# Role of Gut Microbiome in HIV/Opioid Induced Peripheral Neuropathy

> **NIH NIH R01** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2022 · $464,517

## Abstract

Project Summary
Prolonged use opioids results in a paradoxical increase in atypical pain (hyperalgesia). Despite its known
limitations, mechanisms underlying opioid-induced hyperalgesia still remains a significant gap in knowledge.
Peripheral neuropathy has become the most common neurologic complication in HIV patients, with prevalence
as high as 69.4% in infected patients, Notably, HIV-infected opioid abusers appear to exhibit more severe
neuropathy than HIV-infected non-drug users. Furthermore, repeated use of opioid analgesics are reported to
promote neuropathic pain in HIV patients. Very little is known if ART contributes to peripheral neuropathy and if
it is exacerbated in chronic opioid users. The main metabolic pathway for morphine and morphine derivatives
in mammals is glucuronidation catalyzed by UDP-glucuronosyltransferase (UGT) enzymes. Morphine is
metabolized predominantly to two metabolites, morphine-3-glucuronide (M3G) and morphine-6-glucuronide
(M6G) (1,2). M-3-G is the only metabolite produced in rodents and does not have any analgesic effects but have
been shown in recent studies to activate and modulate TLR signaling. Furthermore, antiretroviral drugs
particularly, intergrase inhibitors, are also metabolized through the UGT- glucuronidation pathway. Recent
studies show that the metabolites of the intergrase inhibitor zidovudine to be more toxic than the parent
compound. In preliminary data we show that chronic morphine treatment results in significant gut microbial
dysbiosis with significant decrease in bacterial communities that synthesize β-glucuronidase with a concurrent
decrease in glucuronidase activity. We show in preliminary data that depletion in the bacterial communities
involved in the synthesis of β -glucuronidase results in a) increased accumulation M-3-G in the gut and serum
and b) reduced enterohepatic recycling of morphine. We further demonstrate that morphine treatment in the
context of HIV infection results in significant hyperalgesia in the both the Mechanical allodynia (Von Frey) and
Thermal hyperalgesia test (Hargraves) tests. Proinflammatory cytokine levels and morphine induced
hyperalgesia are significantly attenuated in TLR2 knock out mice. Based on these observations we hypothesize
that decreased microbial communities associated with β glucuronidase synthesis following prolonged
exposure to high dose morphine results in accumulation of M-3-G morphine metabolite and toxic
glucuronidated ART in the small intestine contributing to Specific Aim 1: Establish that accumulation of
the morphine metabolite M-3-glucoronide in the gut results in opioid induced hyperalgesia and HIV induced
peripheral neuropathy in opiod using HIV patients. Specific Aim 2: Determine the role of TLR2 signaling in
morphine induced hyperalgesia and HIV associated peripheral neuropathy in the context of ART treatment.
Specific Aim 3: Treatment with genetically engineered commensal bacteria with controlled expression of B-
glucuronidase in...

## Key facts

- **NIH application ID:** 10407591
- **Project number:** 5R01DA047089-05
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** SHUANGLIN HAO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $464,517
- **Award type:** 5
- **Project period:** 2018-07-15 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10407591

## Citation

> US National Institutes of Health, RePORTER application 10407591, Role of Gut Microbiome in HIV/Opioid Induced Peripheral Neuropathy (5R01DA047089-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10407591. Licensed CC0.

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