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Progressive proximal-to-distal reduction in expression of the tight junction complex in colonic epithelium of virally-suppressed HIV+ individuals.

ABSTRACT: Effective antiretroviral therapy (ART) dramatically reduces AIDS-related complications, yet the life expectancy of long-term ART-treated HIV-infected patients remains shortened compared to that of uninfected controls, due to increased risk of non-AIDS related morbidities. Many propose that these complications result from translocated microbial products from the gut that stimulate systemic inflammation--a consequence of increased intestinal paracellular permeability that persists in this population. Concurrent intestinal immunodeficiency and structural barrier deterioration are postulated to drive microbial translocation, and direct evidence of intestinal epithelial breakdown has been reported in untreated pathogenic SIV infection of rhesus macaques. To assess and characterize the extent of epithelial cell damage in virally-suppressed HIV-infected patients, we analyzed intestinal biopsy tissues for changes in the epithelium at the cellular and molecular level. The intestinal epithelium in the HIV gut is grossly intact, exhibiting no decreases in the relative abundance and packing of intestinal epithelial cells. We found no evidence for structural and subcellular localization changes in intestinal epithelial tight junctions (TJ), but observed significant decreases in the colonic, but not terminal ileal, transcript levels of TJ components in the HIV+ cohort. This result is confirmed by a reduction in TJ proteins in the descending colon of HIV+ patients. In the HIV+ cohort, colonic TJ transcript levels progressively decreased along the proximal-to-distal axis. In contrast, expression levels of the same TJ transcripts stayed unchanged, or progressively increased, from the proximal-to-distal gut in the healthy controls. Non-TJ intestinal epithelial cell-specific mRNAs reveal differing patterns of HIV-associated transcriptional alteration, arguing for an overall change in intestinal epithelial transcriptional regulation in the HIV colon. These findings suggest that persistent intestinal epithelial dysregulation involving a reduction in TJ expression is a mechanism driving increases in colonic permeability and microbial translocation in the ART-treated HIV-infected patient, and a possible immunopathogenic factor for non-AIDS related complications.

SUBMITTER: Chung CY

PROVIDER: S-EPMC4072797 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Progressive proximal-to-distal reduction in expression of the tight junction complex in colonic epithelium of virally-suppressed HIV+ individuals.

Chung Charlotte Y CY Alden Stephanie L SL Funderburg Nicholas T NT Fu Pingfu P Levine Alan D AD

PLoS pathogens 20140626 6

Effective antiretroviral therapy (ART) dramatically reduces AIDS-related complications, yet the life expectancy of long-term ART-treated HIV-infected patients remains shortened compared to that of uninfected controls, due to increased risk of non-AIDS related morbidities. Many propose that these complications result from translocated microbial products from the gut that stimulate systemic inflammation--a consequence of increased intestinal paracellular permeability that persists in this populati ...[more]

PMID: 24968145

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Project description:Comparison of global gene expression in the proximal and distal colonic epithelium in azoxymethane treated rats. Experiment Overall Design: Ten male Sprague Dawley rats weighing approximately 245 Â± 14.5 g were housed in wire-bottomed caging in a temperature controlled room (22-24Â°C) with a 12 h light/dark cycle. They were randomly allocated into two groups (n=5) with approximately equal body weights. They were given free access to water and modified AIN-93G diet for 10 days when they were injected with 15 mg of AOM/kg subcutaneously (Sigma Chemical Co., St. Louis, MO, USA). They were anaesthetised with isoflurane and killed by exsanguination six hours after injection. The large bowel (excluding the rectum) was removed, opened longitudinally along the mesenteric border and digesta removed. The colon was rinsed clean with PBS and transferred to a chilled ceramic plate. The most distal and the most proximal 0.5 cm were discarded. Mucosal samples for gene expression and protein analyses were collected by scraping the next 4 cm of proximal and distal colon with new microscope slides. Experiment Overall Design: The mucosal scraping was transferred into RNAlater (Sigma Chemical Co., St. Louis, MO, USA) and stored at -80oC for later processing. All instruments were replaced or cleaned thoroughly between animals. All procedures involving animals were approved by the Commonwealth Scientific and Industrial Research Organisation (CSIRO) Human Nutrition Animal Ethics Committee and complied with the Australian code of practice (2004). Experiment Overall Design: The distal and proximal colonic mucosal samples were removed from the RNAlater stabilisation reagent (Sigma, Australia) and placed in 1ml of TRIzolÂ® Reagent (Invitrogen, Sydney, N.S.W., Australia). Samples were then homogenised using beads (mix of 2.5mm glass and 0.1 - 1.0mm diameter silicon-zirconian beads) in a MiniBeadbeater-8â¢ (BioSpec Products Inc. Oklahoma, US). Total RNA was then extracted according to the TRIzolÂ® Reagent manufacturerâs instruction after which samples were further purified using RNAeasy mini spin columns (QIAGEN, Doncaster, Victoria, Australia) with a DNase on-column digestion as per the manufactureâs instructions. The integrity of the RNA was checked using a Bioanalyzer 2100 (Agilent Technologies) and quantified using a NanoDropÂ® ND-1000 Spectrophotometer. Experiment Overall Design: RNA (4.5ug) samples were processed for Microarray expression analysis using high-density oligonucleotide arrays (AffymetrixÂ® GeneChip array, AffymetrixÂ®, Santa Clara, CA, USA) commensurate with the manufacturerâs instructions.

Dataset Information

Progressive proximal-to-distal reduction in expression of the tight junction complex in colonic epithelium of virally-suppressed HIV+ individuals.

Publications

Progressive proximal-to-distal reduction in expression of the tight junction complex in colonic epithelium of virally-suppressed HIV+ individuals.

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