Gut Dysbiosis May Affect Distal Neuropathic Pain Development in HIV

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Gut dysbiosis may contribute to the development of distal neuropathic pain in people living with HIV.

In people living with HIV, gut dysbiosis may contribute to the development of distal neuropathic pain, according to research results published in the Journal of Pain.

Research has connected gut dysbiosis with neuropathic pain across clinical conditions. In HIV infection, however, the relationship between gut dysbiosis and neuropathy has not been explored. In the current study, researchers set out to characterize the potential alterations, including differing gut microbial diversity and dysbiosis, in people living with HIV with distal neuropathic pain.

Patients living with and without HIV were recruited to participate in the trial from a single center in San Diego, California. Investigators evaluated physical findings of distal sensory polyneuropathy during a validated neurological examination, while distal neuropathic pain was assessed via a self-report tool. Moderate or “worse” neuropathy was defined as 2 or more clinical signs of neuropathy, and distal neuropathic pain was defined as burning, aching, or shooting symptoms and classified into 5 severity categories.

Participant stool samples were collected to facilitate characterization of the gut microbiome. Microbial diversity was characterized through 16S ribosomal RNA sequencing.

The cohort included 226 people living with HIV and 101 people without HIV (combined mean age, 52±13.5 years; 21.1% women; 44.7% non-White). In the HIV group, the median nadir and current CD4 were 174 (interquartile range [IQR], 21-302) and 618 (IQR, 448-822, respectively). Ninety percent of patients were either virally suppressed or on antiretroviral therapy.

Investigators found that distal sensory polyneuropathy was more frequent in the HIV group (26.2% vs 9.9%), and distal neuropathic pain was both more common and more severe in people living with HIV (34.1% vs 11.9%). Distal neuropathic pain was “much more frequent” in patients with distal sensory polyneuropathy than without (34.8% vs 19.6%).

In terms of gut microbiome, people with and without HIV did not differ in microbiome diversity. In people with HIV, there was an association between more severe distal neuropathic pain and lower microbiome diversity, with “a monotonic decrease in diversity” for each increase in severity of pain.

Patients who self-identified as men who have sex with men (MSM) had a higher Faith’s phylogenetic diversity compared with non-MSM (13.0±3.94 vs 11.3±3.65). Although rates of distal sensory polyneuropathy and distal neuropathic pain were not different between MSM and non-MSM, MSM with HIV had less severe distal neuropathic pain compared with non-MSM.

Results of a stepwise, mixed, multivariable regression examining distal neuropathic pain severity found that MSM was significantly associated with higher phylogenetic diversity. MSM were also more likely to report numbness than non-MSM, but no difference was noted for distal neuropathic pain or paresthesias.

Microbiome diversity did not differ by antiretroviral status, regimen type, or current or nadir CD4. Women with HIV had lower microbiome diversity compared with men, and results of a multivariable model showed that distal neuropathic pain and sex were both significantly associated with microbiome diversity. In this group, age did not confound the relationship between distal neuropathic pain and microbiome diversity.

Investigators averaged coefficients for distal neuropathic pain:HIV+ for each genus, then sorted these to determine which genera were most associated with distal neuropathic pain and HIV status relative to all other microbes. Lachnospira had a low average coefficient and high prevalence, indicative of microbes that are “relatively less associated: with distal neuropathic pain:HIV+ status compared with other microbes.

Study limitations include incidences of distal neuropathic pain that may have been incorrectly attributed to distal sensory polyneuropathy, as well as the correlational nature of the study design.

“Pathways linking the gut microbiome to pain processing neural pathways via the gut-brain axis could mediate pain perception in neuropathy,” the study researchers concluded.


Ellis RJ, Heaton RK, Gianella S, Rahman G, Knight R. Reduced gut microbiome diversity in people with HIV who have distal neuropathic pain. J Pain. Published online September 13, 2021. doi:10.1016/j.jpain.2021.08.006