Melatonin improved glucose homeostasis is associated with the reprogrammed gut microbiota and reduced fecal levels of short‐chain fatty acids in db/db mice

Food Science & Nutrition · 11 authors, 6 centres

AI SUMMARY

FIDELITY 88%

POPULATIONTen-week-old male C57BL/KsJ-db/db mice (type 2 diabetes model with leptin receptor deficiency) and age-matched wild-type C57BL/6J-db/m mice

INTERVENTIONMelatonin administered via drinking water at 0.25 mg/mL (M1, ~65 mg/kg/day) or 0.50 mg/mL (M2, ~130 mg/kg/day) for 12 weeks

COMPARISONdb/db mice with plain water (Ctrl) and age-matched wild-type db/m mice (standard control)

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TL;DR

Melatonin supplementation (0.25% and 0.50% in drinking water for 12 weeks) improved insulin sensitivity and reduced fasting blood glucose in db/db mice, a type 2 diabetes model. These improvements were associated with reprogramming of gut microbiota composition and significant reductions in fecal short-chain fatty acids (SCFAs), particularly acetic acid and total SCFAs, which were positively correlated with HOMA-IR and fasting glucose. The findings suggest melatonin's glucose-lowering effects may be mediated through gut microbiota modulation and reduced SCFA production, highlighting a potential adjunctive role for melatonin in diabetes management.

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**Background:** Melatonin, a pineal gland hormone, regulates circadian rhythm and has shown potential to improve glycolipid metabolism. While melatonin is known to influence gut microbiota and glucose homeostasis via receptor signaling pathways, the contribution of gut microbiota modulation to melatonin's glucose-lowering effects in diabetes had not been comprehensively investigated. Short-chain fatty acids (SCFAs), key gut microbiota metabolites, have conflicting roles in metabolic health—some studies suggest they are beneficial, while others indicate overproduction may be detrimental in obesity and diabetes.

**Methods:** Ten-week-old male db/db mice (leptin receptor-deficient type 2 diabetes model) were divided into three groups (n=6 per group): control (plain water), low-dose melatonin (0.25 mg/mL, ~65 mg/kg/day), and high-dose melatonin (0.50 mg/mL, ~130 mg/kg/day) administered via drinking water for 12 weeks. Six age-matched wild-type db/m mice served as standard controls. Fluid intake, urine output, and food intake were measured weekly. Fasting blood glucose (FBG) was measured every 6 weeks. At week 12, insulin tolerance test (ITT) was performed (0.3 U/kg insulin, intraperitoneal). Serum insulin, HbA1c, and lipid profiles (TC, TG, HDL-C, LDL-C) were measured. HOMA-IR was calculated as [Glucose (mmol/L) × Insulin (mU/L)] ÷ 22.5. Fecal SCFAs (acetic, butyric, isovaleric, caproic, isobutyric, valeric, propionic acids) were quantified by GC-MS. Gut microbiota was profiled by 16S rRNA gene sequencing (V3+V4 regions) on NovaSeq6000. Hepatic mRNA expression of gluconeogenic genes (FBP1, Foxo1α, TXNIP, PEPCK, PEPCK1, G6Pc, Trx1) was measured by qRT-PCR. Statistical analysis used two-way ANOVA with post-hoc Bonferroni or Student's t-test; Pearson correlation analysis was performed for associations among microbiota, SCFAs, and diabetes parameters.

**Key Results:** Melatonin significantly reduced fluid intake and urine output in db/db mice without affecting food intake or body weight. High-dose melatonin (M2) significantly improved insulin sensitivity, reflected by decreased HOMA-IR index and reduced AUC of ITT. FBG and HbA1c levels were significantly lowered in both melatonin-treated groups. Serum TC, TG, HDL-C, and LDL-C were elevated in db/db mice versus db/m mice, and melatonin did not prevent these elevations. At the hepatic level, melatonin downregulated mRNA expression of gluconeogenic genes: FBP1, Foxo1α, Trx1, TXNIP, PEPCK1, PEPCK, and G6Pc. Gut microbiota analysis showed that melatonin altered microbial community structure (beta-diversity) without significantly changing alpha-diversity. High-dose melatonin significantly reduced Lachnospiraceae family and unidentified_Lachnospiraceae genus (SCFA-producing bacteria), increased Parabacteroides (including P. goldsteinii), increased Bacteroides (including B. stercorirosoris and B. sartorii), reduced Dubosiella, and increased Alistipes. Fecal SCFA analysis revealed that acetic acid (the most abundant SCFA) was significantly increased in db/db mice versus db/m mice; high-dose melatonin significantly decreased acetic acid, butyric acid, isovaleric acid, caproic acid, isobutyric acid, and total SCFAs. Low-dose melatonin showed similar trends but did not reach statistical significance. Correlation analysis demonstrated that acetic acid and total SCFA levels were positively correlated with HOMA-IR index (acetic acid: p<.05; total SCFAs: p<.01) and FBG levels (acetic acid: p<.05; total SCFAs: p<.01). Specific SCFAs showed both positive and negative correlations with various bacterial taxa at order and species levels.

**Clinical Implications:** This study provides evidence that melatonin supplementation improves glucose homeostasis in a type 2 diabetes model through mechanisms involving gut microbiota reprogramming and reduced fecal SCFA levels, particularly acetic acid and total SCFAs. The positive correlation between fecal SCFAs and diabetes parameters (HOMA-IR, FBG) suggests that in hyperglycemic conditions, overproduction of SCFAs may be deleterious, and reducing SCFA levels could be beneficial—contrasting with findings in dietary fiber supplementation studies where SCFA deficiency exists. These results support the potential of melatonin as an adjunctive therapy for type 2 diabetes, though the authors acknowledge limitations including lack of data on melatonin/metabolite concentrations in organs and blood, absence of germ-free or antibiotic-treated animal experiments to establish causality, and the need to investigate glucagon's counterregulatory role. The high safety profile of melatonin and its potential synergistic effects with polyphenols (e.g., EGCG) are noted as promising areas for future research.

PICO

PPOPULATION

Ten-week-old male C57BL/KsJ-db/db mice (type 2 diabetes model with leptin receptor deficiency) and age-matched wild-type C57BL/6J-db/m mice

IINTERVENTION

Melatonin administered via drinking water at 0.25 mg/mL (M1, ~65 mg/kg/day) or 0.50 mg/mL (M2, ~130 mg/kg/day) for 12 weeks

OOUTCOME

Fasting blood glucose, insulin tolerance test (ITT), HOMA-IR, serum insulin, HbA1c, fecal SCFA levels (acetic, butyric, isovaleric, caproic, isobutyric, valeric, propionic acids), gut microbiota composition (16S rRNA sequencing), hepatic gluconeogenic gene expression (FBP1, Foxo1α, TXNIP, PEPCK, PEPCK1, G6Pc, Trx1)

STUDY TYPE

other

SPECIALTY

endocrinology

SUMMARISED BY

AI pipeline

FIDELITY CHECK

88% · B

ORIGINAL PAPER

PMC10084979

Melatonin improved glucose homeostasis is associated with the reprogrammed gut microbiota and reduced fecal levels of short‐chain fatty acids in db/db mice

Food Science & Nutrition

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ABSTRACT

Abstract Accumulated evidence shows that melatonin possesses the potential to improve lipid metabolism by modifying gut microbiota and glucose metabolism via regulating the melatonin receptor signaling pathway. However, the contribution of melatonin consumption on glucose homeostasis by affecting gut microbiota has not been investigated in diabetes. In the current work, we investigated the effect of melatonin administration on gut microbiota and glucose homeostasis in db/db mice, a type 2 diabetes model with leptin receptor deficiency. Administration of melatonin through drinking water (at 0.25% and 0.50%) for 12 weeks decreased diabetic polydipsia and polyuria, increased insulin sensitivity and impeded glycemia. The accumulated fecal levels of total short‐chain fatty acids (SCFAs) and acetic acid are positively correlated with diabetes‐related parameters—homeostasis model assessment of insulin resistance (HOMA‐IR) index and fasting blood glucose (FBG) level. The reprogramming of gut microbiota structure and abundance and the reduction of fecal levels of SCFAs, including acetic acid, butyric acid, isovaleric acid, caproic acid, and isobutyric acid, by melatonin may be beneficial for enhancing insulin sensitivity and lowering FBG, which were verified by the results of correlation analysis between acetic acid or total SCFAs and HOMA‐IR and FBG. In addition, the melatonin downregulated hepatic genes, including fructose‐1,6‐bisphosphatase 1, forkhead box O1 alpha, thioredoxin‐interacting protein, phosphoenolpyruvate carboxy‐kinase (PEPCK), PEPCK1 and a glucose‐6‐phosphatase catalytic subunit, that responsible for gluconeogenesis support the result that melatonin improved glucose metabolism. Overall, results showed that the melatonin supplementation reduced fecal SCFAs level via reprogramming of gut microbiota, and the reduction of fecal SCFAs level is associated with improved glucose homeostasis in db/db mice.

CITATION EXPORT

Qiuyan Ban, Wenjing Chi, Yu Tan et al.. Melatonin improved glucose homeostasis is associated with the reprogrammed gut microbiota and reduced fecal levels of short‐chain fatty acids in db/db mice. Food Science & Nutrition. (2023). https://doi.org/10.1002/fsn3.3237

AUTHORS

11 · 6 CENTRES

Qiuyan Ban, Wenjing Chi, Yu Tan, Shiqiong Wang, Ning Li, Lianjun Song, Xianqing Huang, Dongxu Wang, Wanxi Peng, Daniel Granato, Guangshan Zhao

1 Department of Tea Science, College of Horticulture Henan Agricultural University Zhengzhou China
2 Department of Cell Biology, College of Life Science and Technology Jinan University Guangzhou China
3 Innovation Team of Food Nutrition and Safety Control, College of Food Science & Technology Henan Agricultural University Zhengzhou China
4 School of Grain Science and Technology Jiangsu University of Science and Technology Zhenjiang China
5 Henan Province Engineering Research Center for Biomass Value‐added Products, School of Forestry Henan Agricultural University Zhengzhou China
6 Bioactivity and Applications Lab, Department of Biological Sciences, Faculty of Science and Engineering University of Limerick Limerick Ireland