A 12 week longitudinal study of microbial translocation and systemic inflammation in undernourished HIV-infected Zambians initiating antiretroviral therapy

Abstract

BackgroundUndernourished, HIV-infected adults in sub-Saharan Africa have high levels of systemic inflammation, which is a risk factor for mortality and other adverse health outcomes. We hypothesized that microbial translocation, due to the deleterious effects of HIV and poor nutrition on intestinal defenses and mucosal integrity, contributes to heightened systemic inflammation in this population, and reductions in inflammation on antiretroviral therapy (ART) accompany reductions in translocation.MethodsHIV-infected, Zambian adults with a body mass index <18.5 kg/m2 were recruited for a pilot study to assess the relationships between microbial translocation and systemic inflammation over the first 12 weeks of ART. To assess microbial translocation we measured serum lipopolysaccharide binding protein (LBP), endotoxin core IgG and IgM, and soluble CD14, and to assess intestinal permeability we measured the urinary excretion of an oral lactulose dose normalized to urinary creatinine (Lac/Cr ratio). Linear mixed models were used to assess within-patient changes in these markers relative to serum C-reactive protein (CRP), tumor necrosis factor-α receptor 1 (TNF-α R1), and soluble CD163 over 12 weeks, in addition to relationships between variables independent of time point and adjusted for age, sex, and CD4+ count.ResultsThirty-three participants had data from recruitment and at 12 weeks: 55% were male, median age was 36 years, and median baseline CD4+ count was 224 cells/μl. Over the first 12 weeks of ART, there were significant decreases in serum levels of LBP (median change -8.7 μg/ml, p = 0.01), TNF-α receptor 1 (-0.31 ng/ml, p < 0.01), and CRP (-3.5 mg/l, p = 0.02). The change in soluble CD14 level over 12 weeks was positively associated with the change in CRP (p < 0.01) and soluble CD163 (p < 0.01). Pooling data at baseline and 12 weeks, serum LBP was positively associated with CRP (p = 0.01), while endotoxin core IgM was inversely associated with CRP (p = 0.01) and TNF-α receptor 1 (p = 0.04). The Lac/Cr ratio was not associated with any serum biomarkers.ConclusionsIn undernourished HIV-infected adults in Zambia, biomarkers of increased microbial translocation are associated with high levels of systemic inflammation before and after initiation of ART, suggesting that impaired gut immune defenses contribute to innate immune activation in this population.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2334-14-521) contains supplementary material, which is available to authorized users.

From Wasting to Obesity: The Contribution of Nutritional Status to Immune Activation in HIV Infection

“…These findings suggest that the changes in mucosal integrity accompanying HIV infection involve permanent changes in gastrointestinal cellular function, including the loss of IL-17-and IL-22-producing cells and altered epithelial gene expression, which require time to emerge. While most studies of microbial translocation and innate immune activation in HIV infection are from developed countries, similar findings are reported from resource-limited settings [13,14].…”

“…The combined effects of environmental factors, nutrient deficits, and HIV infection on gastrointestinal mucosal barrier defenses and microbiome composition (discussed below) contribute to increased translocation of microbes and microbial proteins into the bowel wall and circulation in malnourished HIV-infected individuals [13][14][15][16]. Microbial translocation, as measured by circulating lipopolysaccharide (LPS; a component of the bacterial cell wall), anti-endotoxin immunoglobulin M and immunoglobulin G antibodies, soluble CD14, and other biomarkers is associated with accelerated HIV disease progression and a higher risk of mortality in untreated HIV infection [17,18], although the prognostic value of these biomarkers is less clear after ART initiation [19,20].…”

Correlation of (1→3)-β-D-glucan with other inflammation markers in chronically HIV infected persons on suppressive antiretroviral therapy

“…The enteropathy associated with HIV infection is characterized by microbial over-growth in the intestinal lumen and disrupted intestinal permeability resulting in increased levels of lipopolysaccharides (LPS) and 16S rRNA in blood plasma. Such microbial translocation most likely leads to local and systemic immune activation, characterized by increased levels of pro-inflammatory cytokines such as tumour-necrosis-factor α (TNF-α), neopterin, cluster of differentiation 14 (CD14), interleukin-8 (IL-8), and interleukin-6 (IL-6) [6], [7], [8], [9]. In particular, plasma neopterin is an established marker of monocyte activation and was repeatedly associated with HIV disease progression, greater peripheral monocyte HIV DNA reservoirs and negative neurocognitive and cardiovascular outcomes [10], [11], [12].…”

Markers of microbial translocation during pregnancy: differences among HIV+ women of African and European provenance

“…While the evaluation of MT biomarkers as a measure of the degree of immune activation has provided solid evidence in HIV patients from Europe or North America [5,29] it still needs further assessment in patients of African origin. Although many studies conducted in Africa reported higher levels of inflammatory markers in HIV infected individuals with respect to their seronegative counterparts [8,30,31], others found contrasting results; no correlation between HIV progression and sCD14 and LPS levels was found in Ugandan patients, that also had concentrations of sCD14 and LPS similar to those of matched seronegative Afro-American individuals [32]; similarly, a trend toward lower levels of I-FABP in HIV-positive participants compared to HIVuninfected individuals has been observed in a sub Saharan cohort, suggesting differential relationships among biomarkers of intestinal barrier integrity and innate immune activation [33]. In a recent study, our group found levels of sCD14 lower than expected in Malawian HIV pregnant women prior to ART treatment, but still associated to the immune virological parameters and to low birth weight [17].…”