Intestinal microbiota regulates diabetes and cancer progression by IL-1ß and NOX4 dependent signaling cascades.

Diabetes changes the host microbiota, a condition known as dysbiosis. Dysbiosis is an important factor for the pathogenesis of diabetes and colorectal cancer (CRC). We aimed at identifying the microbial signature associated with diabetes and CRC; and identifying the signaling mechanism altered by dysbiosis and leading to CRC progression in diabetes. MKR mice that can spontaneously develop type 2 diabetes were used. For CRC induction, another subset of mice was treated with azoxymethane and dextran sulfate sodium. To identify the role of microbiota, microbiota-depleted mice were inoculated with fecal microbial transplant from diabetic and CRC mice. Further, a mouse group was treated with probiotics. At the end of the treatment, 16S rRNA sequencing was performed to identify microbiota in the fecal samples. Blood was collected, and colons were harvested for molecular, anatomical, and histological analysis. Our results show that diabetes is associated with a microbial signature characterized by reduction of butyrate-forming bacteria. This dysbiosis is associated with gastrointestinal complications reflected by a reduction in colon lengths. These changes are reversed upon treatment with probiotics, which rectified the observed dysbiosis. Inoculation of control mice with diabetic or cancer microbiota resulted in the development of increased number of polyps. Our data also show that inflammatory cytokines (mainly interleukin (IL)-1ß) and NADPH oxidase (NOX)4 are over-expressed in the colon tissues of diabetic mice. Collectively our data suggest that diabetes is associated with dysbiosis characterized by lower abundance of butyrate-forming bacteria leading to over-expression of IL-1ß and NOX4 leading to gastrointestinal complications and CRC.

Bullying Victimization and Use of Substances in High School: Does Religiosity Moderate the Association?

Alcohol, tobacco and other drug use continue to pose serious public health concerns among youth. Bullying victimization has been identified as a risk factor and religiosity a protective factor for adolescent substance use. No previous research has examined the potential moderating role of religiosity. We explore the association between bullying victimization and substance use in adolescents with low and high levels of religiosity. A cross-sectional survey was conducted with a representative sample of high school students in greater Beirut. Binary and multinomial logistic models were used, adjusting for demographics, and stratified by level of religiosity. Of the 986 students responding to the survey, 65% were females; 48% had experienced some form of bullying; and 52% self-rated as low in religiosity. Between 10 and 30% were current users of alcohol or tobacco. Students of lower religiosity levels who had been bullied were more likely to use substances than those who self-rated as high religiosity. Religiosity may be a potential moderator of the association between being bullied and substance use, but the exact mechanisms and underlying reasons need further investigation.

The risk factors for the recurrent upper gastrointestinal hemorrhage among acute peptic ulcer disease patients in Syria: A prospective cohort study.

BACKGROUND: Upper gastrointestinal bleeding (UGIB) is a life-threatening medical emergency characterized by bleeding from the esophagus, stomach, or duodenum. This study aims to analyze the risk factors for upper gastrointestinal tract rebleeding among acute peptic ulcer patients. METHODS: This is a cohort clinical study conducted between July 2018 and June 2020. Patients admitted or hospitalized because of UGIB or developed it during their hospital stay were included.s The patients were divided into two groups for the statistical analysis using Forrest's ulcer rebleeding risk classification. Group 1: Forrest 1a+1b+2a+2b, and group 2: Forrest 2c+3. The fasting time before the endoscopic procedure was from 12 to 24 hours. Follow-ups were conducted for 30 days after the treatment. RESULTS: The total number of included subjects was 152, out of which 57.89% (n = 88) were male patients. The mean SD for patients' age was 52.63 16.89±; more than 40% (n = 62) of subjects were using antiplatelet medications, while only 13.15% (n = 20) used NSAIDs, and the mean SD for the transferred units was 2.32 ± 1.88, 7.24% (n = 11) of patients died. After 30 days of the treatment, 6.57% (n = 10) of patients suffered from recurrent bleeding. The most common presentation was melena 67.95% (n = 103), 53% (n = 81) of patients had hematemesis, 69.73% (n = 106) patients had gastric ulcer and 30.26% (n = 46) had duodenal ulcers. CONCLUSION: Age, NSAIDs, altered mental capacity, Forrest classification (Ia,Ib, and IIa), and blood transfusion were associated with a higher risk of rebleeding. Furthermore, patients who needed 3.83 blood units were at higher risk of recurrent bleeding.

GDAP1 loss of function inhibits the mitochondrial pyruvate dehydrogenase complex by altering the actin cytoskeleton.

Charcot-Marie-Tooth (CMT) disease 4A is an autosomal-recessive polyneuropathy caused by mutations of ganglioside-induced differentiation-associated protein 1 (GDAP1), a putative glutathione transferase, which affects mitochondrial shape and alters cellular Ca2+ homeostasis. Here, we identify the underlying mechanism. We found that patient-derived motoneurons and GDAP1 knockdown SH-SY5Y cells display two phenotypes: more tubular mitochondria and a metabolism characterized by glutamine dependence and fewer cytosolic lipid droplets. GDAP1 interacts with the actin-depolymerizing protein Cofilin-1 and beta-tubulin in a redox-dependent manner, suggesting a role for actin signaling. Consistently, GDAP1 loss causes less F-actin close to mitochondria, which restricts mitochondrial localization of the fission factor dynamin-related protein 1, instigating tubularity. GDAP1 silencing also disrupts mitochondria-ER contact sites. These changes result in lower mitochondrial Ca2+ levels and inhibition of the pyruvate dehydrogenase complex, explaining the metabolic changes upon GDAP1 loss of function. Together, our findings reconcile GDAP1-associated phenotypes and implicate disrupted actin signaling in CMT4A pathophysiology.

Butyrate modulates diabetes-linked gut dysbiosis: epigenetic and mechanistic modifications.

Diabetic dysbiosis has been described as a novel key player in diabetes and diabetic complications. However, the cellular/molecular alterations associated with dysbiosis remain poorly characterized. For that, control, non-obese type 2 diabetic MKR mice and MKR mice treated with butyrate were used to delineate the epigenetic, cellular and molecular mechanisms by which dysbiosis associated with diabetes induces colon shortening and inflammation attesting to gastrointestinal disturbance. Our results show that dysbiosis is associated with T2DM and characterized by reduced Bacteroid fragilis population and butyrate-forming bacteria. The reduction of butyrate-forming bacteria and inadequate butyrate secretion result in alleviating HDAC3 inhibition and altering colon permeability. The observed changes are also associated with an increase in ROS production, a rise in NOX4 proteins, and a shift in the inflammatory markers, where IL-1ß is increased and IL-10 and IL-17α are reduced. Treatment with butyrate restores the homeostatic levels of NOX4 and IL-1ß. In summary, our data suggest that in T2DM, dysbiosis is associated with a reduction in butyrate content leading to increased HDAC3 activity. Butyrate treatment restores the homeostatic levels of the inflammatory markers and reduces ROS production known to mediate diabetes-induced colon disturbance. Taken together, our results suggest that butyrate could be a potential treatment to attenuate diabetic complications.