Gut Microbiota: A Potential Key Player in Boosting Immune Reconstitution Of Immunological Nonresponders

Keywords::

• gut microbiota
• HIV
• immune reconstitution
• immunological nonresponders
• treatment outcome

“Apart from bacterial composition, researchers report that metabolites originating from gut microbiota are also involved in immune processes.”

It is well established that HIV-positive individuals do not respond in a uniformly similar manner to antiretroviral treatment (ART). A substantial but poorly described subset of ART-treated adults (approximately 15–30% of HIV-infected adults), referred to as immunological nonresponders (INRs), maintain abnormally low peripheral blood CD4+ T-cell counts of <350 cells/mm³, or even lower (<200 cells/mm³), long after virological suppression has been achieved [1]. The reasons for such disparities in terms of immune recovery have yet to be elucidated. Nevertheless, the accumulating evidence points to the influence of the gut microbiota on critical immunopathological processes during HIV infection.

The gut microbiome is essential in maintaining immune homeostasis, and when its composition becomes aberrant, chronic inflammation and/or pathological conditions follow [2]. Evidence has shown that HIV infection may result in significant changes in the gut microbiota, referred to as HIV-associated dysbiosis, and is independently associated with age, gender and sexual practice [3,4]. This is characterized by a damaged intestinal barrier, impaired mucosal immunological function, increased microbial translocation and long-term immune activation in people living with HIV (PLWH) [3–5]. Thus, microbial communities residing in the intestines of PLWH significantly differ from those within the gut of HIV-negative individuals. Furthermore, past studies have demonstrated that gut microbiota differ significantly between INRs and immunological responders (IRs) who achieve and maintain undetectable plasma HIV RNA levels as well as CD4+ T-cell counts of >350 cells/mm³ [6]. Researchers have observed that two families of bacteria (Succinivibrionaceae, known for their protective role against gut inflammation, and Erysipelotrichaceae) were significantly enriched in IRs, whereas neither bacterial family was identified as being altered in INRs [7]. Lu et al. [8] have demonstrated that INRs possess a gut microbiome enriched in Faecalibacterium prausnitzii, unclassified Subdoligranulum sp., and Coprococcus comes. An interesting observation from the preceding study was that a relative abundance of F. prausnitzii and Subdoligranulum sp. has been observed to have a close association with CD4+ T-cell counts. Indeed, F. prausnitzii and Subdoligranulum sp. abundance was found to be inversely proportional to CD4+ T-cell recovery and directly proportional to T-cell activation [8]. Furthermore, a larger cohort study (28 IRs and 30 INRs) by Xie et al. [9] has demonstrated that there was no significant difference between IRs and INRs at the bacterial phylum level. However, two predominant genera, Escherichia–Shigella and Blautia, were observed at a significantly higher level in IRs than in INRs. Analysis revealed that the CD4+/CD8+ ratio and CD8+ T-cell counts negatively and positively correlate, respectively, with the abundance of Escherichia–Shigella. In addition, an abundance of the Blautia genus of bacteria was found to negatively correlate with nadir CD4+ T-cell counts, on the one hand, and to positively correlate with CD8+ T-cell counts, on the other. Recently, Nganou-Makamdop et al. [10] have found that increased CD4+ T-cell numbers over the first year of ART were associated with high Serratia abundance, proinflammatory innate cytokines and metabolites that drive Th17 gene expression signatures and restoration of mucosal integrity.

Apart from bacterial composition, researchers report that metabolites originating from gut microbiota are also involved in immune processes. In a study by Serrano-Villar et al. [7], 1190 gut metabolites were identified, and one of these metabolites, which displayed levels positively correlated with CD8+ T-cell counts, was of particular interest. Indeed, lower levels of C16 ceramide, a ceramide-related metabolite, and lower levels of CD8+ T cells were observed in healthy controls and IRs. One previously published article reported that ceramide accumulation by opportunistic pathogens suggests their ability to scavenge lipids from the host and to destroy tissues [11]. Such pathogens responsible for the removal of lipids may also be responsible for the drastic decrease in immune response seen in patients with HIV infection. Within the same study, Serrano-Villar et al. noted the presence of several markers, among which was a marker for structural change in the epithelial barrier [12]. These investigators reported increased levels of the dolichol derivatives dolichol phosphate and dolichyl-β-D-glucosyl phosphate in the gut of ART-naive HIV-infected individuals, IRs and INRs (the increase was not statistically significant in all groups). The most recently investigated marker of this kind is the sialic acid derivative N-acetylneuraminic acid (Neu5Ac), which has only been observed in the guts of ART-naive individuals, suggesting the negative effect that ART may have on bacteria capable of producing Neu5Ac. With respect to the markers of inflammation and immune recovery [13], a similar accumulation of arachidonic acid (AA) in the gut of the studied HIV-infected patients has been reported. Conversely, healthy controls display levels of AA below the detection limit. Meanwhile, an AA proinflammatory metabolic product, leukotriene B4 (LTB₄), was increased only in the gut bacteria of IR patients. Nevertheless, LBT₄ profiling in fecal fluids has revealed that IRs and healthy controls possess 32-fold lower levels of LBT₄ compared with INRs and ART-naive untreated individuals. This finding has been interpreted to imply that gut bacteria play a role in controlling the levels of free LTB₄, and that the consequences of that release control benefit the regulation of proinflammatory signals and, possibly, immune recovery. Similar to LTB₄, the cannabinoid N-acyl amide oleamide has been observed to accumulate significantly in IRs. Markers of hepatic function, HIV viral infectivity and inflammation were also explored [7]. It was also observed that the heme catabolic products biliverdin (BV) and bilirubin (BR, a degradation product of BV) were only accumulated in the gut bacteria of IRs and INRs, respectively. Knowing that BV, but not BR, was observed to be capable of reducing HIV viral infectivity [14], its role as a key component of the gut metabolites in IRs has also been suggested. The final degradation product of BR, urobilinogen, was only detectable in the gut bacteria of ART-naive untreated individuals. None of the healthy controls had any of these metabolites expressed above the detection limit, confirming the fact that heme catabolism is likely to be a minor pathway in uninfected individuals.

In the light of the preceding evidence, it is both valid and sensible to objectively consider the roles that the gut microbiota may play in both host immunity and HIV disease progression. It is also sound to possibly link the development of ART responses in IRs and INRs to alterations in gut microbiota, as it has been reported for immune responses associated with certain cancers [15]. Indeed, it has already been established that fecal microbiome transplantation in patients being treated for melanoma can effectively transform melanoma immunotherapy nonresponders into responders. Another approach would be to provide targeted nutritional supplementation to modulate the growth of gut microbiota and thus induce immune recovery in INRs [16,17]. However, owing to the paucity of specific investigations of this nature, more studies comparing IRs and INRs are warranted to further elucidate patient outcomes in relation to the composition of gut microbiota and to develop novel gut microbiome-derived therapeutic interventions for INRs.

Financial & competing interests disclosure

This work was supported by the Chongqing Talent Cultivation Program (cstc2021ycjh-bgzxm0275). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Additional information

Funding

This work was supported by the Chongqing Talent Cultivation Program (cstc2021ycjh-bgzxm0275). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.