Vagal dysfunction and small intestinal bacterial overgrowth: novel pathways to chronic inflammation in HIV

Abstract

Objective: Chronic inflammation in HIV-infected individuals drives disease progression and the development of comorbidities, despite viral suppression with combined antiretroviral therapy. Here, we sought evidence that vagal dysfunction, which occurs commonly as part of HIV-associated autonomic neuropathy, could exacerbate inflammation through gastrointestinal dysmotility, small intestinal bacterial overgrowth (SIBO), and alterations in patterns of soluble immune mediators.

Design: This is a cross-sectional observational study.

Methods: Forty participants on stable combined antiretroviral therapy with gastrointestinal symptoms, and no causes for vagal or gastrointestinal dysfunction other than HIV, underwent autonomic testing, hydrogen/methane breath testing for SIBO, and gastric emptying scintigraphy. A panel of 41 cytokines, high-mobility group box 1, and markers of bacterial translocation (lipopolysaccharide) and monocyte/macrophage activation (sCD14 and sCD163) were tested in plasma.

Results: We found that participants with vagal dysfunction had delayed gastric emptying and higher prevalence of SIBO. SIBO was associated with IL-6, but not sCD14; lipopolysaccharide could not be detected in any participant. We also found alteration of cytokine networks in participants with vagal dysfunction, with stronger and more numerous positive correlations between cytokines. In the vagal dysfunction group, high mobility group box 1 was the only soluble mediator displaying strong negative correlations with other cytokines, especially those cytokines that had numerous other strong positive correlations.

Conclusion: The current study provides evidence that the vagal component of HIV-associated autonomic neuropathy is associated with changes in immune and gastrointestinal function in individuals with well treated HIV. Further study will be needed to understand whether therapies targeted at enhancing vagal function could be of benefit in HIV.

Figure 1

Hypothesized mechanisms by which vagal dysfunction could lead to chronic inflammation in HIV

Figure 2

Gastric emptying abnormalities in participants with vagal dysfunction shows gastric emptying scintigraphy images at 4 hours after ingestion of a radiolabeled meal. (a) is a normal anterior image in which all radiolabeled material has exited the stomach and moved distally. (b) and (c) are anterior images from the participants with vagal dysfunction and gastroparesis demonstrating retained radiolabeled material in the stomach (arrows). (d)-(f) are the analogous posterior images.

Figure 3

Gas content in breath following glucose ingestion in participants with and without vagal dysfunction depicts mean hydrogen and methane breath content in parts per million (± standard error of the mean). The solid line represents participants with vagal dysfunction and the dotted line represents participants with normal vagal function. The baseline measurement is taken after an overnight fast. The participant then immediately drinks a standardized glucose solution and repeat samples are taken every 20 minutes for a total of 180 minutes. The grey box (minutes 0-100) represents the time during which gas production is likely to represent fermentation of glucose by small intestinal bacteria, whereas later times represent the large intestine.

Figure 4

Correlations and hierarchical clustering of cytokine expression in participants with and without vagal dysfunction depicts correlations between individual cytokines for participants with and without vagal dysfunction. Each small colored square represents the degree of correlation (i.e. value of Spearman’s ρ for bivariate correlation) between two individual cytokines. Darker shades of blue-green indicate stronger positive correlations. Cytokines are ordered according to the hierarchical clustering for each group as depicted by the dendrograms.