Causal effects of gut microbiota on diabetic neuropathy: a two-sample Mendelian randomization study.

Objective: Previous observational studies have suggested an association between gut microbiota and diabetic neuropathy (DN). However, confounding factors and reverse causality make the causal relationship between gut microbiota and DN uncertain. We aimed to investigate the interactive causal relationships between the abundance of gut microbiota and DN. Methods: We conducted a Mendelian randomization (MR) analysis to examine the causal relationship between gut microbiota and DN. Genomic data on gut microbiota at the genus level were obtained from the MiBioGen Consortium, including 18,340 individuals of European descent. Data on diabetic polyneuropathy (DPN) were obtained from the FinnGen Consortium, which included 1,048 cases and 374,434 controls, while data on diabetic autonomic neuropathy (DAN) were also obtained from the FinnGen Consortium, including 111 cases and 374,434 controls. Causal effects were primarily estimated using inverse variance weighted (IVW) analysis, supplemented with four validation methods, and additional sensitivity analyses to assess the pleiotropy, heterogeneity, and robustness of instrumental variables. Results: The IVW analysis indicated that Prevotella 9 had a protective effect on DPN (OR = 0.715, 95% CI: 0.521-0.982, P = 0.038), and Bacteroides also showed a protective effect (OR = 0.602, 95% CI: 0.364-0.996, P = 0.048). On the other hand, Ruminococcus 2 had a promoting effect on DPN (OR = 1.449, 95% CI: 1.008-2.083, P = 0.045). Blautia (OR = 0.161, 95% CI: 0.035-0.733, P = 0.018), Clostridium innocuum group (OR = 3.033, 95% CI: 1.379-6.672, P = 0.006), and Howardella (OR = 2.595, 95% CI: 1.074-6.269, P = 0.034) were causally associated with DAN in the IVW analysis, with no evidence of heterogeneity or pleiotropy. Sensitivity analyses showed no significant pleiotropy or heterogeneity. Conclusion: Our study identified a causal relationship between gut microbiota and the increased or decreased risk of diabetic neuropathy. These findings underscore the importance of adopting a comprehensive approach that combines gut microbiota modulation with other therapeutic interventions in the management of diabetic neuropathy.

Association between gut microbiota and diabetic microvascular complications: a two-sample Mendelian randomization study.

Background: Gut microbiota (GM) homeostasis in the human body is closely associated with health, which can be used as a regulator for preventing the onset and progression of disease. Diabetic microvascular complications bring about not only a huge economic burden to society, but also miserable mental and physical pain. Thus, alteration of the GM may be a method to delay diabetic microvascular complications. Objective: A two-sample Mendelian randomization (MR) analysis was conducted to reveal the causal inference between GM and three core diabetic microvascular complications, namely, diabetic kidney disease (DKD), diabetic retinopathy (DR), and diabetic neuropathy (DNP). Methods: First, genome-wide association study (GWAS) summary statistics for GM from the MiBioGen consortium and three main diabetic microvascular complications acquired from the FinnGen research project were assessed. Second, a forward MR analysis was conducted to assess the causality of GM on the risk of DKD, DR, and DNP. Third, a series of sensitivity studies, such as heterogeneity tests, pleiotropy evaluations, and leave-one-out analyses, were further conducted to assess the accuracy of MR analysis. Finally, Steiger tests and reverse MR analyses were performed to appraise the possibility of reverse causation. Results: A total of 2,092 single-nucleotide polymorphisms related to 196 bacterial traits were selected as instrumental variables. This two-sample MR analysis provided strongly reasonable evidence that 28 genetically predicted abundance of specific GM that played non-negligible roles in the occurrence of DKD, DR, and DNP complications were causally associated with 23 GM, the odds ratio of which generally ranged from 0.9 to 1.1. Further sensitivity analysis indicated low heterogeneity, low pleiotropy, and high reliability of the causal estimates. Conclusion: The study raised the possibility that GM may be a potential target to prevent and delay the progression of diabetic microvascular complications. Further experiments of GM therapy on diabetic microvascular complications are warranted to clarify their effects and specific mechanisms.

Antidepressant effect of carvedilol on streptozotocin-induced diabetic peripheral neuropathy mice by altering gut microbiota.

RATIONALE: Although diabetic peripheral neuropathic pain (DPNP) and depression have been recognized for many years, their co-morbidity relationship and effective treatment choices remain uncertain. OBJECTIVES: To evaluate the antidepressant effect of carvedilol on streptozotocin-induced DPNP mice, and the relationship with gut microbiota. METHODS: The hyperalgesia and depressive behaviors of mice with comorbidity of DPNP and depression were confirmed by pain threshold of the mechanical sensitivity test (MST), immobility time of the tail suspension test (TST) and the forced swimming test (FST). The anti-depressive effect and fecal gut microbiota composition were studied in DPNP mice treated with carvedilol (10 mg/kg/day), and the relationships between them were analyzed by Spearman's correlation. RESULTS: Depression was successfully induced in DPNP mice. Carvedilol can reverse the decreased mechanical pain threshold and relieve the depressive behaviors of DPNP mice, while increasing the abundance of Prevotella, Ruminococcus, Helicobacter and Desulfovibrio, and decreasing the abundance of Akkermansia and Allobaculum. CONCLUSIONS: Carvedilol can alleviate the mechanical hyperalgesia and alter gut microbiota to ameliorate the depression-like behaviors which induced by DPNP.

The causal relationship between gut microbiota and diabetic neuropathy: a bi-directional two-sample Mendelian randomization study.

Background: Many studies suggest a strong correlation between gut microbiota (GM) and diabetic neuropathy (DN). However, the precise causal relationship between GM and DN has yet to be fully elucidated. Hence, a bi-directional Mendelian randomization (MR) analysis was used to examine the association between GM and DN. Methods: Widely known genome-wide association study (GWAS) of GM was collected from the MiBio Gen project. Summary-level datasets for DN were taken from the FinnGen project. Inverse variance weighted approach was used for evaluating the causal relationship between GM and DN. Subsequently, pleiotropy and heterogeneity tests were performed to verify the reliability of the data. Furthermore, a bidirectional two-sample MR analysis was done to investigate the directionality of the causal relationships. Gene Ontology analysis was conducted to identify the associations that could indicate biological functions. Results: We identified potential causal associations between GM and DN (p< 0.05 in all three MR methods). Among them, we found increased levels of Christensenellaceae R-7 (Odds ratio, OR= 1.52; 95% confidence interval, CI = 1.03-2.23; p = 0.03), Ruminococcaceae UCG013 (OR =1.35; 95% CI = 1.00-1.85; p = 0.04), and Eggerthella groups (OR = 1.27; 95% CI = 1.05-1.55; p = 0.01), which may be associated with a higher risk of DN, while increased levels of Peptococcaceae (OR = 0.69; 95% CI = 0.54-0.90; p< 0.01) and Eubacterium coprostanoligenes groups (OR = 0.68; 95% CI = 0.49-0.93; p = 0.01) could be associated with a lower risk. Gene Ontology pathway analysis revealed enrichment of genes regulated by the associated single-nucleotide polymorphisms (SNPs) in the apical plasma membrane, glycosyltransferase activity, hexosyltransferase activity and membrane raft. Reverse MR analyses indicated that DN was associated with five microbial taxa in all three MR methods. Conclusion: The results of our study validate the possible causative relationship between GM and DN. This discovery gives new perspectives into the mechanism on how GM influences DN, and establishes a theoretical foundation for future investigations into targeted preventive measures.

Association between Gut Microbiota Compositions with MicrovascularComplications in Individuals with Diabetes: A Systematic Review.

BACKGROUND: Diabetes is one of the chronic and very complex diseases that can lead to microvascular complications. Recent evidence demonstrates that dysbiosis of the microbiota composition might result in low-grade, local, and systemic inflammation, which contributes directly to the development of diabetes mellitus and its microvascular consequences. OBJECTIVE: The aim of this systematic review was to investigate the association between diabetes microvascular complications, including retinopathy, neuropathy, nephropathy, and gut microbiota composition. METHODS: A systematic search was carried out in PubMed, Scopus, and ISI Web of Science from database inception to March 2023. Screening, data extraction, and quality assessment were performed by two independent authors. The Newcastle-Ottawa Quality Assessment Scale was used for quality assessment. RESULTS: About 19 articles were selected from 590 retrieved articles. Among the included studies, nephropathy has been studied more than other complications of diabetes, showing that the composition of the healthy microbiota is changed, and large quantities of uremic solutes that cause kidney injury are produced by gut microbes. Phyla, including Fusobacteria and Proteobacteria, accounted for the majority of the variation in gut microbiota between Type 2 diabetic patients with and without neuropathy. In cases with retinopathy, an increase in pathogenic and proinflammatory bacteria was observed. CONCLUSION: Our results revealed that increases in Bacteroidetes, Proteobacteria and Fusobacteria may be associated with the pathogenesis of diabetic nephropathy, neuropathy, and retinopathy. In view of the detrimental role of intestinal dysbiosis in the development of diabetes-related complications, gut microbiota assessment may be used as a biomarker in the future and interventions that modulate the composition of microbiota in individuals with diabetes can be used to prevent and control these complications.

The gut microbiota to the brain axis in the metabolic control.

The regulation of glycemia is under a tight neuronal detection of glucose levels performed by the gut-brain axis and an efficient efferent neuronal message sent to the peripheral organs, as the pancreas to induce insulin and inhibit glucagon secretions. The neuronal detection of glucose levels is performed by the autonomic nervous system including the enteric nervous system and the vagus nerve innervating the gastro-intestinal tractus, from the mouth to the anus. A dysregulation of this detection leads to the one of the most important current health issue around the world i.e. diabetes mellitus. Furthemore, the consequences of diabetes mellitus on neuronal homeostasis and activities participate to the aggravation of the disease establishing a viscious circle. Prokaryotic cells as bacteria, reside in our gut. The strong relationship between prokaryotic cells and our eukaryotic cells has been established long ago, and prokaryotic and eukaryotic cells in our body have evolved synbiotically. For the last decades, studies demonstrated the critical role of the gut microbiota on the metabolic control and how its shift can induce diseases such as diabetes. Despite an important increase of knowledge, few is known about 1) how the gut microbiota influences the neuronal detection of glucose and 2) how the diabetes mellitus-induced gut microbiota shift observed participates to the alterations of autonomic nervous system and the gut-brain axis activity.

Fecal microbiota transplantation relieve painful diabetic neuropathy: A case report.

RATIONALE: Fecal microbiota transplantation (FMT) has been used in a wide variety of diseases. In this article, we reported a 46-year-old female with diabetic neuropathy (DN) achieved remission by the treatment of FMT. PATIENT CONCERNS: The patient with an 8-year history of diabetes and hypertension was admitted to hospital due to sensitive pain of her right thigh and poor blood glucose control. The traditional hypoglycemic and analgesic treatment were useless to her symptoms. DIAGNOSIS: Diabetic-induced neuropathy was considered. INTERVENTIONS: This patient received twice FMTs for 3 months. OUTCOMES: After twice FMTs, the clinical response of patient was pleasant. The glycemic control was improved, with a remarkable relief of the symptoms of painful DN in particular. No obvious adverse effects were observed during the FMTs and follow-up observation-testing. LESSONS: We proposed that FMT could be a promising treatment in patients with diabetes or diabetes-related complications like DN. FMT also appeared to be definitely safer and more tolerable than the pharmacologic treatment in patients with DN.

Clinical and microbiological profile of diabetic foot ulcer patients in a tertiary care hospital.

AIM: To evaluate the clinical and microbiological profile of diabetic foot ulcer patients admitted to a tertiary care hospital. METHODOLOGY: This study recruited 120 diabetic foot ulcer patients of all grade. Their medical records were evaluated retrospectively. RESULTS: We found that median age of patient was 60(52, 67.75) years. 68.3% of patients were males. Median duration of diabetes mellitus was 15(10, 20) years. Mean HbA1C and fasting glucose was 10.3±2.3 and 167.6±52.42 respectively. Neuropathy (35%) and peripheral vascular disease (23.3%) was major micro vascular and macro vascular complication associated. Different locations of ulcers were toe (23.3%), sole (20%), dorsum (18.3%), shin (16.6%), heel (13.3%), and ankle (8.3%). Bacterial infection was seen in 81.66% patients out of which 23.3% had poly microbial infection. CONCLUSION: Diabetic foot ulcer patient had poor blood glucose control with elevated HbA1C and fasting blood glucose level. Neuropathy and peripheral vascular disease, hypertension were major complications. Staphylococcus aureus, Pseudomonas aeruginosa were common infecting bacteria.

Classification of diabetic foot ulcers.

It is known that the relative importance of factors involved in the development of diabetic foot problems can vary in both their presence and severity between patients and lesions. This may be one of the reasons why outcomes seem to vary centre to centre and why some treatments may seem more effective in some people than others. There is a need therefore to classify and describe lesions of the foot in patients with diabetes in a manner that is agreed across all communities but is simple to use in clinical practice. No single system is currently in widespread use, although a number have been published. Not all are well validated outside the system from which they were derived, and it has not always been made clear the clinical purposes to which such classifications should be put to use, whether that be for research, clinical description in routine clinical care or audit. Here the currently published classification systems, their validation in clinical practice, whether they were designed for research, audit or clinical care, and the strengths and weaknesses of each are explored.

Methane intestinal production and poor metabolic control in type I diabetes complicated by autonomic neuropathy.

AIM: At the state of art it's unknown the correlation between diabetes and lower gastrointestinal disorders. Some studies show a significantly higher prevalence of small intestinal bacterial overgrowth in patients with type I diabetes in particular complicated by autonomic neuropathy. No data exists about gastrointestinal methane production in patients with diabetes and autonomic diabetic neuropathy. The aim of this paper was to evaluate the correlation of small intestinal bacterial overgrowth and gastrointestinal methane production with metabolic control and daily insulin requirements in patients with type 1 diabetes and. autonomic diabetic neuropathy. METHODS: Thirty subjects with type 1 diabetes and autonomic diabetic neuropathy were underwent hydrogen and methane lactulose breath test (LBT) to evaluate the presence of small intestinal bacterial overgrowth (double peak of hydrogen) and methane production. The metabolic control was evaluated through the glycated hemoglobin and the daily insulin requirement (calculated as ratio between total insulin units in a day and body weight). Methane producers were treated with metronidazole (500 mg bid for 10 days) and perform a LBT 8 weeks after the end of therapy RESULTS: Eight over thirty patients (26.6%) met the diagnostic criteria for small intestinal bacterial overgrowth. 11/30 patients (36%) were methane-producers (mean baseline value 16.37 ± 13.01 ppm; mean peak 26.62 ± 11.41 ppm); interestingly this subset of patients showed a worse glycemic control (mean HbA1c 8.16 ± 0.9% vs. 7.49 ± 0.8%, P<0.05). After metronidazole therapy 7/11 (63.3%) reduced CH4 production and they showed a mean HbA1c significantly lower than corresponding value before antibiotic therapy (7.63 ± 0.7% vs. 8.25 ± 0.8%). CONCLUSION: Our study showed for the first time a possible role of CH4 production in metabolic control. In particular, the most interesting data is that an increased values of HbA1c seems to be related to a gut CH4 production as confirmed by its significant improvement after eradication therapy. We are not yet able to determine whether poor glycemic control is the cause or the consequence of the selection of methanogenic flora.

Tissue and swab culture in diabetic foot infections: neuropathic versus neuroischemic ulcers.

We evaluated the diagnostic performance of swabs versus tissue cultures in 28 diabetic patients with neuropathic (group A) and 22 diabetic patients with neuroischemic foot ulcer (group B) and the differences in bacterial isolates between the 2 groups. In group A, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of swab cultures for the diagnosis of infection were 100%, 40%, 88.5%, and 100%, respectively. In group B, the corresponding values were 100%, 22.2%, 65%, and 100%. In group A, sensitivity, specificity, PPV, and NPV of swab cultures for the identification of pathogens were 100%, 14.3%, 53.8%, and 100%, respectively. In group B, the corresponding values were 100%, 18.2%, 55%, and 100%. In each group, Staphylococcus aureus and Pseudomonas aeruginosa were the most common isolates. The number of isolates was significantly higher on swab versus tissue cultures only in group A (P = .033). No differences were observed between groups in number of isolates and colony forming units. In conclusion, swab cultures are highly sensitive but less specific and have an excellent NPV both in diabetic patients with neuropathic and in those with neuroischemic foot ulcer. There are no differences between the groups in microbial load.

Role of Helicobacter pylori in causation of diabetic gastropathies and non-gastrointestinal complications in type 2 diabetes.

A cross-sectional case-control study was conducted in 80 diabetic patients, to evaluate the incidence of gastropathy by endoscopy in type 2 diabetes mellitus. An association between Helicobacter pylori infection and non-gastrointestinal complication of diabetes mellitus was also looked into. Gastric biopsies were subjected to rapid urease test for demonstration of Helicobacter pylori. The fasting blood glucose levels among Helicobacter pylori positive diabetes were 175 +/- 36.5 mg %, and in Helicobacter pylori negative diabetics were 138 +/- 39.4 mg %. The prevalence of endoscopically detectable gastro-intestinal complications were higher in Helicobacter pylori infected diabetics (odd's ratio 4:2; p < 0.05). The total prevalence of Helicobacter pylori positive in diabetics by rapid urease test was statistically significant (p < 0.05). Coronary heart disease was more prevalent in diabetics with Helicobacter pylori infection than those without Helicobacter pylori (57%). The prevalence of H. pylori positivity in other complications such as peripheral vascular diseases, cerebrovascular diseases was not significant. The association between nephropathy, retinopathy and neuropathy with Helicobacter pylori, was also observed and the strong association was seen in diabetic retinopathy (p < 0.001), diabetic neuropathy (p < 0.01) and nephropathy (p < 0.001).

Diagnosis and prevalence of onychomycosis in diabetic neuropathic patients: an observational study.

BACKGROUND: An observational study was conducted to assess the prevalence of onychomycosis in clinically suspected diabetic neuropathic patients and to assess the reliability of the diagnosis. METHODS: One hundred successive type 1 and 2 diabetic patients with diabetic neuropathy were followed. Diabetic neuropathy was defined by a vibration perception threshold greater than 25 V and onychomycosis by clinical diagnosis. Samples of the most affected nail were taken. Potassium hydroxide testing and culture were performed. Photographs of the nails were used by two dermatologists for diagnosis. RESULTS: The mean +/- SE age was 62.3 +/- 11.4 years for the 20 onychomycotic patients and 60.3 +/- 10.4 years for the entire cohort; 14 onychomycotic patients (70%) were male versus 56 in the full cohort (56%) (P < .05). The prevalence of onychomycosis was 20% (culture and potassium hydroxide test positive) and 24% (culture positive). Twenty or 30 patients were positive by the potassium hydroxide test, depending on the investigator. The most frequent pathogen found was Trichophyton rubrum (11 of 20 patients; 55%). The positive predictive values of the dermatologist's diagnoses were 57.8% and 35.6%, and the negative predictive values were 85.0% and 90.5%. The two expert's results were significantly different (P < .05). CONCLUSIONS: The diagnosis of onychomycosis is difficult to make. The diagnostic methods commonly used are not satisfactory. If onychomycosis is dangerous for the diabetic foot, a better diagnostic method is needed.

Epidemiology and prevalence of methicillin-resistant Staphylococcus aureus and Staphylococcus epidermidis in patients with diabetic foot ulcers: focus on the differences between species isolated from individuals with ischemic vs. neuropathic foot ulcers.

We examined whether foot ischemia or neuropathy with diabetic foot ulcer (DFU) promote selection of staphylococci species, evaluated frequency of MRSA and MRSE among strains yielded from patients with DFU and assessed multidrug resistance of isolates. Patients with DFU and foot osteomyelitis were divided into ischemic foot ulcer (IFU, n=21) and neuropathic foot ulcer (NFU, n=29) groups. Frequency of Staphylococcus epidermidis yielded from curettage of IFU was higher compared with NFU (P<0.05). S. epidermidis was also more frequently isolated from the toe web surface of patients with IFU compared with NFU (55% vs. 17.9%, respectively) and healthy volunteers (HV, n=20) (17.6%, P<0.05). These mostly MRSE strains (83.3-100%) originating from DFU patients were multidrug resistant (88.8%). Also, most of MRSA isolates were multidrug resistant (70.3%). Higher rates of MSSA from DFU patients than HV showed resistance to antimicrobials. This is the first report indicating that diabetic patients with IFU differ with NFU patients in higher frequency of S. epidermidis skin colonization and ulcer infection. We suggest that IFU should be defined as separate disease state of DFU and S. epidermidis should be appreciated as a nosocomial pathogen.

Mortality and diabetes mellitus in amputations of the lower limbs for gas gangrene: a case report.

The aim of this study was to examine any association between the presence of diabetes in patients with gas gangrene of the legs and mortality following major lower limb amputation. In a retrospective study, patients submitted to amputation of lower limbs for anaerobic infections were evaluated in the period from January 2005 to January 2007 in the University Hospital de Base in Sao Jose do Rio Preto. All the patients were hospitalized for the treatment of ulcerated lesions of the leg. The study sample consisted of 30 men and 10 women aged between 46 and 87 years (mean 69 years) suffering from anaerobic infections. During treatment, the presence of crepitation in the skin was observed as was gas by radiological examination. Amputation was performed within 2 to 6 hours after diagnosis. Diabetes was identified in 33 patients and death occurred within the perioperative period in 12 cases. Diabetes is associated with the necessity of amputation for gas gangrene resulting in a high mortality rate.

Enterococcus gallinarum endocarditis in a diabetic patient.

Recent studies pointed out the increasing rate of infective endocarditis (IE) in diabetic patients. As diabetes mellitus (DM) prevalence is expected to increase in the coming years, infective endocarditis could be more frequently reported in these patients. We here describe a rare case of Enterococcus gallinarum endocarditis developing on normal native heart valve in an elderly diabetic woman. Therapeutic options were restricted due to resistance factors of the microorganism, limited guidance in the medical literature, and the patient's history and underlying condition. Despite these challenges, adequate antibiotic therapy led to the patient's recovery.

Helicobacter pylori prevalence in diabetes mellitus patients with dyspeptic symptoms and its relationship to glycemic control and late complications.

BACKGROUND: There are contradictory reports on Helicobacter pylori prevalence and its relationship to late complications of diabetes mellitus (DM). The aim of this study was to determine the prevalence of H. pylori infection in type 2 DM patients and to evaluate the relationship between H. pylori infection and the glycemic control, late complications. MATERIAL AND METHOD: A total of 141 type 2 DM patients and 142 nondiabetic subjects with upper gastrointestinal symptoms were enrolled in the study. All patients underwent upper gastrointestinal endoscopy with biopsy specimens obtained from gastric antrum and corpus. H. pylori status was evaluated in each patient by both the rapid urease test and histopathological examination. Plasma glucose, HbA1c, microalbuminuria in 24 h collected urine, electroneuromyography, and fundoscopic examinations were performed in all subjects. RESULTS: The prevalence of H. pylori infection was 61.7% and 58.5%, respectively, among type 2 diabetic patients and nondiabetic controls and was not statistically significant (P = 0.577). The duration of diabetes, fasting blood glucose and haemoglobin A1c levels, nephropathy and retinopathy prevalence did not differ significantly between the two groups (diabetics versus nondiabetics). There was no late complication in 60.3% of the type 2 diabetic patients as compared to at least one late complication in the remainders. A statistically significant correlation was found between H. pylori infection and the presence of neuropathy (P = 0.021). CONCLUSIONS: The prevalence of H. pylori infection did not differ significantly between the diabetic patients and nondiabetic controls. Interestingly, diabetics with H. pylori infection had a higher incidence of neuropathy, although there was no association between the duration and regulation of diabetes, retinopathy, nephropathy and H. pylori status.

Peripheral neuropathy and light-preliminary report indicating prevalence of nanobacteria in HIV.

Peripheral neuropathy is a common condition in HIV-positive patients and is often experienced in diabetes mellitus. The primary mechanism of the disease, which can considerably aggravate the patient's state, is unknown. The perineurium of patients with peripheral neuropathy is frequently enveloped by apatite. Nanobacteria (NB) are protectd by a mineral shell consisting of apatite. Light has been shown to elevate the vitality level of cells, and was predicted to inhibit deposition of stressed NB in the cardiovascular system. Results indicate that light can durably restore the condition of patients with severe peripheral neuropathy.