Are Probiotics the Next Wonder Drug in HIV Care?

  • <p><i>Photo Credit: Dr Gopal Murti/Science Source.</i></p>

  • Effect on Diarrhea

    Effect on Diarrhea

    <p>Diarrhea is a common problem in HIV-infected persons. The virus and the use of antiretroviral therapy have been associated with chronic (≥4 weeks) and occasional diarrhea. In these patients, diarrhea is associated with significant morbidity, decreased quality of life, and an increased risk for mortality in those with advanced disease.<sup>1</sup> Therefore, prevention and effective treatment of diarrhea are essential, and some studies have suggested probiotics may be the solution.<sup>2</sup></p> <p>A systematic review found level B evidence for use of probiotics to treat diarrhea, but not enough data were available to make recommendations regarding their use in HIV-infected patients.<sup>2</sup> Two studies assessing the fungal species <i>Saccharomyces boulardii</i> in patients with advanced AIDS reported significant benefits, indicating this species may be particularly promising; however, further studies are needed to determine which doses and species alone or in combination may provide the most benefit.<sup>2</sup> <i>Photo Credit: Scimat /Science Source</i></p>

  • Effect on CD4 Counts

    Effect on CD4 Counts

    <p>HIV has been found to attack the gut and gut-associated lymphoid tissue, which is the largest immune compartment in the body, harboring more than 60% of the body's immune cells, including CD4 cells.<sup>3,4</sup> This has led researchers to investigate whether probiotics might improve or help maintain CD4 cell counts in people living with HIV.<sup>5</sup> </p> <p>In a 2016 systematic review of 13 studies that assessed the effect of probiotics on CD4 counts, 7 studies reported benefit and 6 reported insignificant benefits or negative CD4 outcomes.<sup>5</sup> On the basis of these findings, the authors concluded "consumption of probiotics over a prolonged period of time may improve CD4 counts in people living with HIV."<sup>5</sup> Another systematic review, which included 15 studies, reached a similar conclusion, with the authors noting, "our analysis suggests a potential role for the use of probiotics in improving CD4 counts modestly.”<sup>2</sup></p>

  • Preventing HIV-Associated Bacterial Translocation

    Preventing HIV-Associated Bacterial Translocation

    <p>Bacterial translocation is "the passage of viable bacteria from the [gastrointestinal] tract to extraintestinal sites, such as the mesenteric lymph node complex, liver, spleen, kidneys, and bloodstream."<sup>6</sup> In HIV-infected persons, it can occur when the virus breaches the gut's mucosal integrity, enabling gut microbiome organisms to migrate to other organ systems, resulting in infections. Animal studies have suggested probiotics may prevent bacterial translocation by improving intestinal barrier function.<sup>7</sup></p> <p>A 2016 systematic review provided further evidence of this, with 4 of 6 studies showing probiotics to have some beneficial effects on bacterial translocation markers, such as increases in CD4 counts and reductions in interleukin 6 and lipopolysaccharide binding protein.<sup>2</sup> The authors concluded that although "the data are inconclusive, there is a signal that prebiotics may have a modest impact on markers of translocation and/or markers of inflammation and immune activation.”<sup>2</sup></p>

  • Delaying Disease Progression

    Delaying Disease Progression

    <p>Gut microbiota dysbiosis has been associated with HIV disease progression. One study found abundant Proteobacteria and depleted Bacteroidia in HIV+ patients, which was associated with mucosal immune disruption, T-cell activation, and chronic inflammation, including in those receiving highly active antiretroviral therapy.<sup>8</sup> The level of dysbiosis correlated with tryptophan catabolism and plasma concentrations of interleukin 6. On the basis of these findings, the authors concluded "gut-resident microbial populations may influence intestinal homeostasis during HIV disease."<sup>8</sup></p> <p>Probiotics have been reported to facilitate intestinal epithelial homeostasis via numerous biological mechanisms, such as by preventing cytokine and chemical-induced epithelial apoptosis and disruption of barrier function.<sup>9</sup> Studies examining whether maintaining epithelial homeostasis via probiotics can protect against HIV are ongoing.</p>

  • Protecting Against Inflammation

    Protecting Against Inflammation

    <p>Although modern antiretroviral therapy has significantly enhanced the care and life expectancies of HIV+ patients, they continue to be at higher risk for adverse health conditions, such as cardiovascular, neurodegenerative, and gastrointestinal diseases resulting from HIV-associated inflammation. A 2016 study by investigators in Rome suggests a high concentration of probiotic could reduce inflammation in these patients.<sup>10</sup></p> <p>The study investigators measured the inflammatory markers neopterin in cerebrospinal fluid and expression of indolamine-2,3-dioxygenase mRNA in gut-associated lymphoid tissue in HIV-1-infected patients receiving effective combined antiretroviral therapy at baseline and 6 months after adding a probiotic regimen using a high-potency formulation containing 8 bacterial strains. They found a significant reduction of both markers after probiotic supplementation.<sup>10</sup> Other studies investigating the probiotic combination are ongoing and are recruiting patients (ClinicalTrials.gov: NCT02441231; NCT02441244).</p>

  • Effect on Bacterial Vaginosis

    Effect on Bacterial Vaginosis

    <p>Bacterial vaginosis (BV) increases women's susceptibility to acquiring HIV and might result in higher HIV levels and easier disease transmission, particularly to male partners.<sup>2,11</sup> A systematic review found 1 study assessing the effect of a probiotic in HIV+ women with BV, and none of the participants was cured after 6 months of treatment.<sup>2</sup> However, researchers from Harvard reported promising results using an engineered form of <i>Lactobacillus jensenii</i>, an organism prevalent in healthy vaginal microbiomes, to express the HIV-1 entry inhibitor modified cyanovirin-N, enabling it to act as a live vaginal anti-HIV microbicide.<sup>12</sup></p> <p>Some evidence suggests probiotics, particularly <i>Lactobacilli</i>, might protect against BV, and even against HIV, via multiple mechanisms, such as by producing bacteriocins, lowering pH of the genital tract, and/or releasing hydrogen peroxide.<sup>13</sup> Further high-quality studies are needed to determine the role of probiotics in BV. <i>Photo Credit: CDC/M Rein.</i></p>

  • Most Common Adverse Effects

    Most Common Adverse Effects

    <p>Because probiotics are ingested as living organisms, there is potential for toxicity and even infections.<sup>13</sup> But probiotics are generally well tolerated across patient populations, with few to no adverse effects and benefits that far outweigh any risks.</p> <p>When adverse effects occur, they are typically gastrointestinal-related, with gas and bloating being the most common. A systematic review found that patients with HIV or AIDS are no more vulnerable to experiencing these effects than noninfected persons.<sup>2</sup> However, a variety of factors can affect probiotics' overall safety and tolerability, including vulnerability of the user (eg, age, presence of underlying medical conditions), dose and duration of consumption, and method and frequency of administration, all of which should be considered by clinicians before recommending probiotics to individual patients.<sup>14</sup></p>

  • Risk for Systemic Infections

    Risk for Systemic Infections

    <p>There is some evidence that probiotics might increase the risk for systemic infections, including bacteremia and fungemia, in a variety of patient populations, including immunocompromised individuals.<sup>15</sup> In 2016, bacteremia in a patient with AIDS was reported that was attributed to excess consumption of a <i>Lactobacillus acidophilus</i>-enriched yogurt.<sup>16</sup> Although <i>Lactobacillus</i> species have been increasingly associated with invasive infection among immunocompromised individuals,<sup>15</sup> other organisms have also been implicated, including <i>S boulardii</i>, <i>Bacillus subtilis</i>, and <i>Bifidobacterium breve</i>.<sup>15</sup></p> <p>A systematic review that sought to better elucidate the risk for systemic infections from probiotic consumption in persons with HIV or AIDS found the risk to be exceedingly low, regardless of species, with an estimated number needed to harm of 7369.<sup>2</sup> There were no reports of any probiotic-associated bacteremia or fungemia in the study sample (N=5060).<sup>2</sup></p>

  • Role in Developing Countries

    Role in Developing Countries

    <p>The role of probiotics in preventing HIV, slowing disease progression, and treating HIV- or antiretroviral-associated symptoms has yet to be definitively defined. However, their use may be particularly beneficial in developing counties, where HIV is most prevalent and access to nutrition and HIV treatments are scarce or individuals may be resistant to receiving Western treatments.</p> <p>A study investigating <i>Lactobacillus rhamnosus GR-1</i>-enriched yogurt in HIV+ individuals in Sub-Saharan Africa found it to be safely consumed, with many showing benefits in gut health, nutritional status, and immune status, with an average increase in CD4 counts of 0.16 cells/μL daily.<sup>17</sup> The probiotic yogurt was produced in a local, community-run kitchen, enabling it to be readily available and easily accessible. In another study, hospitalized HIV+ children in Malawi who had severe acute malnutrition and received a probiotic had reduced outpatient mortality, indicating further studies are warranted.<sup>18</sup></p>

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Probiotics are live bacteria or yeasts that are thought to promote health, particularly of the digestive system. They are most commonly administered via food, particularly yogurt, but can also be given as supplements or suppositories. Probiotic formulations vary significantly, with some including only 1 organism and others containing multiple organisms. Research into the benefits of probiotics is ongoing, but current evidence suggests they may be beneficial for patients with HIV or AIDS, potentially alleviating HIV-related symptoms and/or delaying disease progression. There is also some indication that probiotics might help prevent disease transmission. 


Compiled by Christina Loguidice


References

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  2. Carter G, Esmaeili A, Shah H, et al. Probiotics in human immunodeficiency virus infection: a systematic review and evidence synthesis of benefits and risks. Open Forum Infect Dis. 2016;3:ofw164. doi: 10.1093/ofid/ofw164
  3. Mehandru S. The gastrointestinal tract in HIV-1 infection: questions, answers, and more questions! Physicians' Research Network. http://www.prn.org/index.php/progression/article/hiv_1_gastrointestinal_galt_267. Accessed April 6, 2017.
  4. Guadalupe M, Reay E, Sankaran S, et al. Severe CD4+ T-cell depletion in gut lymphoid tissue during primary human immunodeficiency virus type 1 infection and substantial delay in restoration following highly active antiretroviral therapy. J Virol. 2003;77:11708-11717. doi: 10.1128/JVI.77.21.11708-11717.2003
  5. Miller H, Ferris R, Phelps BR. The effect of probiotics on CD4 counts among people living with HIV: a systematic review. Benef Microbes. 2016;7:345-351. doi: 10.3920/BM2015.0163
  6. Berg RD. Bacterial translocation from the gastrointestinal tract. Adv Exp Med Biol. 1999;473:11-30.
  7. Zareie M, Johnson‐Henry K, Jury J, et al. Probiotics prevent bacterial translocation and improve intestinal barrier function in rats following chronic psychological stress. Gut. 2006;55:1553-1560.
  8. Vujkovic-Cvijin I, Dunham RM, Iwai S, et al. Dysbiosis of the gut microbiota is associated with HIV disease progression and tryptophan catabolism. Sci Transl Med. 2013;5:193ra91. doi: 10.1126/scitranslmed.3006438
  9. Yan F, Polk DB. Probiotics: progress toward novel therapies for intestinal diseases. Curr Opin Gastroenterol. 2010;26:95-101. doi: 10.1097/MOG.0b013e328335239a
  10. Scagnolari C, Corano Scheri G, Selvaggi C, et al. Probiotics differently affect gut-associated lymphoid tissue indolamine-2,3-dioxygenase mrna and cerebrospinal fluid neopterin levels in antiretroviral-treated HIV-1 infected patients: a pilot study. Int J Mol Sci. 2016;17:1639. doi: 10.3390/ijms17101639
  11. Cohen CR, Lingappa JR, Baeten JM, et al. Bacterial vaginosis associated with increased risk of female-to-male HIV-1 transmission: a prospective cohort analysis among African couples. PLoS Med. 2012;9:e1001251. doi: 10.1371/journal.pmed.1001251
  12. Yamamoto HS, Xu Q, Fichorova RN. Homeostatic properties of Lactobacillus jensenii engineered as a live vaginal anti-HIV microbicide. BMC Microbiology. 2013;13:4. doi: 10.1186/1471-2180-13-4
  13. Woodman Z. Can one size fit all? Approach to bacterial vaginosis in sub-Saharan Africa. Ann Clin Microbiol Antimicrob. 2016;15:16. doi: 10.1186/s12941-016-0132-6
  14. Sanders ME, Akkermans LM, Haller D, et al. Safety assessment of probiotics for human use. Gut Microbes. 2010;1:164-185. doi: 10.4161/gmic.1.3.12127
  15. Doron S, Snydman DR. Risk and safety of probiotics. Clin Infect Dis. 2015;60(Suppl 2):S129-S134. doi: 10.1093/cid/civ085
  16. Haghighat L, Crum-Cianflone NF. The potential risks of probiotics among HIV-infected persons: Bacteraemia due to Lactobacillus acidophilus and review of the literature. Int J STD AIDS. 2016;27:1223-1230. doi: 10.1177/0956462415590725
  17. Reid G. The potential role for probiotic yogurt for people living with HIV/AIDS. Gut Microbes. 2010;1:411-414. doi: 10.4161/gmic.1.6.14079
  18. Kerac M, Bunn J, Seal A, et al. Probiotics and prebiotics for severe acute malnutrition (PRONUT study): a double-blind efficacy randomised controlled trial in Malawi. Lancet. 2009;374:136-144. doi: 10.1016/S0140-6736(09)60884-9

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