The study team's prior research has shown that dysfunction of a specific nerve, called the vagus nerve, is associated with small intestinal bacterial overgrowth (SIBO), and that SIBO is associated with signs of inflammation in the blood of people living with HIV (PLWH). This research will explore pathways linking vagal dysfunction to inflammation in HIV, focusing on the gastrointestinal tract, and study whether a medication called pyridostigmine and stimulation of the vagus nerve are beneficial therapies.

Objectives Aim 1: To elucidate mechanisms linking VD, SIBO and chronic inflammation in PLWH. PLWH (N=150) will undergo autonomic function tests (AFTs) for VD, hydrogen/methane breath testing (HBT) for SIBO, Wireless Motility Capsule (WMC, SmartPill) testing for GI transit times and pH measurements, blood draw for quantification of inflammatory mediators, and collection of stool samples and oral swabs for characterization of the GI microbiome.

Hypothesis 1a (primary): The relationship between VD and SIBO in HIV is mediated by prolonged small bowel transit time (SBTT) and hypochlorhydria.

Hypothesis 1b (exploratory): There is an additional pathway linking VD and elevated IL-6 in PLWH which is independent of SIBO and bacterial translocation.

Aim 2: To determine whether the relationship between VD and SIBO is modified by the presence of HIV-infection. HIV-infection results in disruption of the GI mucosal barrier,5 which could make PLWH more vulnerable to adverse GI effects of VD. HIV-uninfected controls (N=100), age and gender matched to the PLWH from Aim 1, will undergo the same assessment as the PLWH. The study team will test for effect modification of the VD-SIBO relationship by HIV status, using logistic regression to examine the interaction between VD and HIV.

Aim 3: To establish vagal pathways as a viable treatment target for individuals with well-controlled HIV. PLWH with VD, SIBO and/or prolonged SBTT (N=96) will be identified from the Aim 1 cohort. The first 86 eligible patients will be randomized to 8 weeks of pyridostigmine versus placebo; the remaining 10 will receive 8 weeks of open-label noninvasive vagal nerve stimulation (nVNS) to assess feasibility. All patients will then be retested (AFTs, HBT, SmartPill, blood draw, stool samples and oral swabs).

Hypothesis 3a (primary): Eight weeks of low-dose pyridostigmine (30mg PO TID) will reduce SIBO as compared to placebo in PLWH. Hypothesis 3b (exploratory): Non-invasive VNS is safe, well tolerated and acceptable to PLWH.

Inclusion Criteria :

• Greater than or equal to18 years old (18 to 64 Years, 65 Years and Over)
• Documentation of HIV-1 infection
• Stable CART for greater or equal to 3 months
• HIV-1 viral load <100 copies/ml (within 3m)
• No diagnosis known to cause autonomic or GI dysfunction other than HIV (e.g. Parkinson's disease, diabetes, peptic ulcer disease, infectious diarrhea)
• Willing to refrain from nicotine use for 24h prior to all testing
• No contraindication to autonomic testing (e.g. uncontrolled glaucoma, heart rate not under sinus control)
• No medications with significant autonomic or GI effects (e.g. sympathomimetics, prokinetics, anti-diarrheals, antibiotics)
• Urine test negative for stimulants and opiates/opioids and pregnancy test (if applicable)

Exclusion Criteria:

• Dysphagia to food or pills
• Known or suspected obstructive disease of the GI tract (e.g. bezoar, strictures, fistulae, physiologic GI obstruction)
• GI surgery within 3m, Crohn's disease, diverticulitis, any electromechanical medical device (e.g. pacemaker, infusion pump).
• Contraindication to pyridostigmine (e.g. mechanical intestinal or urinary obstruction, hypersensitivity to pyridostigmine, cardiac arrhythmias, asthma, chronic obstructive pulmonary disease); use of pyridostigmine within the past 6m.
• History of intracranial aneurysm/hemorrhage, brain tumor, abnormal neck anatomy, or implants or metal hardware near site of stimulation; exposure to VNS within the past 6m.

Individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures, and appendices).

Beginning 3 months and ending 5 years following article publication.

Anyone who wishes to access the data. Data will be published.