To the Editors:
Non–AIDS-related mortality today exceeds AIDS-related mortality in populations with access to antiretroviral treatment (ART).1 The relative risk of cardiovascular disease is reported to be around 1.5- to 2-fold compared with that of the general population,2 and it has been suggested that chronic immune activation, in part triggered by microbial translocation from a damaged gut mucosa, may contribute to this excess cardiovascular risk.2 Notably, measures of microbial translocation and immune activation are reduced but normalized despite ART with viral suppression.3–6 Hence, microbial translocation may occur in HIV-infected individuals at a permanent basis, resulting in chronic low-grade elevation of lipopolysaccharide (LPS).
We and others have shown that measures of microbial translocation correlate with several cardiometabolic risk factors in HIV-infection, including coagulation abnormalities, hypertension, body composition, dyslipidemia, insulin resistance, and global cardiovascular risk score.7–11 Hence, strategies to reduce LPS could be relevant for reducing cardiovascular risk in HIV infection.2
We have previously shown that strength training reduced trunk fat and triglycerides and improved insulin sensitivity in HIV-infected patients receiving ART.12 The aim of this was to investigate whether strength training reduces LPS levels through a reduction in trunk fat and triglycerides.
The study cohort has previously been described in detail.12 In brief, 20 sedentary middle-aged HIV-infected men on stable ART and with lipodystrophy were randomly assigned to supervised strength or endurance training 3 times per week for 16 weeks. At baseline, the strength and endurance group did not differ significantly in CD4+ T-cell count (median, 569 vs. 530 cells), ART duration (10.3 vs. 9.0 years), body mass index (23.4 vs. 24.0 kg/m2), fasting glucose (5.5 vs. 5.4 mmol/L), triglycerides (2.6 vs. 2.3 mmol/L), or trunk fat mass (9.7 vs. 10.8 kg). Fifteen age- and VO2max-matched HIV-seronegative healthy men served as controls at baseline.
Body fat composition was measured by dual-energy x-ray absorptiometry scan, insulin-mediated glucose uptake was measured by euglycemic–hyperinsulinemic clamp combined with stable isotope infusion, and LPS was measured with the limulus amebocyte lysate assay (Lonza, Walkersville, MD). Lipids and LPS were measured at 8 (0, 30, 60, 90, 120, 130, 140, and 150 minutes) and 4 (0, 30, 60, and 90 minutes) time points, respectively, during the basal condition of the clamp procedure. Changes within groups and between groups were analyzed by a linear mixed model, and skewed data (LPS and triglycerides) were log transformed.
At baseline, LPS levels were elevated in HIV-infected individuals [mean, 98.6 (95% confidence interval: 85.6 to 113.6) pg/mL] compared with controls [52.9 (45.3 to 61.8), P< 0.001]. After 16 weeks of intervention in the HIV cohort, LPS levels were not significantly changed in the strength training group [6.8% reduction (20% reduction to 6.4%increase), P = 0.3] or in the endurance training group [3.6% reduction (18.3% reduction to 11.1% increase), P = 0.6].
When analyzing all HIV-infected participants, irrespective of intervention, LPS decreased by 11.2% (−6.3% to −16.2%, P < 0.0001) for each unit decrease in triglycerides. For each kilogram decrease in trunk fat, LPS decreased 1.95% (0.3% to −4.2%, P = 0.09), and for each unit increase in insulin-mediated glucose-uptake, LPS decreased 0.7% (−0.1% to −1.3%, P = 0.022). As previously reported, both training modalities increased insulin-mediated glucose uptake, whereas strength training, but not endurance training, reduced triglyceride levels and trunk fat mass.12
When analyzing the strength group separately, LPS levels were reduced by 9.6% (−5.0% to −14.7%, P = 0.0001) for each unit reduction in triglycerides. Furthermore, for each unit increase in insulin-mediated glucose uptake, LPS decreased 0.7% (−0.1% to −1.3%, P = 0.026), and for each kilogram reduction in trunk fat, LPS levels were reduced by 3.58% (−1.07% to −5.97%, P = 0.006). In a model with trunk fat and triglycerides, the modest effect of trunk fat reduction on LPS-levels was no longer present (not shown), suggesting that this effect is mainly mediated through a reduction in triglycerides.
When analyzing the endurance group separately, LPS levels were reduced by 16.6% (−0.8% to −32.4%, P = 0.04) for each unit reduction in triglycerides. There were no significant associations between changes in insulin-mediated glucose uptake, trunk fat, and LPS levels.
In summary, our data show that although plasma levels of LPS were not significantly reduced by the interventions, there was an association between reduced trunk fat mass, triglycerides, improved insulin sensitivity, and reduced LPS levels after strength training. Furthermore, the potential effect of trunk fat reduction on LPS levels seemed to be mainly mediated through a reduction in triglycerides.
One limitation of this study is that dual-energy x-ray absorptiometry scan does not separate between subcutaneous and visceral adipose tissue compartments. Of note, we recently found a strong association between LPS levels and visceral fat volumes, but not subcutaneous fat volumes in obese subjects undergoing bariatric surgery.13
The close association between reduced triglyceride levels and reduced plasma LPS could be explained by several contributing mechanisms: First, LPS is cotransported with lipids in chylomicrons from the gut to circulation,14 where 75%–80% of circulating LPS associates with proatherogenic lipoproteins such as triglyceride-rich very low-density lipoprotein particles,15 as well as high-density lipoprotein cholesterol, which has antiatherogenic properties and acts as a scavenger of LPS.16 Furthermore, LPS stimulates triglyceride production in the liver17 and downregulates lipoprotein lipase activity, leading to reduced elimination of triglycerides,18 whereas lipase expression is increased in human skeletal muscles after exercise training with weight loss.19
In conclusion, reduced trunk fat, triglycerides, and improved insulin sensitivity after strength training were associated with reduced LPS levels, possibly mediated through a reduction in triglycerides, although the direction of these associations should be explored in future studies. Our findings suggest that strategies to improve body composition and in particular lipid profile may improve the cardiovascular risk profile in HIV infection, partly through a reduction in LPS levels.
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