Altered interactions between the gut mucosa and bacteria during HIV infection seem to contribute to chronic immune dysfunction. A deeper understanding of how nutritional interventions could ameliorate gut dysbiosis is needed. Forty-four subjects, including 12 HIV⁺ viremic untreated (VU) patients, 23 antiretroviral therapy-treated (ART⁺) virally suppressed patients (15 immunological responders and 8 non-responders) and 9 HIV⁻ controls (HIV⁻), were blindly randomized to receive either prebiotics (scGOS/lcFOS/glutamine) or placebo (34/10) over 6 weeks in this pilot study. We assessed fecal microbiota composition using deep 16S rRNA gene sequencing and several immunological and genetic markers involved in HIV immunopathogenesis. The short dietary supplementation attenuated HIV-associated dysbiosis, which was most apparent in VU individuals but less so in ART⁺ subjects, whose gut microbiota was found more resilient. This compositional shift was not observed in the placebo arm. Significantly, declines in indirect markers of bacterial translocation and T-cell activation, improvement of thymic output, and changes in butyrate production were observed. Increases in the abundance of Faecalibacterium and Lachnospira strongly correlated with moderate but significant increases of butyrate production and amelioration of the inflammatory biomarkers soluble CD14 and high-sensitivity C-reactive protein, especially among VU. Hence, the bacterial butyrate synthesis pathway holds promise as a viable target for interventions.

Targeted disruption of the lipid droplet protein, perilipin, in mice leads to constitutional lipolysis associated with marked reduction in white adipose tissue as a result of unbridled lipolysis. To investigate the metabolic adaptations in response to the constitutive lipolysis, we studied perilipin-null (plin^–/–) mice in terms of their fatty acid oxidation and glycerol and glucose metabolism homeostasis by using dynamic biochemical testing and clamp and tracer infusion methods. plin^–/– mice showed increased β-oxidation in muscle, liver, and adipose tissue resulting from a coordinated regulation of the enzymes and proteins involved in β-oxidation. The increased β-oxidation helped remove the extra free fatty acids created by the constitutive lipolysis. An increase in the expression of the transcripts for uncoupling proteins-2 and -3 also accompanied this increase in fatty acid oxidation. Adult plin^–/– mice had normal plasma glucose but a reduced basal hepatic glucose production (46% that of plin^+/+). Insulin infusion during low dose hyperinsulinemic-euglycemic clamp further lowered the glucose production in plin^–/– mice, but plin^–/– mice also showed a 36% decrease (p < 0.007) in glucose disposal rate during the low dose insulin clamp, indicating peripheral insulin resistance. However, compared with plin^+/+ mice, 14-week-old plin^–/– mice showed no significant difference in glucose disposal rate during the high dose hyperinsulinemic clamp, whereas 42-week-old plin^–/– mice displayed significant insulin resistance on high dose hyperinsulinemic clamp. Despite increasing insulin resistance with age, plin^–/– mice at different ages maintained a normal glucose response during an intraperitoneal glucose tolerance curve, being compensated by the increased β-oxidation and reduced hepatic glucose production. These experiments uncover the metabolic adaptations associated with the constitutional lipolysis in plin^–/– mice that allowed the mice to continue to exhibit normal glucose tolerance in the presence of peripheral insulin resistance.