Therapeutic Opportunities for Intestinal Angioectasia- Targeting PPARγ and Oxidative Stress.

Recurrent and acute bleeding from intestinal tract angioectasia (AEC) presents a major challenge for clinical intervention. Current treatments are empiric, with frequent poor clinical outcomes. Improvements in understanding the pathophysiology of these lesions will help guide treatment. Using data from the US Food and Drug Administration (FDA)'s Adverse Event Reporting System (FAERS), we analyzed 12 million patient reports to identify drugs inversely correlated with gastrointestinal bleeding and potentially limiting AEC severity. FAERS analysis revealed that drugs used in patients with diabetes and those targeting PPARγ-related mechanisms were associated with decreased AEC phenotypes (P < 0.0001). Electronic health records (EHRs) at University of Cincinnati Hospital were analyzed to validate FAERS analysis. EHR data showed a 5.6% decrease in risk of AEC and associated phenotypes in patients on PPARγ agonists. Murine knockout models of AEC phenotypes were used to construct a gene-regulatory network of candidate drug targets and pathways, which revealed that wound healing, vasculature development and regulation of oxidative stress were impacted in AEC pathophysiology. Human colonic tissue was examined for expression differences across key pathway proteins, PPARγ, HIF1α, VEGF, and TGFß1. In vitro analysis of human AEC tissues showed lower expression of PPARγ and TGFß1 compared with controls (0.55 ± 0.07 and 0.49 ± 0.05). National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) RNA-Seq data was analyzed to substantiate human tissue findings. This integrative discovery approach showing altered expression of key genes involved in oxidative stress and injury repair mechanisms presents novel insight into AEC etiology, which will improve targeted mechanistic studies and more optimal medical therapy for AEC.

Gut microbiota and obesity: An opportunity to alter obesity through faecal microbiota transplant (FMT).

Obesity is a global pandemic with immense health consequences for individuals and societies. Multiple factors, including environmental influences and genetic predispositions, are known to affect the development of obesity. Despite an increasing understanding of the factors driving the obesity epidemic, therapeutic interventions to prevent or reverse obesity are limited in their impact. Manipulation of the human gut microbiome provides a new potential therapeutic approach in the fight against obesity. Specific gut bacteria and their metabolites are known to affect host metabolism and feeding behaviour, and dysbiosis of this biosystem may lead to metabolic syndrome. Potential therapies to alter the gut microbiota to treat obesity include dietary changes, supplementation of the diet with probiotic organisms and prebiotic compounds that influence bacterial growth, and the use of faecal microbiota transplant, in which gut microbiota from healthy individuals are introduced into the gut. In this review, we examine the growing scientific evidence supporting the mechanisms by which the human gut microbiota may influence carbohydrate metabolism and obesity, and the various possible therapies that may utilize the gut microbiota to help correct metabolic dysfunction.

Clostridium difficile recurrence is characterized by pro-inflammatory peripheral blood mononuclear cell (PBMC) phenotype.

Clostridium difficile infection (CDI) is a prevalent nosocomial and increasingly community-acquired problem. Little is known about the productive cellular response in patients. We used flow cytometry to define inflammatory (Th1 and Th17) and regulatory [Foxp3(+) T-regulatory (Treg)] cells present in circulating peripheral blood mononuclear cells (PBMC) from CDI patients. We consented 67 inpatients that tested either positive or negative for CDI and 16 healthy controls and compared their PBMC phenotypes. PBMC were collected, isolated, and stained for CD3, CD8 and either IL17 (Th17), IFN-γ (Th1) or Foxp3 (Treg) and analysed using flow cytometry. Twenty thousand events were collected in the lymphocyte gate (gate 1) and T-cell phenotypes were defined. CDI patients who clear the primary initial infection have greater numbers of non-CD3 PBMC. CDI patients who develop recurrence of CDI have a greater percentage of CD3(+)CD8(+), CD3(+)CD4(+)Foxp3 and fewer low granular CD3(-)Foxp3(+) PBMC. These patients have greater numbers of IFN-γ-producing lymphocytes, as well as PBMC phenotypes represented by increased IFN-γ- and IL17-co-expressing CD4(+)CD3(+). This initial pro-inflammatory phenotype decreases with repeated recurrence, demonstrating importance of timing of sample collection and history of symptoms. Patients with a history of recurrence had increased Foxp3(+)CD3(+)CD4(+) and IL17(+)CD3(+)CD4(+) populations. Hence, CDI recurrence is hallmarked by greater numbers of circulating CD3(+) lymphocytes skewed towards a Th1/Th17 inflammatory population as well as possible immune plasticity (Th17/Treg).