Direct Biomarkers of Microbial Translocation Correlate with Immune Activation in Adult Zambians with Environmental Enteropathy and Hepatosplenic Schistosomiasis.

Patrick Kaonga,Evans Kaimoyo,Paul Kelly,Kanekwa Zyambo,Edford Sinkala,Ellen Besa

doi:10.4269/ajtmh.17-0365

Abstract

.Microbial translocation is a poorly understood consequence of several disorders such as environmental enteropathy (EE) and hepatosplenic schistosomiasis (HSS). Herein, we compared biomarkers of microbial origin and immune activation in adults with these disorders and in healthy controls. A cross-sectional study was conducted in participants with EE recruited from Misisi compound, Lusaka, Zambia; HSS patients and healthy controls from the University Teaching Hospital, Lusaka. Plasma lipopolysaccharides (LPSs) was measured by limulus amoebocyte lysate assay, plasma 16S ribosomal RNA (16S rRNA) gene copy number was quantified by quantitative real-time polymerase chain reaction, Toll-like receptor ligand (TLRL) activity by QUANTI-Blue detection medium, and cytokines from cell culture supernatant by Cytometric Bead Array. In univariate analysis LPS, 16S rRNA gene copy number, and TLR activity were all high and correlated with each other and with cytokines tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-10, and IL-4 secreted by the RAW-Blue cells. After controlling for baseline characteristic, biomarkers of microbial translocation in blood were predictors of TNF-α, IL-6, and IL-10 activation in cell culture supernatant from EE participants and HSS patients but not in healthy controls. TLR activity showed the strongest correlation with TNF-α. These data provide correlative evidence that microbial translocation contributes to systemic cytokine activation in two disorders common in the tropics, with total TLR ligand estimation showing the strongest correlation with TNF-α (r = 0.66, P < 0.001).

Highlights

Microbial translocation (MT) is the passive movement of microbes and/or their products from the gut into mesenteric lymph nodes and other sterile sites
BMI = body mass index; EE = environmental enteropathy; Hb = hemoglobin; HIV = human immunodeficiency virus; HSS = hepatosplenic schistosomiasis; F = female; M = male. * χ2 was used; percentages are in parentheses
We asked whether direct biomarkers of MT in plasma correlate with immune activation in EE and HSS

Summary

Introduction

Microbial translocation (MT) is the passive movement of microbes and/or their products from the gut into mesenteric lymph nodes and other sterile sites. It is common in environmental enteropathy (EE), a subclinical condition hypothesized to be acquired through repeated exposure to fecal–oral contamination.[1] EE is characterized by loss of barrier function, chronic intestinal inflammation, MT, and chronic immune activation.[2] MT can be measured by detection of direct biomarkers in plasma such as lipopolysaccharide (LPS),3 16S ribosomal RNA (16S rRNA) gene copy number,[4] or other pathogen-associated molecular patterns (PAMPs). One of the major consequences of HSS disease is portal hypertension, which is associated with esophageal varices or gastric varices or both. In certain parts of rural Zambia prevalence of S. mansoni has reached 77%.6

Methods

Results

Conclusion