Search

Background Parkinson Disease (PD) is increasingly being recognized as a disease of the gut-brain axis. Overexpression of human wild type α–synuclein under the neuron-specific Thy1 promoter (Thy1-haSyn) is a well-characterized mouse model of PD. In addition to a progressive motor phenotype, Thy1-haSyn mice have delayed colonic transit at three months of age mirroring prodromal constipation common in human PD. Identification of initial molecular changes in the gastrointestinal tract in PD could lead to early detection of PD and/or gut-targeted therapies to prevent motor symptoms in PD. Methods Colon and striatum gene expression profiling was performed in Thy1-haSyn and wild type (WT) mice aged 1 month and 3 months using 3′ RNA sequencing. Analysis of transcriptomic data included identification of differentially expressed genes, gene set enrichment analysis and weighted gene co-expression network analysis (WGCNA). WGCNA results were further analyzed by linear regression to identify modules most strongly associated with Thy1-haSyn in the colon and striatum, as well as in a combined multivariate model. Module annotation included enrichment for gene ontology terms, cell type signatures and risk genes. Results Differential gene expression in Thy1-haSyn vs WT was greater at one vs three months in both the colon and striatum. There was an opposite pattern of enrichment of mitochondrial genes related to PD (KEGG PD pathway) in striatum (enriched in WT) and colon (enriched in Thy1-haSyn). Colon Thy1-haSyn-associated WGCNA modules were enriched for PD risk genes and PD-relevant pathways including inflammation, autophagy, and oxidative stress. When combined with striatum modules, colon modules remained independent predictors of Thy1-haSyn genotype and increased the model fit (p = 0.048). Conclusions Overexpression of alpha synuclein acutely disrupts gene expression in the colon. While changes in colon gene expression are highly related to known PD-relevant mechanisms, they are distinct from brain changes and in some cases opposite in direction. These findings are in line with the emerging view of PD as a multi-system disease.

Commentary on: Hempel S, Newberry SJ, Maher AR, et al. Probiotics for the prevention and treatment of antibiotic-associated diarrhea: a systematic review and meta-analysis. JAMA 2012;307:1959–69.[OpenUrl][1] The incidence of antibiotic-associated diarrhoea (AAD) is estimated as 29–60% and is associated with increased costs and length of hospital stay.1 The underlying mechanisms of AAD include disruption of the gut flora, effects of altered bacterial breakdown of carbohydrates and direct prokinetic effects of certain antibiotics. Probiotics may prevent AAD by enhancing intestinal barrier function, by promoting competitive exclusion of pathogenic bacteria and by stimulating the host-immune response. This meta-analysis summarises data from randomised controlled trials (RCTs) in which probiotics were administered to … [1]: {openurl}?query=rft.jtitle%253DJAMA%26rft.volume%253D307%26rft.spage%253D1959%26rft.atitle%253DPROBIOTICS%2BFOR%2BTHE%2BPREVENTION%2BAND%2BTREATMENT%2BOF%2BANTIBIOTIC-ASSOCIATED%2BDIARRHEA%253A%2BA%2BSYSTEMATIC%2BREVIEW%2BAND%2BMETA-NALYSIS%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx

Background & Aims Linaclotide is a minimally absorbed, 14-amino acid peptide used to treat patients with irritable bowel syndrome with constipation (IBS-C) or chronic constipation (CC). We performed a meta-analysis to determine the efficacy of linaclotide, compared with placebo, for patients with IBS-C or CC. Methods MEDLINE, EMBASE, and the Cochrane central register of controlled trials were searched for randomized, placebo-controlled trials examining the effect of linaclotide in adults with IBS-C or CC. Dichotomous results were pooled to yield a relative risk (RR), 95% confidence intervals (CIs), and number needed to treat (NNT). Results The search identified 7 trials of linaclotide in patients with IBS-C or CC; 6 were included in the analysis. Two of 3 trials of IBS-C used the end point recommended by the U.S. Food and Drug Administration: an increase from baseline of 1 or more complete spontaneous bowel movement (CSBM)/week and a 30% or more reduction from baseline in the weekly average of daily worst abdominal pain scores for 50% of the treatment weeks. On the basis of this end point, the RR for response to treatment with 290 μg linaclotide, compared with placebo, was 1.95 (95% CI, 1.3−2.9), and the NNT was 7 (95% CI, 5–11). For CC, on the basis of data from 3 trials of patients with CC, the RR for the primary end point (more than 3 CSBMs/week and an increase in 1 or more CSBM/week, for 75% of weeks) was 4.26 for 290 μg linaclotide vs placebo (95% CI, 2.80−6.47), and the NNT was 7 (95% CI, 5–8). Linaclotide also improved stool form and reduced abdominal pain, bloating, and overall symptom severity in patients with IBS-C or CC. Conclusions On the basis of a meta-analysis, linaclotide improves bowel function and reduces abdominal pain and overall severity of IBS-C or CC, compared with placebo.