Identifying and testing candidate genetic polymorphisms in the irritable bowel syndrome (IBS): association with TNFSF15 and TNFα.

OBJECTIVES: The postinfectious irritable bowel syndrome (PI-IBS) suggests that impaired resolution of inflammation could cause IBS symptoms. The authors hypothesised that polymorphisms in genes whose expression were altered by gastroenteritis might be linked to IBS with diarrhoea (IBS-D) which closely resembles PI-IBS. DESIGN: Part 1: 25 healthy volunteers (HVs), 21 patients 6 months after Campylobacter jejuni infection, 37 IBS-D and 19 IBS with constipation (IBS-C) underwent rectal biopsy for gene expression analysis and peripheral blood mononuclear cell cytokine production assessment. Part 2: Polymorphisms in genes whose expression was altered in Part 1 were assessed in 179 HV, 179 IBS-D, 122 IBS-C and 41 PI-IBS. RESULTS: Part 1: Mucosal expression of seven genes was altered in IBS: CCL11, CCL13, Calpain 8 and TNFSF15 increased while NR1D1, GPR161 and GABRE decreased with similar patterns after infection with C jejuni. Part 2: The authors assessed 21 known single nucleotide polymorphisms (SNPs) in these seven genes and one SNP in each of the TNFα and IL-10 genes. Three out of five TNFSF15 SNPs (rs6478108, rs6478109 and rs7848647) showed reduced minor allele frequency (MAF) (0.28, 0.27 and 0.27) in subjects with IBS-D compared with HV (0.38, 0.36 and 0.37; p=0.007, 0.015 and 0.007, respectively) confirming others recent findings. The authors also replicated the previously reported association of the TNFα SNP rs1800629 with PI-IBS which showed an increase in the MAF at 0.30 versus 0.19 for HV (p=0.04). CONCLUSION: IBS-D and PI-IBS patients are associated with TNFSF15 and TNFα genetic polymorphisms which also predispose to Crohn's disease suggesting possible common underlying pathogenesis.

The geography of HIV/AIDS prevalence rates in Botswana.

BACKGROUND: Botswana has the second-highest human immunodeficiency virus (HIV) infection rate in the world, with one in three adults infected. However, there is significant geographic variation at the district level and HIV prevalence is heterogeneous with the highest prevalence recorded in Selebi-Phikwe and North East. There is a lack of age-and location-adjusted prevalence maps that could be used for targeting HIV educational programs and efficient allocation of resources to higher risk groups. METHODS: We used a nationally representative household survey to investigate and explain district level inequalities in HIV rates. A Bayesian geoadditive mixed model based on Markov Chain Monte Carlo techniques was applied to map the geographic distribution of HIV prevalence in the 26 districts, accounting simultaneously for individual, household, and area factors using the 2008 Botswana HIV Impact Survey. RESULTS: Overall, HIV prevalence was 17.6%, which was higher among females (20.4%) than males (14.3%). HIV prevalence was higher in cities and towns (20.3%) than in urban villages and rural areas (16.6% and 16.9%, respectively). We also observed an inverse U-shape association between age and prevalence of HIV, which had a different pattern in males and females. HIV prevalence was lowest among those aged 24 years or less and HIV affected over a third of those aged 25-35 years, before reaching a peak among the 36-49-year age group, after which the rate of HIV infection decreased by more than half among those aged 50 years and over. In a multivariate analysis, there was a statistically significant higher likelihood of HIV among females compared with males, and in clerical workers compared with professionals. The district-specific net spatial effects of HIV indicated a significantly higher HIV rate of 66% (posterior odds ratio of 1.66) in the northeast districts (Selebi-Phikwe, Sowa, and Francistown) and a reduced rate of 27% (posterior odds ratio of 0.73) in Kgalagadi North and Kweneng West districts. CONCLUSION: This study showed a clear geographic distribution of the HIV epidemic, with the highest prevalence in the east-central districts. This study provides age- and location-adjusted prevalence maps that could be used for the targeting of HIV educational programs and efficient allocation of resources to higher risk groups. There is need for further research to determine the social, cultural, economic, behavioral, and other distal factors that might explain the high infection rates in some of the high-risk areas in Botswana.

Abnormal intestinal permeability in subgroups of diarrhea-predominant irritable bowel syndromes.

OBJECTIVES: Irritable bowel syndrome (IBS) is a heterogeneous condition and defined according to symptoms. Low-grade inflammation has been associated with IBS, particularly that following infection, but whether altered intestinal permeability profiles relate to irritable bowel subtype or onset is uncertain. Our aim was to compare small and large intestinal permeability in various subtypes of IBS to healthy controls. METHODS: Intestinal permeability was measured using 1.8 MBq of 51Cr-EDTA and collecting urine over 24 h; Study 1: patients with diarrhea-predominant postinfectious IBS (N=15), constipation-predominant IBS (N=15), and healthy controls (N=15); Study 2: two groups of diarrhea-predominant IBS (D-IBS), one with a history of onset after acute gastroenteritis (postinfectious) (N=15) and the other without such a history (nonpostinfectious) (N=15) both compared with healthy controls (N=12). RESULTS: Permeability expressed as percentage of total dose excreted in urine (median [inter-quartile range]). Study 1: Proximal small intestinal permeability was increased in postinfectious IBS (0.19 [0.12-0.23]) in contrast to constipated IBS (0.085 [0.043-0.13]) and controls (0.07 [0.035-0.19]) (p=0.02). IBS patients with eczema, asthma, or hayfever had increased proximal small intestinal permeability compared with IBS patients without atopy (p=0.02). Study 2: Small intestinal permeability was greater in nonpostinfectious diarrhea-predominant IBS (0.84 [0.69-1.49]) compared with postinfectious IBS (0.43 [0.29-0.63], p=0.028) or controls (0.27 [0.2-0.39]), p=0.001). CONCLUSIONS: Small intestinal permeability is frequently abnormal in diarrhea-predominant IBS. Those without a history of infectious onset appear to have a more severe defect.

Post-infectious irritable bowel syndrome.

PURPOSE OF REVIEW: Irritable bowel syndrome patients form a heterogeneous group with a variable contribution of central and peripheral components. The peripheral component is prominent in irritable bowel syndrome developing after infection (post-infectious irritable bowel syndrome) and this has proved a profitable area of research. RECENT FINDINGS: Recent studies have overthrown the dogma that irritable bowel syndrome is characterized by no abnormality of structure by demonstrating low-grade lymphocytic infiltration in the gut mucosa, increased permeability and increases in other inflammatory components including enterochromaffin and mast cells. Furthermore, increased inflammatory cytokines in both mucosa and blood have been demonstrated in irritable bowel syndrome. While steroid treatment has proved ineffective, preliminary studies with probiotics exerting an anti-inflammatory effect have shown benefit. SUMMARY: The study of post-infectious irritable bowel syndrome has revealed the importance of low-grade inflammation in causing irritable bowel syndrome symptoms. It has suggested novel approaches to irritable bowel syndrome including studies of serotonin and histamine metabolism which may be relevant to other subtypes of the disease.