Due articoli open access appena usciti sul Journal of Clinical Investigation trattano di pre- e pro-biotici per migliorare la funzionalità della mucosa intestinale nelle persone con HIV. Si tratta
TREATMENT OF HIV/SIV-ASSOCIATED MICROBIAL TRANSLOCATION
The detrimental effects of microbial translocation on HIV disease progression, the response to ART, and the development of non-AIDS comorbidities provide a strong rationale for the exploration of novel therapeutic interventions aimed specifically at preventing and reducing microbial translocation, its determinants, and its downstream effects. Several strategies are being investigated, including (i) modification of the intestinal microbiome, (ii) enhancement of the enterocyte barrier, (iii) reduction of local inflammation, and (iv) clearance of microbial bioproducts translocated from the gut.
Modification of GI Microbiome
Strategies aimed at restoring the normal composition of the intestinal microbiome include
antibiotics and probiotics. Ideally, the most suitable antibiotics in such a context would be broad-spectrum, nonabsorbed antibiotics available for oral administration.
Rifaximin is a semisynthetic, rifamycin-based, nonsystemic, broad-spectrum antibiotic, meaning that very little of the drug will pass the gastrointestinal wall into the circulation. Given its unique properties, it is widely used for the treatment of hepatic encephalopathy and as a gut-sterilizing treatment prior to abdominal surgery, while contrasting results have been obtained thus far on its efficacy in the treatment of inflammatory diseases.
Rifaximin is now being intensively tested in HIV/SIV infection. Most recently, the efficacy of 3 months of rifaximin in association with the anti-inflammatory agent sulfasalazine was tested by Pandrea et al. in the acute phase of SIVagm infection of pigtail macaques.
In that study, the rifaximin-sulfasalazine combination resulted in significant reductions in levels of circulating sCD14 cells, activated CD38 HLA-DR T cells, D-dimer, proinflammatory cytokines, and chemokines in treated animals compared to untreated controls. A slight reduction in the magnitude of the CD4 T-cell loss at the GI mucosa was observed for rifaximin-sulfasalazine-treated macaques versus controls, with no changes in circulating CD4 T-cell counts (92). In HIV-infected humans, rifaximin is under investigation within the ACTG A5286 trial, which is a randomized, open-label, two-arm study that will test 4 weeks of treatment with rifaximin in HIV-infected patients on virologically suppressive ART and with low-level CD4 T-cell recovery (350 cells/l). Study endpoints include rifaximin safety and efficacy in preventing persistent HIV-driven inflammation (
https://actgnetwork .org/). While awaiting the completion of ongoing trials, it should be acknowledged that antibiotic treatment holds limited promise as an antimicrobial translocation treatment for HIV infection. Indeed, long-term antibiotic therapies would in fact result in the spread of resistant microbes, metabolic disadvantages, and further damage to the GI barrier.
An alternative approach is represented by the use of
probiotics, which have been shown to modulate the gut microflora by inhibiting proinflammatory cytokines, decreasing gut permeability, and stimulating mucosal immunity. Previous studies demonstrated the usefulness of probiotics in gastrointestinal diseases such as IBD. In an observational, retrospective, 3-year study carried out on a cohort of HIV-infected individuals in Tanzania,
Irvine et al. reported that probiotic-yogurt consumption was associated with an increase in CD4 T-cell counts compared with a control group of participants not consuming the yogurt.
More recently, Klatt et al. assessed the use of probiotics in addition to ART in SIVmac239-infected macaques for about 5 months. Interestingly, those authors observed an increase in antigen-presenting cell frequency and function; enhanced T-cell immunity in the intestinal mucosa, with Th17 cells becoming more polyfunctional; and reduced T-cell activation in animals treated with probiotics. (
NdD: abbiamo parlato di questo trial proprio in questo thread, qui. Non ho invece trovato aggiornamenti sul trial norvegese-svedese di cui si parla qui e in post seguenti.)
Interventions To Improve the Enterocyte Barrier
Given the dramatic structural and functional changes in the intestinalepithelial barrier during HIV infection, the possibility of positively supporting enterocyte homeostasis by means of immunomodulatory molecules is quite intriguing. In this context, two possible candidates are
IL-22 and
IL-17, due to their role in mucosal immunity and the association between the loss of IL-17- and IL-22-secreting lymphocytes and mucosal immune dysfunction during SIV infection.
Of note, encouraging results are provided by data on a murine model of ulcerative colitis, where the administration of IL-22 reduced intestinal inflammation.
More recently, data have been presented to support a possible role of recombinant human IL-7 (rhIL-7) in the restoration of gut mucosal T-cell homeostasis
in HIV-infected individuals. Indeed, the administration of rhIL-7 to a cohort of subjects with low-level CD4 T-cell recovery on ART was efficacious in expanding both circulating and gut-residing naïve and memory CD4 T cells, with parallel reductions in plasma levels of sCD14 and D-dimer. (
NdD: abbiamo parlato di questo trial sempre in questo thread, qui.)
Clearance of Microbial Bioproducts Translocated from the Intestinal Lumen
An intriguing therapeutic option is to
neutralize microbial bioproducts translocated in peripheral blood as shown in Fig. 1 and 2.
One such option is currently being investigated within the ACTG A5296 trial that is specifically aimed at testing the efficacy of
oral sevelamer carbonate (which is effective in reducing inflammation and endotoxemia in the context of renal failure) to decrease endotoxemia in HIV-infected individuals naïve to antiretrovirals with CD4 T-cell counts of 400 cells/l (
https://actgnetwork.org/).
