin, whereas Ruminococcaceae and Muribaculaceae were the main enterotypes following metformin treatment. Dapagliflozin did not increase the abundance of beneficial bacteria including Lactobacillaceae and Bifidobacteriaceae. However, these were increased in the metformin group. It is surprising to find that Proteobacteria (especially Desulfovibrionaceae) were enriched in the dapagliflozin group. Conclusion: Dapagliflozin and metformin exerted complementary effects on the main beneficial bacteria. A combination of these two drugs might be beneficial to improve the structure of fecal microbiota in the treatment of type 2 diabetes.

Effects of metformin, acarbose, and sitagliptin monotherapy on gut microbiota in Zucker diabetic fatty rats.

Objective: Recent studies have demonstrated that gut microbiota was closely related to metabolic disorders such as type 2 diabetes. Oral antidiabetic medications including metformin, acarbose and sitagliptin lowered blood glucose levels via acting on the gastrointestinal tract. The aim of the study was to observe the comparisons among those medications on gut microbiota composition. Research design and methods: Zucker diabetic fatty rats (n=32) were randomly divided into four groups, and had respectively gastric administration of normal saline (control), metformin (215.15 mg/kg/day), acarbose (32.27 mg/kg/day), or sitagliptin (10.76 mg/kg/day) for 4 weeks. Blood glucose levels were measured during an intragastric starch tolerance test after the treatments. 16S rRNA gene sequencing was used to access the microbiota in the fecal samples. Results: Metformin, acarbose, and sitagliptin monotherapy effectively decreased fasting and postprandial blood glucose levels (p<0.001). Acarbose group displayed specific cluster and enterotype mainly composed by Ruminococcus 2 while Lactobacillus was the dominant bacterium in the enterotype of the other three groups. The relative abundance of genera Ruminococcus 2 and Bifidobacterium was dramatically higher in acarbose group. Metformin and sitagliptin increased the relative abundance of genus Lactobacillus. Metagenomic prediction showed that the functional profiles of carbohydrate metabolism were enriched in acarbose group. Conclusions: Metformin, acarbose and sitagliptin exerted different effects on the composition of gut microbiota and selectively increased the beneficial bacteria. Supplementation with specific probiotics may further improve the hypoglycemic effects of the antidiabetic drugs.