Causal relationship between gut microbiota and diabetic nephropathy: A bidirectional mendelian randomization study.

In this study, we summarized the key findings and potential implications of association studies investigating the relationship between gut microbiota composition and risks for Diabetic nephropathy (DN). We used Mendelian randomization (MR) analysis to explore the relationship between gut microbiota and DN using two different publicly available DN databases. The results were also summarized using five mainstream MR analysis methods. We controlled for various possible biases in the results. The results showed that specific bacterial genera were associated with increased or decreased risk of DN. These associations can be attributed to a variety of factors, including metabolites produced by certain bacteria. Most of our findings are consistent with the existing research findings, but there are still some differences with the existing results. In addition, we also pointed out that some microbiota that may be associated with DN but remain unnoticed can bring new research directions. Our work made use of MR, a reliable technique for examining causal correlations using genetic data investigating potential processes, carrying out longitudinal studies, looking into intervention options, and using a multi-omics approach may be future research avenues. Further, our findings also point to a few unexplored possible study paths for DN in the future. These initiatives may improve our reconciliation of the internal relationships between the gut microbiota and DN and pave the way for more precise prevention and treatment methods. However, it is also critical to recognize any potential restrictions, such as those caused by sample size, population variety, and analytical techniques.

The Intestinal Microbiota Composition in Early and Late Stages of Diabetic Kidney Disease.

Many studies have suggested that gut microbiota dysbiosis may be one of the pathogenesis factors of diabetes mellitus (DM), while it is not clear whether it is involved in the development of diabetic kidney diseases (DKD). The objective of this study was to determine bacterial taxa biomarkers during the progression of DKD by investigating bacterial compositional changes in early and late DKD. 16S rRNA gene sequencing was performed on fecal samples, including the diabetes mellitus (DM), DNa (early DKD), and DNb (late DKD) groups. Taxonomic annotation of microbial composition was performed. Samples were sequenced on the Illumina NovaSeq platform. At the genus level, we found counts of Fusobacterium, Parabacteroides, and Ruminococcus_gnavus were significantly elevated both in the DNa group (P = 0.0001, 0.0007, and 0.0174, respectively) and the DNb group (P < 0.0001, 0.0012, and 0.0003, respectively) compared with those in the DM group. Only the level of Agathobacter was significantly decreased in the DNa group than the DM group and in the DNb group than the DNa group. Counts of Prevotella_9, Roseburia were significantly decreased in the DNa group compared with those in the DM group (P = 0.001 and 0.006, respectively) and in the DNb group compared with those in the DM group (P < 0.0001 and 0.003, respectively). Levels of Agathobacter, Prevotella_9, Lachnospira, and Roseburia were positively correlated with an estimated glomerular filtration rate (eGFR), but negatively correlated with microalbuminuria (MAU), 24 h urinary protein quantity (24hUP), and serum creatinine (Scr). Moreover, the areas under the curve (AUCs) of Agathobacter and Fusobacteria were 83.33% and 80.77%, respectively, for the DM and DNa cohorts, respectively. Notably, the largest AUC for DNa and DNb cohorts was also that of Agathobacter at 83.60%. Gut microbiota dysbiosis was found in the early and late stages of DKD, especially in the early stage. Agathobacter may be the most promising intestinal bacteria biomarker that can help distinguish different stages of DKD. IMPORTANCE It is not clear as to whether gut microbiota dysbiosis is involved in the progression of DKD. This study may be the first to explore gut microbiota compositional changes in diabetes, early-DKD, and late DKD. We identify different gut microbial characteristics during different stages of DKD. Gut microbiota dysbiosis is found in the early and late stages of DKD. Agathobacter may be the most promising intestinal bacteria biomarker that can help distinguish different stages of DKD, although further studies are warranted to illustrate these mechanisms.

Alterations of the Gut Microbiota in Patients with Diabetic Nephropathy.

Diabetic nephropathy (DN) is the primary cause of end-stage renal disease. Accumulating studies have implied a critical role for the gut microbiota in diabetes mellitus (DM) and DN. However, the precise roles and regulatory mechanisms of the gut microbiota in the pathogenesis of DN remain largely unclear. In this study, metagenomics sequencing was performed using fecal samples from healthy controls (CON) and type 2 diabetes mellitus (T2DM) patients with or without DN. Fresh fecal samples from 15 T2DM patients without DN, 15 DN patients, and 15 age-, gender-, and body mass index (BMI)-matched healthy controls were collected. The compositions and potential functions of the gut microbiota were estimated. Although no difference of gut microbiota α and ß diversity was observed between the CON, T2DM, and DN groups, the relative abundances of butyrate-producing bacteria (Clostridium, Eubacterium, and Roseburia intestinalis) and potential probiotics (Lachnospira and Intestinibacter) were significantly reduced in T2DM and DN patients. Besides, Bacteroides stercoris was significantly enriched in fecal samples from patients with DN. Moreover, Clostridium sp. 26_22 was negatively associated with serum creatinine (P < 0.05). DN patients could be accurately distinguished from CON by Clostridium sp. CAG_768 (area under the curve [AUC] = 0.941), Bacteroides propionicifaciens (AUC = 0.905), and Clostridium sp. CAG_715 (AUC = 0.908). DN patients could be accurately distinguished from T2DM patients by Pseudomonadales, Fusobacterium varium, and Prevotella sp. MSX73 (AUC = 0.889). Regarding the potential bacterial functions of the gut microbiota, the citrate cycle, base excision repair, histidine metabolism, lipoic acid metabolism, and bile acid biosynthesis were enriched in DN patients, while selenium metabolism and branched-chain amino acid biosynthesis were decreased in DN patients. IMPORTANCE Gut microbiota imbalance is found in fecal samples from DN patients, in which Roseburia intestinalis is significantly decreased, while Bacteroides stercoris is increased. There is a significant correlation between gut microbiota imbalance and clinical indexes related to lipid metabolism, glucose metabolism, and renal function. The gut microbiota may be predictive factors for the development and progression of DN, although further studies are warranted to illustrate their regulatory mechanisms.

Paecilomyces cicadae-fermented Radix astragali ameliorate diabetic nephropathy in mice by modulating the gut microbiota.

The occurrence and development of diabetic nephropathy (DN) are closely related to gut microbiota. Paecilomyces cicadae is a medicinal and edible fungus. Radix astragali is a therapeutic material for unifying Chinese Qi. They can delay the occurrence and development of kidney disease. In recent years, solid-state fermentation of edible fungi and traditional Chinese medicine has become a hot issue.Hypothesis/Gap Statement. We assumed that solid-state fermentation products of R. astragali and Paecilomyces cicadidae (RPF) could ameliorate diabetic nephropathy and modulate gut microbiota composition. We aimed to study the function and mechanism of the RPF for ameliorating DN in mice. We investigated the effect of the potential roles of RPF in DN mice and interaction between DN and gut microbiota using animal experiments and gut microbiota measurements. We found that RPF dramatically reduced urine protein, serum creatinine and blood urea nitrogen in DN mice. Furthermore, RPF ameliorated the physiological condition of DN mice by regulating the abundance of intestinal microbiota such as Ruminococcaceae_UCG-014, Allobaculum, Unclassified_f__Lachnospiraceae Alloprevotella and Bacteroides. RPF can ameliorate diabetic nephropathy and modulate gut microbiota composition.

The change of gut microbiota-derived short-chain fatty acids in diabetic kidney disease.

BACKGROUND: Previous studies found the dysbiosis of intestinal microbiota in diabetic kidney disease (DKD), especially the decreased SCFA-producing bacteria. We aimed to investigate the concentration of the stool and serum short-chain fatty acids (SCFAs), gut microbiota-derived metabolites, in individuals with DKD and reveal the correlations between SCFAs and renal function. METHODS: A total of 30 participants with DKD, 30 participants with type 2 diabetes mellitus (DM), and 30 normal controls (NC) in HwaMei Hospital were recruited from 1/1/2018 to 12/31/2019. Participants with DKD were divided into low estimated glomerular filtration rate (eGFR)(eGFR<60ml/min, n=14) and high eGFR (eGFR≥60ml/min, n=16) subgroups. Stool and serum were measured for SCFAs with gas chromatograph-mass spectrometry. RESULTS: The DKD group showed markedly lower levels of fecal acetate, propionate, and butyrate versus NC (p<0.001, p<0.001, p=0.018, respectively) [1027.32(784.21-1357.90)]vs[2064.59(1561.82-2637.44)]µg/g,[929.53(493.65-1344.26)]vs[1684.57(1110.54-2324.69)]µg/g,[851.39(409.57-1611.65)] vs[1440.74(1004.15-2594.73)]µg/g, respectively, and the lowest fecal total SCFAs concentration among the groups. DKD group also had a lower serum caproate concentration than that with diabetes (p=0.020)[0.57(0.47-0.61)]vs[0.65(0.53-0.79)]µmol/L. In the univariate regression analysis, fecal and serum acetate correlated with eGFR (OR=1.013, p=0.072; OR=1.017, p=0.032). The correlation between serum total SCFAs and eGFR showed statistical significance (OR=1.019, p=0.024) unadjusted and a borderline significance (OR=1.024, p=0.063) when adjusted for Hb and LDL. The decrease in serum acetate and total SCFAs were found of borderline significant difference in both subgroups (p=0.055, p=0.050). CONCLUSION: This study provides evidence that in individuals with DKD, serum and fecal SCFAs levels (fecal level in particular) were lowered, and there was a negative correlation between SCFAs and renal function.

Gut microbiota, key to unlocking the door of diabetic kidney disease.

This review discusses the influence of gut microbiota dysbiosis on diabetic kidney disease through metabolite profile changes and immune and inflammatory mechanisms. We also elaborate on the mechanism of dysbiosis in the onset and development of other kidney diseases.

QiDiTangShen granules modulated the gut microbiome composition and improved bile acid profiles in a mouse model of diabetic nephropathy.

QiDiTangShen granules (QDTS), a traditional Chinese herbal medicine, have been used in clinical practice for treating diabetic kidney disease for several years. In our previous study, we have demonstrated that QDTS displayed good efficacy on reducing proteinuria in mice with diabetic nephropathy (DN). However, the exact mechanism by which QDTS exerts its reno-protection remains largely unknown. To ascertain whether QDTS could target the gut microbiota-bile acid axis, the db/db mice were adopted as a mouse model of DN. After a 12-week of treatment, we found that QDTS significantly reduced urinary albumin excretion (UAE), and attenuated the pathological injuries of kidney in the db/db mice, while the body weight and blood glucose levels of those mice were not affected. In addition, we found that QDTS significantly altered the gut microbiota composition, and decreased serum levels of total bile acid (TBA) and BA profiles such as ß-muricholic acid (ß-MCA), taurocholic acid (TCA), tauro ß-muricholic acid (Tß-MCA) and deoxycholic acid (DCA). These BAs are associated with the activation of farnesoid X receptor (FXR), which is highly expressed in kidney. However, there was no significant difference between QDTS-treated and -untreated db/db mice regarding the renal expression of FXR, indicating that other mechanisms may be involved. Conclusively, our study revealed that QDTS significantly alleviated renal injuries in mice with DN. The gut microbiota-bile acid axis may be an important target for the reno-protection of QDTS in DN, but the specific mechanism merits further study.

The gut microbiome in differential diagnosis of diabetic kidney disease and membranous nephropathy.

BACKGROUND: Diabetic kidney disease (DKD) and membranous nephropathy (MN) are the two major causes of end-stage renal disease (ESRD). Increasing evidence has shown that intestinal dysbiosis is associated with many diseases. The aim of this study was to explore the composition of the gut microbiome in DKD and MN patients. METHODS: 16S rRNA gene sequencing was performed on 271 fecal samples (DKD = 129 and MN = 142), and taxonomic annotation of microbial composition and function was completed. RESULTS: We observed distinct microbial communities between the two groups, with MN samples exhibiting more severe dysbiosis than DKD samples. Relative increases in genera producing short-chain fatty acids (SCFAs) in DKD and a higher proportion of potential pathogens in MN were the main contributors to the microbiome alterations in the two groups. Five-fold cross-validation was performed on a random forest model, and four operational taxonomic unit (OTU)-based microbial markers were selected to distinguish DKD from MN. The results showed 92.42% accuracy in the training set and 94.52% accuracy in the testing set, indicating high potential for these microbiome-based markers in separating MN from DKD. Overexpression of several amino acid metabolic pathways, carbohydrate metabolism and lipid metabolism was found in DKD, while interconversion of pentose/glucoronate and membrane transport in relation to ABC transporters and the phosphotransferase system were increased in MN. CONCLUSION: The composition of the gut microbiome appears to differ considerably between patients with DKD and those with MN. Thus, microbiome-based markers could be used as an alternative tool to distinguish DKD and MN.

Antifungal susceptibility of oral isolates of Candida species from chronic kidney disease patients on chronic dialysis.

Chronic renal disease patients under chronic dialysis (CRDD) have a multifactorial immunological deterioration with an increased risk of Candida infections. Incidence of Candida infections is increasing. Choice of suitable antifungal agents is limited due to the resistance of some species to several antifungals. Aim of the present study was to identify the distribution and antifungal susceptibility patterns of oral isolated Candida species from infected and colonized patients, as well as to investigate the risk factors for oral infection in patients on dialysis. Cross-sectional study, approved by the institutional bioethics committees was performed in CRDD patients. Demographic, clinic data, and oral mucosa samples were obtained. Infection diagnosis was established clinically and confirmed with exfoliative cytology, each sample was plated on CHROMagar Candida and incubated at 36°C for 2 days. Yeast species were identified by carbohydrate assimilation ID 32C AUX system and the apiweb database. For the antifungal susceptibility test, the M44 A-3 method (CLSI) using fluconazole (FCZ), miconazole (MCZ), nystatin (NYS), and voriconazole (VCZ). Study included 119 participants, the main cause of CRD was nephropathy due to DM2 (58%), and three-fourths of the patients were under hemodialysis. Candida prevalence was 56.3% of 67 colonized or infected patients, 88 isolates were obtained. Principal identified species were C. albicans (51.1%), C. glabrata (25%), and C. tropicalis (14.8%). C. glabrata showed a reduced response to FCZ in 50% of isolates and C. albicans had a reduced response in 16% of the isolates. Antifungal agent with the least efficacious response or with the lowest susceptibility in the isolates of these patients was MCZ, followed by VCZ and FCZ, whereas NYS induced the best antifungal response.

Tangshen formula modulates gut Microbiota and reduces gut-derived toxins in diabetic nephropathy rats.

Growing evidence shows that diabetic kidney disease (DKD) is linked with intestinal dysbiosis from gut-derived toxins. Tangshen Formula (TSF) is a traditional Chinese herbal medicine that has been used to treat DKD. In this study, streptozotocin injection and uninephrectomy-induced diabetic nephropathy (DN) rat model was established to explore the impact of TSF on gut microbiota composition, gut-derived toxins, and the downstream inflammatory pathway of urotoxins in the kidney. TSF treatment for 12 weeks showed significant attenuation of both renal histologic injuries and urinary excretion of albumin compared with DN rats without treatment. TSF treatment also reconstructed gut dysbiosis and reduced levels of indoxyl sulfate and metabolic endotoxemia/lipopolysaccharide. MCP-1 and TNF-α were decreased by TSF both in the serum and kidney. In addition, we revealed that the inhibitory effect of TSF on renal inflammation was associated with the inhibition of aryl hydrocarbon, a receptor of indoxyl sulfate, and TLR4, thereby inhibiting JNK and NF-κB signaling in the kidney. Spearman correlation analysis found that a cluster of gut bacterial phyla and genera were significantly correlated with renal pathology, renal function, and systemic inflammation. In conclusion, orally administered TSF significantly inhibited diabetic renal injury, and modulated gut microbiota, which decreased levels of lipopolysaccharide and indoxyl sulfate, and attenuated renal inflammation. Our results indicate that TSF may be used as an agent in the prevention of gut dysbiosis and elimination of intestinal toxins in DN individuals.

The potential role of the gut microbiota in modulating renal function in experimental diabetic nephropathy murine models established in same environment.

Recent studies have shown that laboratory murine autoimmunity models under the same environment display different outcomes. We established diabetic nephropathy model mice under the same environment using the classic streptozotocin method. Renal dysfunction was different among the mice. Proteinuria was more significant in the severe proteinuria group (SP) than in the mild proteinuria group (MP). We hypothesized a role for the gut microbiota in the outcome and reproducibility of induced DN models. 16S rDNA gene sequencing technology was used to analyze the differences in the gut microbiota between the two groups. Here, through fecal microbiota transplantation (FMT) and gas chromatography mass spectrometry (GC-MS), we verified the role of the gut microbiota and its short-chain fatty acid (SCFA) generation in DN mouse renal dysfunction. In the SP group, there was a reduced abundance of Firmicutes (P < 0.0001), and the dominant genus Allobaculum [linear discriminant analysis (LDA) >3, P < 0.05] was positively correlated with body weight (Rho = 0.767, P < 0.01) and blood glucose content (Rho = 0.648, P < 0.05), while the dominant genus Anaerosporobacter (LDA > 3, P < 0.05) was positively correlated with 24-hour urinary protein content (Rho = 0.773, P < 0.01). In the MP group, the dominant genus Blautia (LDA > 3, P < 0.05) was negatively correlated with 24-hour urinary protein content (Rho = -0.829, P < 0.05). The results indicated that Allobaculum and Anaerosporobacter may worsen renal function, while Blautia may be a protective factor in DN. These findings suggested that the gut microbiota may contribute to the heterogeneity of the induced response since we observed potential disease-associated microbial taxonomies and correlations with DN.

Effects of Probiotics on Diabetic Nephropathy: A Systematic Review.

BACKGROUND: Diabetic Nephropathy is a frequent complication of diabetes mellitus due to functional and structural modifications in multiple kidney compartments. Probiotics have risen lately as a forthcoming therapeutic intervention but they have not been systematically evaluated in diabetic nephropathy so far. The aim of this systematic review was to evaluate randomized controlled trials and experimental studies assessing the effect of probiotic supplements on diabetic nephropathy. METHODS: An extensive literature search was conducted through electronic databases (PubMed, Scopus, Cinahl and Medline) with the Medical Subject Headings and entry terms of "diabetic nephropathy", "diabetic renal disease" and "probiotics". The search yielded 116 results, 9 of which met the inclusion criteria for this systematic review. RESULTS: Most of the microorganisms used in the studies belonged to the Lactobacillus and Bifidobacterium genus. The dosage ranged from 2×107 to 6×1010 CFU/ g. The form of the probiotics varied across the studies (capsules, sachets, soy milk, kefir and honey). The majority of the studies demonstrated the benefits of probiotic supplementation on the reduction of inflammation, oxidative stress and on the amelioration of renal function biomarkers in subjects with diabetic nephropathy. No major gastrointestinal adverse events were observed during the intervention time with probiotics. CONCLUSION: Findings of this systematic review demonstrate the positive impact of probiotics on Diabetic Nephropathy without any major adverse events. Moreover, future larger randomized controlled trials with bigger samples and longer follow-up time are deemed necessary for further valid results on the effectiveness of probiotic supplementation on Diabetic Nephropathy.

Dysbiosis of intestinal microbiota mediates tubulointerstitial injury in diabetic nephropathy via the disruption of cholesterol homeostasis.

Background: Our previous study demonstrated that the disruption of cholesterol homeostasis promotes tubulointerstitial injury in diabetic nephropathy (DN). This study aimed to further investigate the effects of gut microbiota dysbiosis on this process and explored its potential mechanism. Methods: Diabetic rats treated with broad-spectrum oral antibiotics or faecal microbiota transplantation (FMT) from the healthy donor group and human kidney 2 (HK-2) cells stimulated with sodium acetate were used to observe the effects of gut microbiota on cholesterol homeostasis. The gut microbiota distribution was measured by 16S rDNA sequencing with faeces. Serum acetate level was examined by gas chromatographic analysis. Protein expression of G protein coupled receptor 43 (GPR43) and molecules involved in cholesterol homeostasis were assessed by immunohistochemical staining, immunofluorescence staining, and Western Blotting. Results: Depletion of gut microbiota significantly attenuated albuminuria and tubulointerstitial injury. Interestingly, serum acetate levels were also markedly decreased in antibiotics-treated diabetic rats and positively correlated with the cholesterol contents in kidneys. An in vitro study demonstrated that acetate significantly increased cholesterol accumulation in HK-2 cells, which was caused by increased expression of proteins mainly modulating cholesterol synthesis and uptake. As expected, FMT effectively decreased serum acetate levels and alleviated tubulointerstitial injury in diabetic rats through overriding the disruption of cholesterol homeostasis. Furthermore, GPR43 siRNA treatment blocked acetate-mediated cholesterol homeostasis dysregulation in HK-2 cells through decreasing the expression of proteins governed cholesterol synthesis and uptake. Conclusion: Our studies for the first time demonstrated that the acetate produced from gut microbiota mediated the dysregulation of cholesterol homeostasis through the activation of GPR43, thereby contributing to the tubulointerstitial injury of DN, suggesting that gut microbiota reprogramming might be a new strategy for DN prevention and therapy.

Modulating the gut microbiota and inflammation is involved in the effect of Bupleurum polysaccharides against diabetic nephropathy in mice.

Dysbiosis of gut microbiota and low grade inflammation has gradually become a highly potential therapeutic agent for diabetic nephropathy (DN). It has been reported that a large number of polysaccharides have positive effects on DN, including Bupleurum polysaccharides. However, the mechanism remained unclear. This study selected two Bupleurum polysaccharides from different origins to investigate the potential relationship between kidney and gut. Diabetic mice model was established by streptozotocin (STZ, 100 mg/kg) and the treatment groups were treated with two Bupleurum polysaccharides (60 mg/kg) for 6 weeks, respectively. The results showed that the administration of Bupleurum polysaccharides ameliorated diabetic nephropathy induced by STZ. Blood glucose, blood creatinine and urine albumin were decreased after the oral administration of Bupleurum polysaccharides. And the dysbiosis of gut microbiota was modulated with higher diversity and gut protective microbiota. The gut barrier was also improved and the expression of inflammatory response both in kidney and colon was reduced. These results provided the evidence that modulating the gut microbiota and inflammation was involved in the effect of Bupleurum polysaccharides against diabetic nephropathy in mice and laid the foundation for the deeper, specific mechanism research on the interaction between kidney and gut.

Understanding the gut-kidney axis among biopsy-proven diabetic nephropathy, type 2 diabetes mellitus and healthy controls: an analysis of the gut microbiota composition.

AIMS: Type 2 diabetes mellitus (T2DM) has a rising prevalence and gut microbiota involvement is increasingly recognized. Diabetic nephropathy (DN) is a major complication of T2DM. The aim of the study was to understand the gut-kidney axis by an analysis of gut microbiota composition among biopsy-proven DN, T2DM without kidney disease, and healthy control. METHODS: Fecal samples were collected from 14 DNs, 14 age/gender-matched T2DMs without renal diseases (DM), 14 age and gender-matched healthy controls (HC) and household contacts (HH) of DM group. The microbiota composition was analyzed by 16sRNA microbial profiling approach. RESULTS: Substantial differences were found in the richness of gut microbiota and the variation of bacteria population in DM compared to HC, and DN compared to DM, respectively. DM could be accurately distinguished from age/gender-matched healthy controls by the variable of genus g_Prevotella_9 (AUC = 0.9), and DN patients could be accurately distinguished from age/gender-matched DM by the variables of two genera (g_Escherichia-Shigella and g_Prevotella_9, AUC = 0.86). The microbiota composition of HH group was close to that of HC group, and was different from DM group. Under the same diet, DM could be more accurately detected by the same genus (g_Prevotella_9, AUC = 0.92). CONCLUSION: Gut microbiota composition was explored to be related to the occurrence of biopsy-proven DN from DM. DM could be distinguished from HC by detecting g_Prevotella_9 level in feces, while DN was different from DM by the variables of g_Escherichia-Shigella and g_Prevotella_9, which potentially contributed to the physiopathological diagnosis of DN from DM.

The Effects of Probiotic Honey Consumption on Metabolic Status in Patients with Diabetic Nephropathy: a Randomized, Double-Blind, Controlled Trial.

To the best of our knowledge, this study is the first evaluating the effects of probiotic honey intake on glycemic control, lipid profiles, biomarkers of inflammation, and oxidative stress in patients with diabetic nephropathy (DN). This investigation was conducted to evaluate the effects of probiotic honey intake on metabolic status in patients with DN. This randomized, double-blind, controlled clinical trial was performed among 60 patients with DN. Patients were randomly allocated into two groups to receive either 25 g/day probiotic honey containing a viable and heat-resistant probiotic Bacillus coagulans T11 (IBRC-M10791) (108 CFU/g) or 25 g/day control honey (n = 30 each group) for 12 weeks. Fasting blood samples were taken at baseline and 12 weeks after supplementation to quantify glycemic status, lipid concentrations, biomarkers of inflammation, and oxidative stress. After 12 weeks of intervention, patients who received probiotic honey compared with the control honey had significantly decreased serum insulin levels (- 1.2 ± 1.8 vs. - 0.1 ± 1.3 µIU/mL, P = 0.004) and homeostasis model of assessment-estimated insulin resistance (- 0.5 ± 0.6 vs. 0.003 ± 0.4, P = 0.002) and significantly improved quantitative insulin sensitivity check index (+ 0.005 ± 0.009 vs. - 0.0007 ± 0.005, P = 0.004). Additionally, compared with the control honey, probiotic honey intake has resulted in a significant reduction in total-/HDL-cholesterol (- 0.2 ± 0.5 vs. + 0.1 ± 0.1, P = 0.04). Probiotic honey intake significantly reduced serum high-sensitivity C-reactive protein (hs-CRP) (- 1.9 ± 2.4 vs. - 0.2 ± 2.7 mg/L, P = 0.01) and plasma malondialdehyde (MDA) levels (- 0.1 ± 0.6 vs. + 0.6 ± 1.0 µmol/L, P = 0.002) compared with the control honey. Probiotic honey intake had no significant effects on other metabolic profiles compared with the control honey. Overall, findings from the current study demonstrated that probiotic honey consumption for 12 weeks among DN patients had beneficial effects on insulin metabolism, total-/HDL-cholesterol, serum hs-CRP, and plasma MDA levels, but did not affect other metabolic profiles. http://www.irct.ir: IRCT201705035623N115.

Diabetic gut microbiota dysbiosis as an inflammaging and immunosenescence condition that fosters progression of retinopathy and nephropathy.

The increased prevalence of type 2 diabetes mellitus (T2DM) and life expectancy of diabetic patients fosters the worldwide prevalence of retinopathy and nephropathy, two major microvascular complications that have been difficult to treat with contemporary glucose-lowering medications. The gut microbiota (GM) has become a lively field research in the last years; there is a growing recognition that altered intestinal microbiota composition and function can directly impact the phenomenon of ageing and age-related disorders. In fact, human GM, envisaged as a potential source of novel therapeutics, strongly modulates host immunity and metabolism. It is now clear that gut dysbiosis and their products (e.g. p-cresyl sulfate, trimethylamine­N­oxide) dictate a secretory associated senescence phenotype and chronic low-grade inflammation, features shared in the physiological process of ageing ("inflammaging") as well as in T2DM ("metaflammation") and in its microvascular complications. This review provides an in-depth look on the crosstalk between GM, host immunity and metabolism. Further, it characterizes human GM signatures of elderly and T2DM patients. Finally, a comprehensive scrutiny of recent molecular findings (e.g. epigenetic changes) underlying causal relationships between GM dysbiosis and diabetic retinopathy/nephropathy complications is pinpointed, with the ultimate goal to unravel potential pathophysiological mechanisms that may be explored, in a near future, as personalized disease-modifying therapeutic approaches.

A 54-year-old male with diabetic nephropathy and suspected disseminated tuberculosis: Clinicopathologic correlation in a rare diagnosis.

Tuberculosis (TB) and Non-Hodgkins lymphoma (NHL) share similar clinical and radiological features, which make diagnosis a challenge. It is often difficult to rule out a diagnosis of extrapulmonary and/or disseminated TB because of its paucibacillary nature and difficulty in accessing the involved organs. In countries with high prevalence of TB like ours, empirical antitubercular treatment (ATT) is started, and the patient is followed up closely for response. We present a rare case of a 54-year old diabetic male who was suspected to be a case of disseminated TB but had a rapid downhill course despite ATT. A postmortem revealed features of a rare, aggressive T-cell NHL masquerading as disseminated TB.

Prevalence and incidence of urinary tract and genital infections among patients with and without type 2 diabetes.

OBJECTIVE: Epidemiological data on genitourinary infections (GUIs) comparing patients with and without type 2 diabetes (T2DM) is scant. We aimed to estimate the incidence of urinary tract infections (UTIs), genital infections (GIs), or any GUI in total and stratified by history of GUI and sex. RESEARCH DESIGN AND METHODS: We identified 39,295 patients in the Kaiser Permanente Northwest health plan with T2DM and an equal number of age and sex matched patients without diabetes. The cohort was followed for up to 9years (2006-2014). We calculated incidence rates and corresponding 95% confidence intervals (CI) of any GUI, UTIs and GIs adjusting for age, sex, race, BMI, presence of chronic kidney disease, annual number of outpatient visits, and diuretic use. RESULTS: Adjusted incidence of any GUI was 97.2/1000person-years (p-y) (95% CI 95.5-98.8) among the T2DM cohort vs. 79.7/1000 p-y (78.3-81.2) among those without diabetes. T2DM was associated with an adjusted 25% increased risk of UTI (rate ratio 1.25, 95% CI 1.22-1.29), a 26% increased risk of GI (1.26, 1.22-1.31) and a 22% increased risk of any GUI (1.22, 1.19-1.25). Incidence rates were lower among those with no GUI history, but the relative risks were similar. Women in both groups had higher incidence rates of GUIs than men. CONCLUSIONS: T2DM was associated with increased risks of any GUI, UTIs and GIs. Incidence rates of UTIs were higher than rates of GIs, but the relative risk of GIs was essentially identical. A similar pattern was observed when stratifying by sex. SIGNIFICANCE OF THE STUDY: RESEARCH QUESTIONS.

Probiotic supplementation in diabetic hemodialysis patients has beneficial metabolic effects.

This study determined the effects of probiotic supplementation on glycemic control, lipid concentrations, biomarkers of inflammation and oxidative stress in 60 diabetic patients on hemodialysis in a parallel randomized double-blind placebo-controlled clinical trial. Participants were initially matched based on sex, duration of dialysis and diabetes, body mass index and age. Subsequently, they were randomly divided into two groups to take either a capsule containing the probiotics Lactobacillus acidophilus, Lactobacillus casei and Bifidobacterium bifidum or placebo for 12 weeks. Based on three-day dietary records throughout the trial, there was no significant change in dietary macro- and micro-nutrients or total dietary fiber to confound results. After the 12 weeks, analysis of patients who received probiotic supplements compared with the placebo showed they had significantly decreased fasting plasma glucose (-22.0 vs. +6.6 mg/dl), serum insulin (-6.4 vs. +2.3 µIU/ml), homeostasis model of assessment-estimated insulin resistance (-2.9 vs. +2.5), homeostasis model of assessment-estimated beta-cell function (-14.1 vs. +6.1) and HbA1c (-0.4 vs. -0.1%,), and improved quantitative insulin sensitivity check index (+0.03 vs. -0.02). Additionally, compared with the placebo, probiotic supplementation resulted in significant reductions in serum high-sensitivity C-reactive protein (-1933 vs. +252 ng/ml), plasma malondialdehyde (-0.3 vs. +1.0 µmol/l), subjective global assessment scores (-0.7 vs. +0.7) and total iron binding capacity (-230 vs. +33 µg/dl), and a significant increase in plasma total antioxidant capacity (+15 vs. -88 mmol/l). Thus, probiotic supplementation for 12 weeks among diabetic hemodialysis patients had beneficial effects on parameters of glucose homeostasis, and some biomarkers of inflammation and oxidative stress.