Probiotics are widely defined as live microorganisms that, when administered in adequate amounts, confer a health benefit on the host . Clinical use of probiotics consists of bacterial and fungal microorganisms. The best characterized species belong to the genera Lactobacillus and Bifidobacterium with additions from Streptococcus, Lactococcus, Ruminococcus, and certain Eschericihia strains, and the fungus Saccharomyces boulardii.
Probiotics’ health promoting properties are mediated through several mechanisms that has been characterized through in-vitro research. They modulate immunity and protect against cellular stress in a contact dependent manner, have antimicrobial effect and protect against pathogens, and enforce mucosal barrier integrity, the latter partly by production of short chain fatty acids like butyrate (reviewed in refs. [2,3]). Notably, most in-vitro research on probiotics has been performed on single strains, whereas the clinical application of probiotics in health promotion is often given as multistrain compounds. How probiotics interact with and affect the resident microbiota and exert their actions in a complex ecological niche such as the human gut has been less characterized [3,4].
Related to probiotics are prebiotics. Prebiotics are substrates selectively utilized by host microorganisms conferring a health benefit, e.g. nondigestible dietary fibers and oligosaccharides . Synbiotics are products that combine prebiotics and probiotics.
The purpose of this review is to highlight recent advances within research on probiotics and its capabilities to alleviate chronic inflammation and improve prognosis in HIV infection. This review is restricted to interventions with probiotics, including synbiotics. Discussions on prebiotics and means to manipulate the microbiota other than through the use of probiotics are beyond the scope of this review.
WHY ARE PROBIOTICS RELEVANT IN HIV INFECTION?
The gut is a major lymphoid organ of the human body. Along its length it contains approximately a total of 50 × 109 lymphocytes situated in the gut associated lymphoid tissue and the lamina propria, which is shielded from the gut lumen by a single layer of mucus-covered epithelial cells .
Disruption of the gut barrier, microbial translocation, and immune activation
In the course of the acute phase of HIV infection there is a massive loss of CD4+ T cells in the gut lamina propria. The depletion far exceeds what is observed in both peripheral blood and lymph nodes [7–9]. Following the loss of CD4+ T cells, dysfunction of the gut mucosal immunity develops as there is a preferential depletion of the CD4+ subset T helper 17 cells (Th17) . Th17 cells produce and secrete interleukin (IL)-17, IL-21, and IL–22 that all are crucial interleukins for maintaining gut immune defense and an intact gut barrier . In chronic HIV infection, there is an additional depletion of the separate subset IL-22-secreting Th22 cells [12,13].
In parallel with the loss of mucosal immune cells, the integrity of the epithelial barrier shows signs of disruption with loss of tight junctions, enterocyte apoptosis, and increased intestinal permeability [14–16]. This allows for persistent translocation of other microbial products from bacteria and fungi into lamina propria and the systemic circulation contributing to chronic immune activation [17–19] (Fig. 1).
These massive alterations in the epithelial barrier and gut immunity during acute HIV infection have a major impact on disease progression and future health in people living with HIV (PLHIV). In the seminal 2006 paper, Brenchley et al. demonstrated that both HIV-infected humans and SIV-infected macaques had increased levels of lipopolysaccharide (LPS) in plasma, which correlated with activation of both the innate and adaptive immune system. Later, numerous studies have shown that the loss of gut mucosal integrity allows microbial products to leak into the gut mucosa and subsequently to the circulation contributing to chronic stimulation of the immune system, a process referred to as microbial translocation [18–21]. Despite suppression of HIV replication by ART, restoration of gut mucosal barrier and gut mucosal immunity is slow and often incomplete [9,22–24].
Importantly, the soluble markers of microbial translocation and inflammation have been directly linked to risk of non-AIDS morbidity and mortality [25–27]. Attenuating the inflammation should therefore confer an improved clinical prognosis for PLHIV.
The human gastrointestinal tract is colonized with approximately 1014 microorganisms and the number increase distally along the intestine. Their interactions with the host are important for gut homeostasis, immune processes and health [28–30]. It was recently demonstrated that the composition of the gut microbiota is decided mainly by environmental factors such as diet and lifestyle, and to a lesser degree by genes . In adults, the core microbiota is relatively stable within individuals, but changes can be induced by diet, infections and use of antibiotics . Furthermore, alterations in the gut microbiome have been well documented in several diseases as for instance inflammatory bowel disease, atherosclerosis, type II diabetes, and obesity [28,30].
Over the last few years it has become clear that PLHIV have changes in the gut microbiota composition characterized by decreased abundances of bacteria important for gut homeostasis, in combination with increased abundance of bacteria with proinflammatory potential [32,33]. This so-called dysbiosis is associated with activation of immune cells in the gut lamina propria, microbial translocation, systemic immune activation, and inflammation [34–40] (Fig. 1). Of note, dysbiosis has been reported in several cohorts of PLHIV on ART [34,36,37,41,42].
Recently, it was demonstrated that sexual preference is a major shaper of the gut microbiome, and several findings in the early studies of the HIV-related gut microbiome were probably biased by sexual practice, that is men who have sex with men . Still, the prevailing HIV-associated dysbiosis across several cohorts seems to consist of enrichment of the phylum Proteobacteria including several subtaxa containing pathogenic bacteria, combined with a depletion of taxa within the bacterial families Ruminococcaea and Lachnospiracea, known for their capacity of producing short-chain fatty acids such as butyrate [33,44]. The relative abundance of probiotic bacteria such as Lactobacilli and Bifidobacteria has been less consistent. Lower levels of Lactobacilli have been described in viremic PLHIV compared with the general population . Higher levels of Lactobacillales were associated with higher fractions or counts of CD4+ T cells and reduced microbial translocation and systemic immune activation, both in recently HIV-infected and during ART [39,46].
Taken together, HIV pathogenesis implies a massive loss of gut mucosal immune cells associated with a dysfunctional mucosal barrier that confer signs of local and systemic inflammation, and with an anatomical proximity to a dysbiotic gut microbiota. Given the in vitro effects of probiotics, there has been a clear rationale to investigate to which extent probiotics could attenuate the gut inflammation and subsequently improve prognosis for PLHIV  (Fig. 1).
WHAT ARE THE CAVEATS IN PROBIOTICS RESEARCH?
Clinical studies have indicated beneficial effect of probiotics for several diseases and conditions such as acute gastritis, Clostridium difficile--associated diarrhea, irritable bowel syndrome, and acute respiratory infections, but the clinical research is of varying quality and the results hampered with uncertainty . When evaluating clinical studies on probiotics’ effect on diseases, there are caveats that have got increasing attention. First, many studies performed on probiotics are generally of limited statistical power and varying scientific quality. The duration of the studies are generally too short to evaluate hard end points. Studies are conducted on divergent populations with a plethora of read-outs and secondary end points that hinder comparisons between studies and meta-analysis to be done . Second, probiotics are not pharmaceutical substances. Probiotics consist of microorganisms administered as single strains or combination compounds. There is little knowledge on how the single strains interact when co-administered. The documented in vitro effect of one probiotic strain is not necessarily reproduced by other strains, so one should be careful not to consider the effect of a probiotic strain or compound as a class effect . The route of administration varies from sachets dissolved in water, to milk-based preparations (e.g. yoghurts) and lyophilized pills and capsules. Probiotics are supposed to be consumed in ‘adequate amounts’  and usually applied in a dose range of 106–1012 colony forming units (cfu)/day, but dose response curves for most strains and conditions have not been described and there is limited data on minimal or maximal doses needed for clinical effects . There is also little data on the significance of dose frequency. Probiotics are marketed as live microorganisms, which makes production, batch variability, dispensing, and storage important issues for maintaining the viability of the probiotics up until consumption. As probiotics are not pharmaceutical substances, they are generally not defined as medicinal products or a therapeutic modality that claim health promoting properties . Hence, production and marketing of probiotics are not subjected to the same legislation regulating pharmaceuticals. The rigorous documentation (e.g. Good Manufacturing Practice) that needs to be provided for a medicinal product to pass approval by national medicinal agencies (e.g. U.S. Food and Drug Administration and European Medicines Agency) is therefore not necessarily required for the marketing of probiotic products . Likely, the quality of over-the-counter sales of probiotic substances are of a much greater variation than the medical community is accustomed to from pharmaceuticals. In conclusion, the heterogeneity of probiotic substances and application and the limited regulation in medicine have hampered the scientific quality of clinical research on probiotics.
Increased insight in the complexity of probiotic administration to humans came last year with Zmora et al.'s [51▪] thorough and comprehensive study, where an 11-strain compound of probiotics was administered to both mice and healthy human volunteers that underwent serial colonoscopies with biopsy collections. Stools, luminal contents and mucosal biopsies were analyzed with a broad multi-omic approach. The study demonstrated that stool samples were not representative for mucosal colonization of the probiotics and that the resident mucosal microbiota provided an over-all colonization resistance to the probiotics. However, there were great inter-individual variations in the susceptibility for the probiotics’ colonization, indicating that there is a person-specific gut mucosal permissiveness for probiotic colonization that may be predicted by resident microbial and host features. Even in the permissive individuals, colonization was transient and lost soon after the probiotic intervention was terminated, as shown in previous studies . In conclusion, the study demonstrated that probiotics cannot be expected to have an effect in every person. The features characterizing a probiotic-colonization permissive person needs further assessments.
WHAT ARE THE RECENT INSIGHTS IN PROBIOTICS ROLE OF MANAGING INFLAMMATION IN HIV INFECTION?
Probiotics have been tested in comparative studies with SIV infection in macaques. Klatt et al. administered a synbiotic concoction of 1011 cfu/day to seven SIV-infected macaques before and after the initiation of ART, but did not show effect on the systemic CD4 counts. However, colonic CD4 counts increased and leukocytes displayed upregulated gene expression related to antigen presenting cells’ activity and reduced fibrosis . The same research group subsequently published a new study where six SIV-infected macaques were given the probiotic compound VSL#3 spiked with injections of IL-21 . This treatment resulted in a subtle increased recovery of Th17 cells in jejunum, but not rectum, and fewer clinical complications. However, whether this effect should be attributed to the probiotics or the IL-21, was not determined .
Human studies attempting to promote better prognosis in PLHIV by administering probiotics are listed in Table 1[55–67,68▪▪,69▪▪,70]. The majority of the studies have been published over the last 5 years with the two largest randomized controlled trials presented this year [68▪▪,69▪▪]. Only studies that report readouts pertaining to inflammation, immune activation, or parameters with established significance to morbidity or mortality are included. No studies on probiotics in PLHIV have been conducted with hard end points.
Only studies performed on PLHIV on ART are of relevance. After the START study and WHO treatment cascade stated that all PLHIV diagnosed should be offered ART [71,72], studies on probiotics in PLHIV off ART lack clinical validity. ART's superior effect over probiotics to improve prognostic parameters in HIV infection was recently demonstrated by Serrano-Villar et al.[68▪▪] in the randomized control trial (RCT) where synbiotics were given at the time of ART initiation. ART greatly improved CD4 count and all parameters of systemic inflammation, while the synbiotic intervention did not display any effect [68▪▪].
Relevant studies on PLHIV are of great heterogeneity with respect to subgroups of PLHIV, applied probiotic strain (s) and dose, and read-outs. We deem the studies to be of varying quality when it comes to documented adherence to study intervention, quality control of assays applied, and stringent data analysis plans.
The studies conducted on probiotics in PLHIV are generally of limited power. Several of them are open-label single-arm studies that must be considered exploratory [61–66,70]. Many of the trials report improvement in some inflammatory parameters only. Typically, they report improvement in one or two soluble markers or a subset of T cells, whereas the rest of the assays employed have come out without significant differences. None of the prospective trials have been able to detect any improvement in clinically relevant readouts, including systemic CD4 counts.
RCTs have greater impact on clinical practice. With the exception of a subtle increase in CD4+ T-cell fraction only described by Yang et al., all RCTs on probiotics in PLHIV report no differences in readout between probiotics-treated participants and control subjects when analyzed according to their predefined protocols. The two most recently reported RCTs by Serrano-Villar et al.[68▪▪] and Overton et al.[69▪▪] are to date the largest RCTs and the ones we consider to be the most stringently conducted studies. They do not report any changes between probiotic and placebo intervention in any of the analyses performed. To be noted, the included PLHIV in Overton et al.'s [69▪▪] study had a median CD4 count of 712 cells/μl ranging from 542 to 893. One could argue that this population of PLHIV is expected to have an excellent prognosis and little inflammation and that the potential benefit of probiotics would therefore be incremental [73,74].
Unfortunately, very few of the studies have assessed systemic CD8 counts and cannot report on alterations in systemic CD4/CD8-ratio, which has emerged as a prognostic parameter with regard to non-AIDS morbidity [75,76].
ARE THERE SAFETY ISSUES TO BE CONSIDERED WHEN ADMINISTRATING PROBIOTICS TO PEOPLE LIVING WITH HIV?
As all sorts of therapy in medicine have potential adverse effects, it is reasonable to question whether probiotics are well tolerated to use in PLHIV. With the heterogeneity and over-the-counter use of probiotics, and the fact that probiotics are not classified as medicinal products, no formal safety studies exist on probiotics consumption in PLHIV. None of the published studies listed in Table 1 have observed adverse events. Published case reports on Lactobacillus bacteremia have occurred in PLHIV with severe immune deficiency . We would consider short-term probiotics consumption for PLHIV on successful ART to not constitute a health risk. Outside the field of HIV infection, a recent report provided insight into probiotics’ potential detrimental effects in restoring the homeostatic gut microbiota after antibiotics . One should also stay observant to identify potential long-term adverse effects of continuous probiotics consumption in PLHIV.
WHAT ARE THE FUTURE PERSPECTIVES FOR PROBIOTICS IN HIV INFECTION?
Over the last 10 years, the belief in potential benefits from probiotics to improve inflammation for PLHIV has drifted from naïve enthusiasm to rational skepticism. In the ART era where early-diagnosed and well treated PLHIV have a life expectancy comparable to the general population [73,74], any benefit of probiotics would be of incremental value in the successfully treated PLHIV. However, the significant fraction of immunological nonresponder (INR) patients that do not restore their CD4 counts in spite of ART-induced viral suppression are more likely to have increased inflammation and immune activation and an unfavorable prognosis with regard to non-AIDS morbidity [79–82]. Only one of the reported studies on probiotics so far has specifically targeted this subpopulation of PLHIV . However, results from two RCTs on probiotics in INRs are pending (ClinicalTrials.gov: NCT02441231, n=36  and NCT03568812, n = 80) and will be met with great interest. We would argue that future studies on probiotics in PLHIV should target subpopulations with known permissiveness to probiotic colonization and high risk for disrupted gut mucosal barrier, dysbiotic microbiota, and chronic immune activation and inflammation, as opposed to including ART-treated PLHIV at large. Clinical studies should be of sufficient statistical power and placebo controlled.
There is a rationale for attempting to modulate the gut microbiota by intake of probiotics to attenuate inflammation in chronic HIV infection and thereby improve the prognosis for PLHIV. Studies that have evaluated the effects of probiotics on inflammation in HIV infection lack power and are of varying scientific quality. The current scientific evidence does not support the use of probiotics as an addition to ART. There are no reports stating that short-term use of probiotics are harmful to ART-treated PLHIV.
The authors gratefully thank Jon Sponheim for graphical assistance.
Financial support and sponsorship
The authors are funded through South-Eastern Norway Regional Health Authority, Oslo University Hospital, and the University of Oslo.
Conflicts of interest
D.H.R. was supported with an educational grant via the Gilead Nordic Fellowship program and has in the past received lecture salaries from Bristol-Meyer-Squibb and Medivir. There are no other conflicts of interests.
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