A story of metformin-butyrate synergism to control various pathological conditions as a consequence of gut microbiome modification: Genesis of a wonder drug?

Maniar, Kunal; Moideen, Amal; Mittal, Ankur; Patil, Amol; Chakrabarti, Amitava; Banerjee, Dibyajyoti

doi:10.1016/j.phrs.2016.12.003

Cited by 59 publications

(68 citation statements)

References 350 publications

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“…An abnormal change in the gut microbiota composition suggests dysbiosis of the gut microenvironment. Gut microbiota diversity decreases significantly in people with type-2 diabetes mellitus (T2DM) [12], but gut-flora diversity only declines slightly in T2DM patients compared with healthy individuals [32]. The gut microbiota composition decreases in T1DM patients [33].…”

Section: Discussionmentioning

confidence: 99%

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Magnesium lithospermate B improves the gut microbiome and bile acid metabolic profiles in a mouse model of diabetic nephropathy

et al. 2018

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Magnesium lithospermate B (MLB) is a new drug marketed in China to treat angina, but its low oral bioavailability limits its clinical application to the intravenous route. Paradoxically, orally administered low-dose MLB was found to alleviate kidney injury in diabetic nephropathy (DN) rats, but its mechanism of action remains unknown. In recent years, the kidney-gut axis has been suspected to be involved in kidney damage pathogenesis, potentially representing a non-classical pathway for pharmacologic intervention. To ascertain whether MLB targets the kidney-gut axis, streptozotocin (STZ)-treated mice were prepared as a mouse model of DN. The STZ mice were treated with MLB (50 mg kg d, p.o.) for 8 weeks. Twenty-four-hour urinary albumin was detected to mirror kidney function. At week 4, 6, 8, feces were collected; bile acids (BAs) were quantified to examine the alterations in the BA metabolic profiles, and bacterial 16S rRNA gene fragments were sequenced to identify alterations in gut microbial composition. In STZ mice, 24-h urinary albumin levels and total fecal BAs, especially cholic acids (CAs) and deoxycholic acids (DCAs) were greatly increased, and the gut microbiome was dramatically shifted compared with control mice. Oral administration of MLB significantly decreased 24-h urinary albumin levels and total BAs, CAs and DCAs, and reversed CA:TCA (taurocholic acid) and DCA:CA ratios. It also changed the microbiome composition in STZ mice based on operational units. Thus the therapeutic effect of MLB on kidney injury might be attributed (at least partially) to its ability to modulate the disordered gut microbiome and BA metabolism.

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Section: Discussionmentioning

confidence: 99%

“…The gut microbiome can shift markedly in CKD patients and uremic rats [7]. Gut microbiotaderived metabolites, such as ammonia [8,9], indoxyl sulfate, pcresyl sulfate [10], short-chain fatty acids [11,12], and lipopolysaccharides [13] may be associated with kidney injury and DM progression.…”

Section: Introductionmentioning

confidence: 99%

Magnesium lithospermate B improves the gut microbiome and bile acid metabolic profiles in a mouse model of diabetic nephropathy

et al. 2018

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“…Metformin, now a first‐line oral antidiabetic drug recommended for the treatment of type 2 diabetes mellitus, exerts an insulin sensitizing effect and may have anti‐inflammatory, anti‐ageing, anticancer, and even antimicrobial effects . It is interesting that the early Finnish study showed a paradox of a positive association with obesity and a negative association with diabetes .…”

Section: Introductionmentioning

confidence: 99%

Metformin reduces risk of varicose veins in patients with type 2 diabetes

Tseng

2019

Diabetes Metabolism Res

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Aim: This population-based retrospective cohort study compared the incidence of varicose veins in an unmatched cohort and a cohort of 1:1 propensity score (PS)matched pairs of ever and never users of metformin in type 2 diabetes patients. Methods: Patients with new-onset type 2 diabetes during 1999 to 2005 were enrolled from Taiwan's National Health Insurance and followed until December 31, 2011. Analyses were conducted in an unmatched cohort of 123 710 ever users and 15 095 never users and in 15 088 PS-matched pairs of ever users and never users.Hazard ratios were estimated by Cox proportional hazards model incorporated with the inverse probability of treatment weighting using the PS. Results: New-onset varicose veins were diagnosed in 126 never users and 633 ever users in the unmatched cohort and in 126 never users and 80 ever users in the matched cohort. The respective incidences were 191.36 and 110.04 per 100 000 person-years in the unmatched cohort and 191.41 and 115.81 per 100 000 person-years in the matched cohort. The hazard ratio for ever versus never users in the unmatched cohort was 0.57 (95% confidence interval, 0.47-0.69) and was 0.60 (0.45-0.80) for the matched cohort. In the unmatched cohort, the hazard ratios for the first, second, and third tertiles of cumulative duration were 1.03 (0.83-1.28), 0.55 (0.44-0.69), and 0.29 (0.23-0.37), respectively. The respective hazard ratios in the matched cohort were 0.97 (0.65-1.43), 0.79 (0.55-1.15), and 0.24 (0.13-0.42). Conclusion: Metformin use is associated with a lower risk of varicose veins in patients with type 2 diabetes. KEYWORDS diabetes mellitus, metformin, Taiwan, varicose veins 1 | INTRODUCTION Varicose veins often start from the lower extremities and are always diagnosed by physicians at a stage with clinical manifestations of oedema, engorging and tortuous veins, or venous ulceration. It affects more women than men in most populations. 1 An early survey in Fin-land showed that the prevalence rates of physician-diagnosed varicose veins were 25% in women and 7% in men. 2 However, reported prevalence rates varied remarkably in different studies, from less than 1% to 73% in women and 2% to 56% in men. 1 The Finnish study identified risk factors such as age, body height, body mass index, standing at work, high socio-economic status, and the numbers of births (in women). 2 Interestingly, diabetes was negatively associated with varicose veins in this early study. 2 The positive association between varicose veins and obesity has been confirmed in a recent study, 3 but the negative association with diabetes has not gained much attention and has been rarely investigated in other epidemiological studies.Because obesity and diabetes are both characterized by increased

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“…Recently, an oral anti-diabetic agent, metformin, was proven to have beneficial effects on the gut microbiome in moderate hyperglycemia [ 15 ]. In a clinical trial, vildagliptin decreased the HbA1c and fasting blood glucose levels as an add-on therapy in patients with type 2 diabetes inadequately controlled by metformin [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

Vildagliptin increases butyrate-producing bacteria in the gut of diabetic rats

Zhang

Xiao

et al. 2017

PLoS ONE

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Emerging evidence supports a key role for the gut microbiota in metabolic diseases, including type 2 diabetes (T2D) and obesity. The dipeptidyl peptidase-4 inhibitor vildagliptin is highly efficacious in treating T2D. However, whether vildagliptin can alter the gut microbiome is still unclear. This study aimed to identify whether vildagliptin modifies the gut microbiota structure during T2D treatment. Diabetic Sprague-Dawley (SD) rats were induced by a high-fat diet and streptozotocin injection (HFD/STZ). Diabetic rats were orally administered a low dose of vildagliptin (LV, 0.01 g/kg/d vildagliptin), high dose of vildagliptin (HV, 0.02 g/kg/d vildagliptin), or normal saline for 12 weeks. Fasting blood glucose, blood glucose after glucose loading, and serum insulin levels were significantly reduced in the LV and HV groups compared with those in the T2D group. The serum GLP-1 level increased more in the vildagliptin-treated group than in the T2D group. Pyrosequencing of the V3-V4 regions of 16S rRNA genes revealed that vildagliptin significantly altered the gut microbiota. The operational taxonomic units (OTUs) and community richness (Chao1) index were significantly reduced in the vildagliptin and diabetic groups compared with those in the control group. At the phylum level, a higher relative abundance of Bacteroidetes, lower abundance of Firmicutes, and reduced ratio of Fimicutes/Bacteroidetes were observed in the vildagliptin-treated group. Moreover, vildagliptin treatment increased butyrate-producing bacteria, including Baceroides and Erysipelotrichaeae, in the diabetic rats. Moreover, Lachnospira abundance was significantly negatively correlated with fasting blood glucose levels. In conclusion, vildagliptin treatment could benefit the communities of the gut microbiota.

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A story of metformin-butyrate synergism to control various pathological conditions as a consequence of gut microbiome modification: Genesis of a wonder drug?

Cited by 59 publications

References 350 publications

Magnesium lithospermate B improves the gut microbiome and bile acid metabolic profiles in a mouse model of diabetic nephropathy

Magnesium lithospermate B improves the gut microbiome and bile acid metabolic profiles in a mouse model of diabetic nephropathy

Metformin reduces risk of varicose veins in patients with type 2 diabetes

Vildagliptin increases butyrate-producing bacteria in the gut of diabetic rats

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