Gut microbiota as a target for prevention and treatment of type 2 diabetes: Mechanisms and dietary natural products

Type 2 diabetes mellitus (T2DM) is among the most remarkable public health concerns globally. Accumulating research evidence documents that alteration of gut microbiota has an indispensable role in the onset and progression of obesity and T2DM. A reduced microbial diversity is linked to insulin resistance and energy metabolism, especially for the rise of the Firmicutes/Bacteroidetes ratio. Changes in metabolites followed by the gut dysbacteriosis are linked to the presence of T2DM. Moreover, endotoxin leakage and gut permeability caused by gut dysbacteriosis is more of a trigger for the onset and progression of T2DM. Research documents that natural products are remarkable arsenals of bioactive agents for the discovery of anti-T2DM drugs. Many studies have elucidated that the possible mechanisms of the anti-T2DM effects of natural products are remarkably linked to its regulation on the composition of gut microflora and the successive changes in metabolites directly or indirectly. This review presents a brief overview of the gut microbiota in T2DM and several relevant mechanisms, including short-chain fatty acids, biosynthesis and metabolism of branched-chain fatty acids, trimethylamine N-oxide, bile acid signaling, endotoxin leakage, and gut permeability, and describes how dietary natural products can improve T2DM via the gut microbiota.     

Holistic perspective of the role of gut microbes in diabetes mellitus and its management

The gut microbiota (GM) plays a role in the development and progression of type 1 and type 2 diabetes mellitus (DM) and its complications. Gut dysbiosis contributes to the pathogenesis of DM. The GM has been shown to influence the efficacy of different antidiabetic medications. Intake of gut biotics, like prebiotics, probiotics and synbiotics, can improve the glucose control as well as the metabolic profile associated with DM. There is some preliminary evidence that it might even help with the cardiovascular, ophthalmic, nervous, and renal complications of DM and even contribute to the prevention of DM. More large-scale research studies are needed before wide spread use of gut biotics in clinical practice as an adjuvant therapy to the current management of DM.     

Renin-angiotensin system blockers-SGLT2 inhibitors-mineralocorticoid receptor antagonists in diabetic kidney disease: A tale of the past two decades!

Several pharmacological agents to prevent the progression of diabetic kidney disease (DKD) have been tested in patients with type 2 diabetes mellitus (T2DM) in the past two decades. With the exception of renin-angiotensin system blockers that have shown a significant reduction in the progression of DKD in 2001, no other pharmacological agent tested in the past two decades have shown any clinically meaningful result. Recently, the sodium-glucose cotransporter-2 inhibitor (SGLT-2i), canagliflozin, has shown a significant reduction in the composite of hard renal and cardiovascular (CV) endpoints including progression of end-stage kidney disease in patients with DKD with T2DM at the top of renin-angiotensin system blocker use. Another SGLT-2i, dapagliflozin, has also shown a significant reduction in the composite of renal and CV endpoints including death in patients with chronic kidney disease (CKD), regardless of T2DM status. Similar positive findings on renal outcomes were recently reported as a top-line result of the empagliflozin trial in patients with CKD regardless of T2DM. However, the full results of this trial have not yet been published. While the use of older steroidal mineralocorticoid receptor antagonists (MRAs) such as spironolactone in DKD is associated with a significant reduction in albuminuria outcomes, a novel non-steroidal MRA finerenone has additionally shown a significant reduction in the composite of hard renal and CV endpoints in patients with DKD and T2DM, with reasonably acceptable side effects.     

The crosstalk of gut microbiota and chronic kidney disease: role of inflammation,proteinuria, hypertension,and diabetes mellitus

Chronic kidney disease (CKD) has been shown to result in profound changes in the composition and functions of the gut microbial flora which by disrupting intestinal epithelial barrier and generating toxic by-products contributes to systemic inflammation and the associated complications. On the other hand, emerging evidence points to the role of the gut microbiota in the development and progression of CKD by provoking inflammation, proteinuria, hypertension, and diabetes. These observations demonstrate the causal interconnection between the gut microbial dysbiosis and CKD. The gut microbiota closely interacts with the inflammatory, renal, cardiovascular, and endocrine systems via metabolic, humoral, and neural signaling pathways, events which can lead to chronic systemic inflammation, proteinuria, hypertension, diabetes, and kidney disease. Given the established role of the gut microbiota in the development and progression of CKD and its complications, favorable modification of the composition and function of the gut microbiome represents an appealing therapeutic target for prevention and treatment of CKD. This review provides an overview of the role of the gut microbial dysbiosis in the pathogenesis of the common causes of CKD including hypertension, diabetes, and proteinuria as well as progression of CKD.     

Diabetic kidney disease in pediatric patients: A current review

In the last decades, a significant increase in the incidence of diabetic kidney disease (DKD) was observed concomitant with rising diabetes mellitus (DM) incidence. Kidney disease associated with DM in children and adolescents is represented by persistent albuminuria, arterial hypertension, progressive decline in estimated glomerular filtration rate to end-stage renal disease and increased cardiovascular and all-cause morbidity and mortality of these conditions. In medical practice, the common and still the “gold standard” marker for prediction and detection of diabetic kidney involvement in pediatric diabetes is represented by microalbuminuria screening even if it has low specificity to detect early stages of DKD. There are some known limitations in albuminuria value as a predictor biomarker for DKD, as not all diabetic children with microalbuminuria or macroalbuminuria will develop end-stage renal disease. As tubular damage occurs before the glomerular injury, tubular biomarkers are superior to the glomerular ones. Therefore, they may serve for early detection of DKD in both type 1 DM and type 2 DM. Conventional and new biomarkers to identify diabetic children and adolescents at risk of renal complications at an early stage as well as renoprotective strategies are necessary to delay the progression of kidney disease to end-stage kidney disease. New biomarkers and therapeutic strategies are discussed as timely diagnosis and therapy are critical in the pediatric diabetic population.     

加强对正常蛋白尿糖尿病肾脏疾病的认识

糖尿病肾脏疾病(DKD)是导致终末期肾脏病(ESRD)的主要原因,早期及时诊断对防治DKD进展非常重要。以往DKD临床诊断多注重尿白蛋白排泄率(UAER),并以此作为诊断与临床分期的重要依据。实际上许多糖尿病(DM)有时表现为无临床诊断价值的蛋白尿,而以肾功能减退为突出肾脏受累表现,即正常蛋白尿糖尿病肾脏疾病(NADKD),或称无蛋白尿糖尿病肾病(nonalbuminuric diabetic nephropathy),及糖尿病无蛋白尿肾功能不全(nonalbuminuric renal impairment in diabetes)。本文结合国内外研究现状,从流行病学、病理、临床特征、诊断及治疗等方面对NADKD进行了描述,以翼引起同行重视。     

Efficacy of probiotics on the modulation of gut microbiota in the treatment of diabetic nephropathy

Diabetic nephropathy (DN) is a major cause of end-stage renal disease, and therapeutic options for preventing its progression are insufficient. The number of patients with DN has been increasing in Asian countries because of westernization of dietary lifestyle, which may be associated with the following changes in gut microbiota. Alterations in the gut microbiota composition can lead to an imbalanced gastrointestinal environment that promotes abnormal production of metabolites and/or inflammatory status. Functional microenvironments of the gut could be changed in the different stages of DN. In particular, altered levels of short chain fatty acids, D-amino acids, and reactive oxygen species biosynthesis in the gut have been shown to be relevant to the pathogenesis of the DN. So far, evidence suggests that the gut microbiota may play a key role in determining networks in the development of DN. Interventions directing the gut microbiota deserve further investigation as a new protective therapy in DN. In this review, we discuss the potential roles of the gut microbiota and future perspectives in the protection and/or treatment of kidneys.     

Impact of gut microbiota on kidney transplantation

Kidney transplantation is recognized as one of the most effective treatments for patients who suffer from end-stage renal disease. The major potential outcomes following kidney transplantation include engraftment, rejection, and associated complications. The outcomes are dependent on a variety of factors in those who underwent renal grafts or kidney transplant recipients. Those factors include the administration of immunosuppressive drugs and prophylactic antimicrobial agents to recipients. Recent studies have shown that gut microbiota play an important role in the outcome of subjects with kidney transplantation. An imbalance of the components/diversity of gut microbiota, known as gut dysbiosis, has been shown to have a big impact on the immune system of the host and the modification of host inflammatory cytokines. Although gut dysbiosis is affected by variation in diet and medication, a substantial amount of evidence showing a link between alteration in human gut microbiota and outcomes of kidney transplantation has recently been reported. Therefore, the objective of this review is to comprehensively summarize and discuss the major findings from in vivo and clinical data pertaining to the impact of gut microbiota on kidney transplantation. Any controversial findings are compiled to enable a clear overview of the role of gut microbiota and the outcome of kidney transplantation.     

微小RNA在糖尿病肾病发病机制中的研究进展

糖尿病肾病(diabetic kidney disease,DKD)是糖尿病(diabetes mellitus,DM)引起的微血管并发症之一,是DM患者预期寿命减少的主要原因.现已明确DKD发病机制与细胞外基质积累、氧化应激、炎症反应、自噬等有关.微小RNA(microRNA,miRNA)很稳定,可以在人的体液中检测...     

Prediction models for risk of diabetic kidney disease in Chinese patients with type 2 diabetes mellitus

BackgroundDiabetic kidney disease (DKD) is a common and serious complication in patients with diabetic mellitus (DM), the risk of cardiovascular events and all-cause mortality also increases in DKD patients. This study aimed to detect the influencing factors of DKD in type 2 DM (T2DM) patients, and construct DKD prediction models and nomogram for clinical decision-making.MethodsA total of 14,628 patients with T2DM were included. These patients were divided into pre-DKD and non-DKD groups, depending on the occurrence of DKD during a 3-year follow-up from first clinic attendance. The influencing indicators of DKD were analyzed, the prediction models were established by multivariable logistic regression, and a nomogram was drawn for DKD risk assessment.ResultsTwo prediction models for DKD were built by multivariate logistic regression analysis. Model 1 was created based on 17 variables using the forward selection method, Model 2 was established by 19 variables using the backward elimination method. The Somers’ D values of both models were 0.789. Four independent predictors were selected to build the nomogram, including age, UACR, eGFR, and neutrophil percentages. The C-index of the nomogram reached 0.864, suggesting a good predictive accuracy for DKD development.ConclusionsOur prediction models had strong predictive powers, and our nomogram provided visual aids to DKD risk calculation, which was simple and fast. These algorithms can provide early DKD risk prediction, which might help to improve the medical care for early detection and intervention in T2DM patients, and then consequently improve the prognosis of DM patients.     

Is bariatric surgery resolving NAFLD via microbiota-mediated bile acid ratio reversal? A comprehensive review

Despite the fact that there is still insufficient evidence to consider non-alcoholic fatty liver disease (NAFLD) as an stand-alone indication for bariatric surgery, many clinical and histopathological beneficial effects on both NAFLD and non-alcoholic steatohepatitis (NASH) have been shown. Although weight loss seems to be the obvious mechanism, weight-loss independent factors are also believed to be involved. Among them, changes in gut microbiota and bile acids (BA) composition may be playing an unappreciated role in the improvement of NAFLD. In this review we examine the mechanisms and interdependence of the gut microbiota and BA, and their influence on NAFLD pathogenesis and its reversal following bariatric surgery. According to the currently available evidence, gut microbiota has a major influence on BA composition. In fact, both BA and microbiome disturbances (dysbiosis) play a role in the etiopathogenesis of NAFLD and might be potential therapeutic targets. In addition, bariatric surgery can modify the intraluminal ileal environment in a way that causes significant repopulation of the gut microbiota and a reversal of the plasma primary/secondary BA ratio, which, in turn, induces weigh-independent metabolic improvements.     

Probiotics and fecal microbiota transplantation in surgical disorders

The importance of the gut microbiota in health and disease has led to interest in developing methods to modify it. Probiotics administration and fecal microbiota transplantation (FMT) are two such approaches that can alter the gut microbiota, potentially offering health benefits by blocking gut colonization by pathogenic organisms and preventing a maladaptive immune response. Both methods have been studied in a variety of settings relevant to colorectal surgeons, including colorectal cancer, inflammatory bowel disease, Clostridium difficile colitis, and surgical site infections. However, both therapies offer risks and benefits in surgical patients. Probiotics allow for targeted alterations of the microbiome, but lingering questions remain regarding strain selection. FMT offers to more completely restore the healthy gut microbial ecosystem but it is difficult to study in animals and to determine its precise mechanism of action. Standardizing study methodologies and using modern molecular and genetic techniques to elucidate the mechanisms of action will be needed to determine the role of probiotic administration and FMT in treating or preventing complications in patients undergoing major abdominal surgery.     

肠菌移植治疗骨质疏松症的研究进展及临床前景

骨质疏松症是临床上常见的骨代谢性疾病,骨折风险高,致残、致死率高.我国正逐步进入老龄化社会,骨质疏松症已经成为影响老年人身体健康的重大公共健康问题.近年来,肠道菌群与骨代谢的关联受到了越来越多的关注,肠道菌群与骨质疏松症之间存在密切关系.肠菌移植是指将肠道菌群从健康的供体转移到肠道菌群失调的受体,其目的是恢复肠道微生物...     

The gut microbiota regulates bone mass in mice

The gut microbiota modulates host metabolism and development of immune status. Here we show that the gut microbiota is also a major regulator of bone mass in mice. Germ-free (GF) mice exhibit increased bone mass associated with reduced number of osteoclasts per bone surface compared with conventionally raised (CONV-R) mice. Colonization of GF mice with a normal gut microbiota normalizes bone mass. Furthermore, GF mice have decreased frequency of CD4(+) T cells and CD11b(+) /GR 1 osteoclast precursor cells in bone marrow, which could be normalized by colonization. GF mice exhibited reduced expression of inflammatory cytokines in bone and bone marrow compared with CONV-R mice. In summary, the gut microbiota regulates bone mass in mice, and we provide evidence for a mechanism involving altered immune status in bone and thereby affected osteoclast-mediated bone resorption. Further studies are required to evaluate the gut microbiota as a novel therapeutic target for osteoporosis.     

肠道菌群调节肠道MicroRNA治疗骨质疏松症

骨质疏松症是以骨量减少,骨组织结构退化进而极易导致骨质疏松性骨折的一类疾病。严重影响患者生活质量,同时也带来了极大的经济负担。近年来有关调节肠道菌群进而干预骨质疏松症的研究逐渐兴起。炎症性肠病是由肠道菌群失调引起的炎症免疫变态反应,而炎症性肠病与骨量丢失密切相关。近来有研究表明肠道菌群与肠道MicroRNA直接的相互作用可以治疗炎症性肠病。为此,我们提出设想,肠道菌群可能调节肠道MicroRNA具有治疗骨质疏松症潜力,现从肠道菌群与骨质疏松症;MicroRNA与骨质疏松症;肠道菌群与MicroRNA;炎症性肠病与骨质疏松症四方面展开综述,支持肠道菌群通过调节肠道MicroRNA治疗骨质疏松症的观点,为骨质疏松症治疗提供新思路。     

肠道微生物与骨质疏松症的相关性研究进展

骨质疏松症作为骨骼退化性疾病，严重影响患者的生命质量，并给患者带来一定的经济和心理压力。近年来，肠道微生物作为被遗忘的“器官”逐渐成为研究热点，最近研究发现肠道微生物和骨质疏松症有着很高的相关性。笔者对最近有关肠道微生物和骨质疏松症的研究成果进行综述，希望为防治骨质疏松症提供新的研究靶点，为临床治疗提供新的思路。     

Micro-inflammation et translocation bactérienne d’origine digestive dans la maladie rénale chronique

Micro-inflammation has been recognized as a major factor associated with the poor prognosis of patients with chronic kidney disease. Those patients have an increased rate of pro-inflammatory markers like interleukin 6, C-Reactive protein, Tumor Necrosis Factor α and fibrinogen. Among multiple and complex causes of micro-inflammation the gut microbiota could be an important actor considering the dysbiosis in chronic kidney disease which would enhance the synthesis of uremic toxins with cardiovascular toxicity and the bacterial translocation. This review details the role of the gut microbiota in human pathology and in chronic kidney disease focusing on the bacterial translocation that could occur because of an impaired digestive permeability. This bacterial translocation could induce a chronic immune response and could take part in the raise of pro-inflammatory markers in chronic kidney disease. New therapeutic strategies aiming at preventing metabolic and cardiovascular complications could emerge from the understanding of the relationships between gut microbiota and host in this particular pathology.     

Crosstalk between gut microbiota and antidiabetic drug action

Type 2 diabetes(T2 D) is a disorder characterized by chronic inflated blood glucose levels(hyperglycemia), at first due to insulin resistance and unregulated insulin secretion but with tendency towards global spreading. The gut microbiota is recognized to have an influence on T2 D, although surveys have not formed a clear overview to date. Because of the interactions between gut microbiota and host homeostasis, intestinal bacteria are believed to play a large role in various diseases, including metabolic syndrome, obesity and associated disease. In this review, we highlight the animal and human studies which have elucidated the roles of metformin, α-glucosidase inhibitors, glucagon-like peptide-1 agonists,peroxisome proliferator-activated receptors γ agonists, inhibitors of dipeptidyl peptidase-4, sodium/glucose cotransporter inhibitors, and other less studied medications on gut microbiota. This review is dedicated to one of the most widespread diseases, T2 D, and the currently used antidiabetic drugs and most promising new findings. In general, the gut microbiota has been shown to have an influence on host metabolism, food consumption, satiety, glucose homoeostasis, and weight gain. Altered intestinal microbiota composition has been noticed in cardiovascular diseases, colon cancer, rheumatoid arthritis, T2 D,and obesity. Therefore, the main effect of antidiabetic drugs is on the microbiome composition, basically increasing the short-chain fatty acids-producing bacteria,responsible for losing weight and suppressing inflammation.     

Involvement of the Gut Microbiota and Barrier Function in Glucocorticoid-Induced Osteoporosis

Glucocorticoids (GCs) are potent immune-modulating drugs with significant side effects, including glucocorticoid-induced osteoporosis (GIO). GCs directly induce osteoblast and osteocyte apoptosis but also alter intestinal microbiota composition. Although the gut microbiota is known to contribute to the regulation of bone density, its role in GIO has never been examined. To test this, male C57/Bl6J mice were treated for 8 weeks with GC (prednisolone, GC-Tx) in the presence or absence of broad-spectrum antibiotic treatment (ABX) to deplete the microbiota. Long-term ABX prevented GC-Tx-induced trabecular bone loss, showing the requirement of gut microbiota for GIO. Treatment of GC-Tx mice with a probiotic (Lactobacillus reuteri [LR]) prevented trabecular bone loss. Microbiota analyses indicated that GC-Tx changed the abundance of Verrucomicobiales and Bacteriodales phyla and random forest analyses indicated significant differences in abundance of Porphyromonadaceae and Clostridiales operational taxonomic units (OTUs) between groups. Furthermore, transplantation of GC-Tx mouse fecal material into recipient naïve, untreated WT mice caused bone loss, supporting a functional role for microbiota in GIO. We also report that GC caused intestinal barrier breaks, as evidenced by increased serum endotoxin level (2.4-fold), that were prevented by LR and ABX treatments. Enhancement of barrier function with a mucus supplement prevented both GC-Tx–induced barrier leakage and trabecular GIO. In bone, treatment with ABX, LR or a mucus supplement reduced GC-Tx–induced osteoblast and osteocyte apoptosis. GC-Tx suppression of Wnt10b in bone was restored by the LR and high-molecular-weight polymer (MDY) treatments as well as microbiota depletion. Finally, we identified that bone-specific Wnt10b overexpression prevented GIO. Taken together, our data highlight the previously unappreciated involvement of the gut microbiota and intestinal barrier function in trabecular GIO pathogenesis (including Wnt10b suppression and osteoblast and osteocyte apoptosis) and identify the gut as a novel therapeutic target for preventing GIO. © 2019 American Society for Bone and Mineral Research.