THE PAth study tageting the gut brain connection to improve cognition

The Path Study uses a hybrid trial design to evaluate two biomedical interventions targeting the gut brain axis, a portable Transcutaneous Vagus Nerve Stimulator, tVNS, and probiotic supplement intended to increase beneficial gut bacteria to reduce dysbiosis in persons with HIV.


HIV remains a significant clinical and public health problem. As persons living with HIV (PLWH) live longer, approximately 50% will experience HIV-related cognitive dysfunction, which may affect daily activities and quality of life. Alcohol consumption among PLWH may further exacerbate cognitive dysfunction, with the presumed mechanism involving the gut microbiome, microbial translocation, systemic inflammation, and ultimately neuroinflammation. Still, there are many gaps in our understanding of the specific pathophysiological mechanisms linking the gut microbiome to brain and cognitive dysfunction.

The proposed research will investigate

  • (1) Determine the impact of tVNS on neurocognition, and inflammation (neuro and systemic), among PLWH who are high-risk drinkers.
  • (2) Determine the impact of bifidogenic/butyrogenic probiotics on gut microbial dysbiosis, barrier function, systemic inflammation and neurocognitive dysfunction.
  • (3) Evaluate the combined efficacy of tVNS and probiotics on neurocognitive, inflammation (neuro and systemic), and measures of GI Barrier function.

The path study Hypotheses

  • (1) tVNS, compared to sham stimulation, will result in: (1) Cognitive function improvement as indexed by NIH toolbox Fluid Composite score, (2) Improvement on neuroimaging metrics of brain health (e.g., GABA and Glutathione concentrations on MRS and neural network connectivity on resting-state fMRI) and (3) Reduced proinflammatory circulating serum cytokines.
  • (2) Probiotics supplementation, compared to placebo, will result in: (1) Improvement in the gut microbiome, intestinal permeability, and microbial translocation, (2) Reductions in circulating pro-inflammatory cytokines, and (3) Improved cognition (NIH toolbox Fluid Composite score) and indices of brain health from neuroimaging.
  • (3) Combined tVNS + probiotics will have greater improvements in outcomes for Aims 1 and 2, compared to either intervention.

The Path Study Participant resources

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