A shared mucosal gut microbiota signature in primary sclerosing cholangitis before and after liver transplantation.

BACKGROUND AND AIMS: Several characteristic features of the fecal microbiota have been described in primary sclerosing cholangitis (PSC), whereas data on mucosal microbiota are less consistent. We aimed to use a large colonoscopy cohort to investigate key knowledge gaps, including the role of gut microbiota in PSC with inflammatory bowel disease (IBD), the effect of liver transplantation (LT), and whether recurrent PSC (rPSC) may be used to define consistent microbiota features in PSC irrespective of LT. APPROACH AND RESULTS: We included 84 PSC and 51 liver transplanted PSC patients (PSC-LT) and 40 healthy controls (HCs) and performed sequencing of the 16S ribosomal RNA gene (V3-V4) from ileocolonic biopsies. Intraindividual microbial diversity was reduced in both PSC and PSC-LT versus HCs. An expansion of Proteobacteria was more pronounced in PSC-LT (up to 19% relative abundance) than in PSC (up to 11%) and HCs (up to 8%; Q FDR < 0.05). When investigating PSC before (PSC vs. HC) and after LT (rPSC vs. no-rPSC), increased variability (dispersion) in the PSC group was found. Five genera were associated with PSC before and after LT. A dysbiosis index calculated from the five genera, and the presence of the potential pathobiont, Klebsiella , were associated with reduced LT-free survival. Concomitant IBD was associated with reduced Akkermansia . CONCLUSIONS: Consistent mucosal microbiota features associated with PSC, PSC-IBD, and disease severity, irrespective of LT status, highlight the usefulness of investigating PSC and rPSC in parallel, and suggest that the impact of gut microbiota on posttransplant liver health should be investigated further.

Human Immunodeficiency Virus-Infected Immunological Nonresponders Have Colon-Restricted Gut Mucosal Immune Dysfunction.

BACKGROUND: Human immunodeficiency virus (HIV)-infected immunological nonresponders (INRs) fail to reconstitute their CD4+ T-cell pool after initiation of antiretroviral therapy, and their prognosis is inferior to that of immunological responders (IRs). A prevailing hypothesis is that the INR phenotype is caused by a persistently disrupted mucosal barrier, but assessments of gut mucosal immunology in different anatomical compartments are scarce. METHODS: We investigated circulating markers of mucosal dysfunction, immune activation, mucosal Th17 and Th22 cells, and mucosa-adherent microbiota signatures in gut mucosal specimens from sigmoid colon and terminal ileum of 19 INRs and 20 IRs in addition to 20 HIV-negative individuals. RESULTS: INRs had higher blood levels of the enterocyte damage marker intestinal fatty acid-binding protein than IRs. In gut mucosal biopsies, INRs had lower fractions of CD4+ T cells, higher fractions of interleukin 22, and a tendency to higher fractions of interleukin 17-producing CD4+ T cells. These findings were all restricted to the colon and correlated to circulating markers of enterocyte damage. There were no observed differences in gut microbial composition between INRs and IRs. CONCLUSIONS: Restricted to the colon, enterocyte damage and mucosal immune dysfunction play a role for insufficient immune reconstitution in HIV infection independent of the gut microbiota.

Probiotics to HIV-Infected Immunological Nonresponders: Altered Mucosal Immunity and Microbial Diversity Restricted to Ileum.

BACKGROUND: HIV-infected immunological nonresponders (INRs) have increased risk of non-AIDS morbidity and compromised gut barrier immunity. Probiotics are widely used to improve health. We assessed the effects of probiotics in INRs with a comprehensive analysis of gut immunity and microbiome in terminal ileum and sigmoid colon. METHODS: The study involved clinical intervention with five-strain probiotic capsules (1.2 × 1010 CFUs/d) for 8 weeks in 20 INRs with CD4+ T-cell counts <400 cells/µL and plasma HIV RNA <50 copies/mL for more than 3.5 years. Colonoscopy with sampling of gut biopsies from terminal ileum and sigmoid colon and fecal and blood sampling were performed before and after the intervention. Flow cytometry (cytokine production, immune activation, and exhaustion), ELISA (inflammation, microbial translocation, and enterocyte damage), and 16S rRNA sequencing analyses were applied. RESULTS: In the terminal ileum, increased alpha diversity, increased abundance of Bifidobacterium sp., and decreased frequencies of IL-22+ CD4+ T cells were observed. The increased abundance of Bifidobacterium sp. in the terminal ileum correlated with increased fraction of CD4+ T cells in the same compartment (r = 0.54, P = 0.05) and increased CD4/CD8 ratio in peripheral blood (r = 0.49, P = 0.05). There were no corresponding changes in the sigmoid colon and no changes in fecal microbiome. Probiotic intervention did not affect peripheral blood CD4 count, viral load, or soluble markers of inflammation and microbial translocation. CONCLUSIONS: Probiotics induced segment-specific changes in the terminal ileum but did not affect systemic CD4 counts in INRs. Further clinical studies are warranted to recommend probiotics to INRs.

Enhanced Gut-Homing Dynamics and Pronounced Exhaustion of Mucosal and Blood CD4+ T Cells in HIV-Infected Immunological Non-Responders.

Immunological non-responders (INR), a subgroup of people living with HIV (PLHIV) who fail to restore CD4+ T cell numbers upon effective antiretroviral treatment, have impaired gut mucosal barrier function and an inferior clinical prognosis compared with immunological responders (IR). The contribution of gut-homing and exhaustion of mucosal T cells to the INR phenotype was previously unknown. Flow cytometry analysis of mononuclear cells from peripheral blood and ileal and colonic lamina propria showed that INR had higher fractions of gut-homing CD4+ T cells in blood compared with IR. In addition, gut-homing cells were more likely to display signs of exhaustion in INR. The increased CD4+ T cell exhaustion in INR was ubiquitous and not restricted to subpopulations defined by activation, differentiation or regulatory T cell markers. In INR, colon CD4+ T cell exhaustion correlated negatively with the fraction of CD4+ T cells in the same compartment, this was not apparent in the ileum. The fraction of exhausted mucosal CD4+ T cells correlated with I-FABP and REG3α, markers of enterocyte damage. We conclude that alterations of gut-homing and exhaustion of T cells may contribute to impaired gut immune and barrier functions associated with immunological non-response in PLHIV.

Probiotics to manage inflammation in HIV infection.

PURPOSE OF REVIEW: To evaluate the current scientific basis for administering probiotics to people living with HIV (PLHIV) to alleviate chronic inflammation and subsequently improve their prognosis. RECENT FINDINGS: The gut microbiome is a potential contributing factor to low-grade inflammation in HIV infection, and there is a scientific rationale for attempting to attenuate inflammation by administering probiotics. Sixteen reports from clinical studies in antiretroviral therapy (ART)-treated PLHIV assessing inflammation after probiotic intervention have been identified; half of them randomized control trials (RCT). Some of the studies report improvement in some parameters of inflammation, but results are inconsistent. No studies report improvement of CD4 counts. None of the RCTs report improvements in any markers of inflammation when analyzed according to protocol. SUMMARY: Current scientific evidence does not support the use of probiotics to alleviate inflammation in HIV infection. The potential effect of probiotic intervention in ART-treated PLHIV with high risk for inflammation remains to be investigated.