The gut microbiota-bile acid axis in cholestatic liver disease.

Cholestatic liver diseases (CLD) are characterized by impaired normal bile flow, culminating in excessive accumulation of toxic bile acids. The majority of patients with CLD ultimately progress to liver cirrhosis and hepatic failure, necessitating liver transplantation due to the lack of effective treatment. Recent investigations have underscored the pivotal role of the gut microbiota-bile acid axis in the progression of hepatic fibrosis via various pathways. The obstruction of bile drainage can induce gut microbiota dysbiosis and disrupt the intestinal mucosal barrier, leading to bacteria translocation. The microbial translocation activates the immune response and promotes liver fibrosis progression. The identification of therapeutic targets for modulating the gut microbiota-bile acid axis represents a promising strategy to ameliorate or perhaps reverse liver fibrosis in CLD. This review focuses on the mechanisms in the gut microbiota-bile acids axis in CLD and highlights potential therapeutic targets, aiming to lay a foundation for innovative treatment approaches.

The Gut and the Translocated Microbiomes in HIV Infection: Current Concepts and Future Avenues.

It is widely acknowledged that HIV infection results in disruption of the gut's mucosal integrity partly due a profound loss of gastrointestinal CD4+ T cells that are targets of the virus. In addition, systemic inflammation and immune activation that drive disease pathogenesis are reduced but not normalized by antiretroviral therapy (ART). It has long been postulated that through the process of microbial translocation, the gut microbiome acts as a key driver of systemic inflammation and immune recovery in HIV infection. As such, many studies have aimed at characterizing the gut microbiota in order to unravel its influence in people with HIV and have reported an association between various bacterial taxa and inflammation. This review assesses both contra-dictory and consistent findings among several studies in order to clarify the overall mechanisms by which the gut microbiota in adults may influence immune recovery in HIV infection. Independently of the gut microbiome, observations made from analysis of microbial products in the blood provide direct insight into how the translocated microbiome may drive immune recovery. To help better understand strengths and limitations of the findings reported, this review also highlights the numerous factors that can influence microbiome studies, be they experimental methodologies, and host-intrinsic or host-extrinsic factors. Altogether, a fuller understanding of the interplay between the gut microbiome and immunity in HIV infection may contribute to preventive and therapeutic approaches.

Excess of body weight is associated with accelerated T-cell senescence in hospitalized COVID-19 patients.

BACKGROUND: Several risk factors have been involved in the poor clinical progression of coronavirus disease-19 (COVID-19), including ageing, and obesity. SARS-CoV-2 may compromise lung function through cell damage and paracrine inflammation; and obesity has been associated with premature immunosenescence, microbial translocation, and dysfunctional innate immune responses leading to poor immune response against a range of viruses and bacterial infections. Here, we have comprehensively characterized the immunosenescence, microbial translocation, and immune dysregulation established in hospitalized COVID-19 patients with different degrees of body weight. RESULTS: Hospitalised COVID-19 patients with overweight and obesity had similarly higher plasma LPS and sCD14 levels than controls (all p < 0.01). Patients with obesity had higher leptin levels than controls. Obesity and overweight patients had similarly higher expansions of classical monocytes and immature natural killer (NK) cells (CD56+CD16-) than controls. In contrast, reduced proportions of intermediate monocytes, mature NK cells (CD56+CD16+), and NKT were found in both groups of patients than controls. As expected, COVID-19 patients had a robust expansion of plasmablasts, contrasting to lower proportions of major T-cell subsets (CD4 + and CD8+) than controls. Concerning T-cell activation, overweight and obese patients had lower proportions of CD4+CD38+ cells than controls. Contrasting changes were reported in CD25+CD127low/neg regulatory T cells, with increased and decreased proportions found in CD4+ and CD8+ T cells, respectively. There were similar proportions of T cells expressing checkpoint inhibitors across all groups. We also investigated distinct stages of T-cell differentiation (early, intermediate, and late-differentiated - TEMRA). The intermediate-differentiated CD4 + T cells and TEMRA cells (CD4+ and CD8+) were expanded in patients compared to controls. Senescent T cells can also express NK receptors (NKG2A/D), and patients had a robust expansion of CD8+CD57+NKG2A+ cells than controls. Unbiased immune profiling further confirmed the expansions of senescent T cells in COVID-19. CONCLUSIONS: These findings suggest that dysregulated immune cells, microbial translocation, and T-cell senescence may partially explain the increased vulnerability to COVID-19 in subjects with excess of body weight.

Comprehensive insight into the alterations in the gut microbiome and the intestinal barrier as a consequence of iron deficiency anaemia.

BACKGROUND: Iron deficiency is the top leading cause of anaemia, whose treatment has been shown to deteriorate gut health. However, a comprehensive analysis of the intestinal barrier and the gut microbiome during IDA have not been performed to date. This study aims to delve further into the analysis of these two aspects, which will mean a step forward minimising the negative impact of iron supplements on intestinal health. METHODS: IDA was experimentally induced in an animal model. Shotgun sequencing was used to analyse the gut microbiome in the colonic region, while the intestinal barrier was studied through histological analyses, mRNA sequencing (RNA-Seq), qPCR and immunofluorescence. Determinations of lipopolysaccharide (LPS) and bacteria-specific immunoglobulins were performed to assess microbial translocation. RESULTS: Microbial metabolism in the colon shifted towards an increased production of certain amino acids, short chain fatty acids and nucleotides, with Clostridium species being enriched during IDA. Structural alterations of the colonic epithelium were shown by histological analysis. RNA-Seq revealed a downregulation of extracellular matrix-associated genes and proteins and an overall underdeveloped epithelium. Increased levels of serum LPS and an increased immune response against dysbiotic bacteria support an impairment in the integrity of the gut barrier during IDA. CONCLUSIONS: IDA negatively impacts the gut microbiome and the intestinal barrier, triggering an increased microbial translocation. This study emphasizes the deterioration of gut health during IDA and the fact that it should be addressed when treating the disease.

Immune activation and inflammation in lactating women on combination antiretroviral therapy: role of gut dysfunction and gut microbiota imbalance.

Introduction: Combination antiretroviral therapy (cART) effectively controls HIV; however, chronic low-level viremia and gut microbiota dysbiosis remain significant drivers of gut and systemic inflammation. In this study, we explored the relationship between gut microbiota composition, intestinal inflammation, microbial translocation, and systemic inflammation in women on cART in Sub-Saharan Africa. Methods: We conducted a study in HIV-infected and HIV-uninfected lactating women followed up at 6 weeks and 6 months postpartum in Harare, Zimbabwe. We used 16S ribosomal Ribonucleic Acid (rRNA) sequencing and MesoScale Discovery V-Plex assays to examine the gut microbiome and to quantify plasma inflammatory biomarkers, respectively. In addition, we measured fecal calprotectin, plasma lipopolysaccharide-binding protein (LBP), and soluble cluster of differentiation 14 (sCD14) by enzyme-linked immunosorbent assay to assess gut inflammation, microbial translocation, and monocyte/macrophage activation. Results: A group of 77 lactating women were studied, of which 35% were HIV-infected. Fecal calprotectin levels were similar by HIV status at both follow-up time points. In the HIV-infected group at 6 weeks postpartum, fecal calprotectin was elevated: median (interquartile range) [158.1 µg/g (75.3-230.2)] in women who had CD4+ T-lymphocyte counts <350 cells/µL compared with those with ≥350 cells/µL [21.1 µg/g (0-58.4)], p = 0.032. Plasma sCD14 levels were significantly higher in the HIV-infected group at both 6 weeks and 6 months postpartum, p < 0.001. Plasma LBP levels were similar, but higher levels were observed in HIV-infected women with elevated fecal calprotectin. We found significant correlations between fecal calprotectin, LBP, and sCD14 with proinflammatory cytokines. Gut microbial alpha diversity was not affected by HIV status and was not affected by use of antibiotic prophylaxis. HIV significantly affected microbial beta diversity, and significant differences in microbial composition were noted. The genera Slackia and Collinsella were relatively more abundant in the HIV-infected group, whereas a lower relative abundance of Clostriduim sensu_stricto_1 was observed. Our study also found correlations between gut microbial taxa abundance and systemic inflammatory biomarkers. Discussion and conclusion: HIV-infected lactating women had increased immune activation and increased microbial translocation associated with increased gut inflammation. We identified correlations between the gut inflammation and microbial composition, microbial translocation, and systemic inflammation. The interplay of these parameters might affect the health of this vulnerable population.

Exploring the diversity of blood microbiome during liver diseases: Unveiling Novel diagnostic and therapeutic Avenues.

Liver diseases are a group of major metabolic and immune or inflammation related diseases caused due to various reasons including infection, abnormalities in immune system, genetic defects, and lifestyle habits. However, the cause-effect relationship is not completely understood in liver disease. The role of microbiome, particularly, the role of gut and oral microbiome in liver diseases has been extensively studied in recent years. More interestingly, the presence of blood microbiome and tissue microbiome has been identified in many liver diseases. The translocation of microbes from the gut into the portal circulation has been attributed to be the major reason for the presence of blood microbial components and its clinical implications in liver disorders. Besides microbial translocation, Pathogen associated Molecular Patterns (PAMPs) derived from gut microbiota might also translocate. The presence of blood microbiome in liver disease has been reviewed earlier. However, the role of blood microbiome as a biomarker and therapeutic target in liver diseases has not been analysed earlier. In this review, we confabulate the origin and physiology of blood microbiome and blood microbial components in relation to the progression and pathogenesis of liver disease. In conclusion, we discuss the translational perspectives targeting the blood microbial components in the diagnosis and therapy of liver disease.

The Influence of Oral Terbinafine on Gut Fungal Microbiome Composition and Microbial Translocation in People Living with HIV Treated for Onychomycosis.

People living with HIV (PLWH) display altered gut epithelium that allows for the translocation of microbial products, contributing to systemic immune activation. Although there are numerous studies which examine the gut bacterial microbiome in PLWH, few studies describing the fungal microbiome, or the mycobiome, have been reported. Like the gut bacterial microbiome, the fungal microbiome and its by-products play a role in maintaining the body's homeostasis and modulating immune function. We conducted a prospective study to assess the effects of oral terbinafine, an antifungal agent widely used against onychomycosis, on gut permeability and microbiome composition in ART-treated PLWH (trial registration: ChiCTR2100043617). Twenty participants completed all follow-up visits. During terbinafine treatment, the levels of the intestinal fatty acid binding protein (I-FABP) significantly increased, and the levels of interleukin-6 (IL-6) significantly decreased, from baseline to week 12. Both markers subsequently returned to pre-treatment levels after terbinafine discontinuation. After terbinafine treatment, the abundance of fungi decreased significantly, while the abundance of the bacteria did not change. After terbinafine discontinuation, the abundance of fungi returned to the levels observed pre-treatment. Moreover, terbinafine treatment induced only minor changes in the composition of the gut bacterial and fungal microbiome. In summary, oral terbinafine decreases fungal microbiome abundance while only slightly influencing gut permeability and microbial translocation in ART-treated PLWH. This study's findings should be validated in larger and more diverse studies of ART-treated PLWH; our estimates of effect size can be used to inform optimal sample sizes for future studies.

Current knowledge of the immune reconstitution inflammatory syndrome in Whipple disease: a review.

Immune reconstitution inflammatory syndrome (IRIS) is characterized by exaggerated and dysregulated inflammatory responses that occur as a result of reconstitution of adaptive or innate immunity. A wide range of microorganisms have been found to be associated with IRIS, such as human immunodeficiency virus (HIV), Mycobacterium and actinobacteria. Whipple disease (WD) is an infectious disorder caused by the Gram-positive bacterium Tropheryma whipplei (T. whipplei) and IRIS also serves as a complication during its treament. Although many of these pathological mechanisms are shared with related inflammatory disorders, IRIS in WD exhibits distinct features and is poorly described in the medical literature. Novel investigations of the intestinal mucosal immune system have provided new insights into the pathogenesis of IRIS, elucidating the interplay between systemic and local immune responses. These insights may be used to identify monitoring tools for disease prevention and to develop treatment strategies. Therefore, this review synthesizes these new concepts in WD IRIS to approach the feasibility of manipulating host immunity and immune reconstitution of inflammatory syndromes from a newer, more comprehensive perspective and study hypothetical options for the management of WD IRIS.

Exploring Plasma-Level Gut Microbiota Mediators and Pro-Inflammatory Markers in Pregnant Women with Short Cervix and Gestational Diabetes Mellitus.

The composition of the gut microbiota (GM) undergoes significant changes during pregnancy, influenced by metabolic status, energy homeostasis, fat storage, and hormonal and immunological modifications. Moreover, dysbiosis during pregnancy has been associated with preterm birth, which is influenced by factors such as cervical shortening, infection, inflammation, and oxidative stress. However, dysbiosis also affects the levels of lipopolysaccharide-binding protein (LBP), short-chain fatty acids (SCFAs), and free fatty acids (FFA) in other tissues and the bloodstream. In this study, we investigated the plasmatic levels of some pro-inflammatory cytokines, such as matrix metalloproteinases-8 (MMP-8), interleukin-8 (IL-8), heat shock protein 70 (Hsp70), and microbial markers in pregnant women with a short cervix (≤25 mm) compared to those with normal cervical length (>25 mm). We examined the differences in the concentration of these markers between the two groups, also assessing the impact of gestational diabetes mellitus. Understanding the relationship between GM dysbiosis, inflammatory mediators, and cervical changes during pregnancy may contribute to the identification of potential biomarkers and therapeutic targets for the prevention and management of adverse pregnancy outcomes, including preterm birth.

Suppressed immune and metabolic responses to intestinal damage-associated microbial translocation in myalgic encephalomyelitis/chronic fatigue syndrome.

The etiology and mechanism of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are poorly understood and no biomarkers have been established. Specifically, the relationship between the immunologic, metabolic, and gastrointestinal abnormalities associated with ME/CFS and their relevance to established symptoms of the condition remain unclear. Relying on data from two independent pairs of ME/CFS and control cohorts, one at rest and one undergoing an exercise challenge, we identify a state of suppressed acute-phase innate immune response to microbial translocation in conjunction with a compromised gut epithelium in ME/CFS. This immunosuppression, along with observed enhancement of compensatory antibody responses to counter the microbial translocation, was associated with and may be mediated by alterations in glucose and citrate metabolism and an IL-10 immunoregulatory response. Our findings provide novel insights into mechanistic pathways, biomarkers, and potential therapeutic targets in ME/CFS, including in the context of exertion, with relevance to both intestinal and extra-intestinal symptoms.

Helminths' therapeutic potential to treat intestinal barrier dysfunction.

The intestinal barrier is a dynamic multi-layered structure which can adapt to environmental changes within the intestinal lumen. It has the complex task of allowing nutrient absorption while limiting entry of harmful microbes and microbial antigens present in the intestinal lumen. Excessive entry of microbial antigens via microbial translocation due to 'intestinal barrier dysfunction' is hypothesised to contribute to the increasing incidence of allergic, autoimmune and metabolic diseases, a concept referred to as the 'epithelial barrier theory'. Helminths reside in the intestinal tract are in intimate contact with the mucosal surfaces and induce a range of local immunological changes which affect the layers of the intestinal barrier. Helminths are proposed to prevent, or even treat, many of the diseases implicated in the epithelial barrier theory. This review will focus on the effect of helminths on intestinal barrier function and explore whether this could explain the proposed health benefits delivered by helminths.

Biohybrids: Textile fibres provide scaffolds and highways for microbial translocation.

Introduction: Living materials (biohybrids, textile-microbial hybrids, hybrid living materials) have gained much attention in recent years with enormous potential for applications in biomedical science, the built environment, construction and architecture, drug delivery and as environmental biosensors. Living materials contain matrices which incorporate microorganisms or biomolecules as the bioactive components. A cross-disciplinary approach, operating at the intersection of creative practice and scientific research, incorporated textile technology and microbiology to demonstrate textile fibres providing microbial scaffolds and highways during this study. Methods: The study evolved from previous research which showed bacteria utilising the water layer surrounding fungal mycelium for motility, termed the 'fungal highway', which led to the investigation of the directional dispersal of microbes across a range of fibre types (natural and synthetic). The application of the study centred around the potential for biohybrids to be used as a biotechnology to improve oil bioremediation through seeding of hydrocarbon-degrading microbes into polluted environments via fungal or fibre highways, therefore treatments in the presence of crude oil were tested. Furthermore, from a design perspective, textiles have huge potential to act as a conduit for water and nutrients, essential to sustain microorganisms within living materials. Using the moisture absorption properties of natural fibres, the research explored how to engineer variable liquid absorption rates using cellulosics and wool to produce shape-changing knitted fabrics suitable for adaptation to oil spill capture. Results: At a cellular scale, confocal microscopy provided evidence to show that bacteria were able to utilise a water layer surrounding the fibres, supporting the hypothesis that fibres can aid bacterial translocation through their use as 'fibre highways'. A motile bacterial culture, Pseudomonas putida, was shown to translocate around a liquid layer surrounding polyester, nylon, and linen fibres, yet no evidence of translocation was apparent on silk or wool fibres, suggesting microbes elicit different responses to specific fibre types. Findings showed that translocation activity around highways did not diminish in the presence of crude oil, known to contain an abundance of toxic compounds, in comparison to oil-free controls. A design series demonstrated the growth of fungal mycelium (Pleurotus ostreatus) through knitted structures, highlighting the ability for natural fabrics to provide a scaffold to support microbial communities whilst retaining the ability to undergo environmentally responsive shape-change. A final prototype, Ebb&Flow, demonstrated the potential to scale up the responsive capacities of the material system using locally produced UK wool. The prototype conceptualised both the uptake of a hydrocarbon pollutant by fibres, and the translocation of microbes along fibre highways. Discussion: The research works towards facilitating the translation of fundamental science and design into biotechnological solutions that can be used in real world applications.

Increased Microbial Translocation is a Prognostic Biomarker of Different Immune Responses to ART in People Living with HIV.

Background: Microbial translocation (MT) is a characteristic of human immunodeficiency virus (HIV) infection. Whether MT is also a biomarker of different immune responses to antiretroviral therapy (ART) received by people living with HIV (PLWH) is not known. Methods: We examined the presence of MT in a cohort of 33 HIV-infected immunological responders (IRs) and 28 immunological non-responders (INRs) (≥500 and <200 cluster of differentiation (CD)4+ T-cell counts/µL after 2 years of HIV-1 suppression, respectively) with no comorbidities. Plasma samples were used to measure the circulating levels of MT markers. All enrolled study participants had received 2 years of viral-suppression therapy. Results: Levels of lipopolysaccharide (P = 0.0185), LPS-binding protein (P < 0.0001), soluble-CD14 (P < 0.0001), and endogenous endotoxin-core antibody (P < 0.0001) at baseline were significantly higher in INRs than in IRs and were associated with an increased risk of an immunological non-response, whereas the level of intestinal fatty acid-binding protein did not show this association. Analysis of receiver operating characteristic (ROC) curves demonstrated the utility of these individual microbial markers in discriminating INRs after ART in people living with HIV with high sensitivity, specificity, and area under the ROC curve. Conclusion: INRs in HIV infection are characterized by increased MT at baseline. These markers could be used as a rapid prognostic tool for predicting immune responses in people infected with the HIV.

The human microbiome and gut-liver axis in people living with HIV.

PURPOSE OF REVIEW: Chronic liver disease is a major cause of morbidity and mortality amongst people living with HIV (PLWH). Emerging data suggests that gut microbial translocation may play a role in driving and modulating liver disease, a bi-directional relationship termed the gut-liver axis. While it is recognized that PLWH have a high degree of dysbiosis and gut microbial translocation, little is known about the gut-liver axis in PLWH. RECENT FINDINGS: Recent studies have shown that microbial translocation can directly lead to hepatic inflammation, and have linked gut microbial signatures, dysbiosis, and translocation to liver disease in PLWH. Additionally, multiple trials have explored interventions targeting the microbiome in PLWH. Emerging research supports the interaction between the gut microbiome and liver disease in PLWH. This offers new opportunities to expand our understanding of the pathophysiology of liver disease in this population, as well as to explore possible clinical interventions.

Relevance of biomarkers indicating gut damage and microbial translocation in people living with HIV.

The intestinal barrier has the daunting task of allowing nutrient absorption while limiting the entry of microbial products into the systemic circulation. HIV infection disrupts the intestinal barrier and increases intestinal permeability, leading to microbial product translocation. Convergent evidence has shown that gut damage and an enhanced level of microbial translocation contribute to the enhanced immune activation, the risk of non-AIDS comorbidity, and mortality in people living with HIV (PLWH). Gut biopsy procedures are invasive, and are not appropriate or feasible in large populations, even though they are the gold standard for intestinal barrier investigation. Thus, validated biomarkers that measure the degree of intestinal barrier damage and microbial translocation are needed in PLWH. Hematological biomarkers represent an objective indication of specific medical conditions and/or their severity, and should be able to be measured accurately and reproducibly via easily available and standardized blood tests. Several plasma biomarkers of intestinal damage, i.e., intestinal fatty acid-binding protein (I-FABP), zonulin, and regenerating islet-derived protein-3α (REG3α), and biomarkers of microbial translocation, such as lipopolysaccharide (LPS) and (1,3)-ß-D-Glucan (BDG) have been used as markers of risk for developing non-AIDS comorbidities in cross sectional analyses and clinical trials, including those aiming at repair of gut damage. In this review, we critically discuss the value of different biomarkers for the estimation of gut permeability levels, paving the way towards developing validated diagnostic and therapeutic strategies to repair gut epithelial damage and to improve overall disease outcomes in PLWH.

Translocation of bacterial LPS is associated with self-reported cognitive abilities in men living with HIV receiving antiretroviral therapy.

BACKGROUND: Gut damage allows translocation of bacterial lipopolysaccharide (LPS) and fungal ß-D-glucan (BDG) into the blood. This microbial translocation contributes to systemic inflammation and risk of non-AIDS comorbidities in people living with HIV, including those receiving antiretroviral therapy (ART). We assessed whether markers of gut damage and microbial translocation were associated with cognition in ART-treated PLWH. METHODS: Eighty ART-treated men living with HIV from the Positive Brain Health Now Canadian cohort were included. Brief cognitive ability measure (B-CAM) and 20-item patient deficit questionnaire (PDQ) were administered to all participants. Three groups were selected based on their B-CAM levels. We excluded participants who received proton pump inhibitors or antiacids in the past 3 months. Cannabis users were also excluded. Plasma levels of intestinal fatty acid binding protein (I-FABP), regenerating islet-derived protein 3 α (REG3α), and lipopolysaccharides (LPS = were quantified by ELISA, while 1-3-ß-D-glucan BDG) levels were assessed using the Fungitell assay. Univariable, multivariable, and splines analyses were performed. RESULTS: Plasma levels of I-FABP, REG3α, LPS and BDG were not different between groups of low, intermediate and high B-CAM levels. However, LPS and REG3α levels were higher in participants with PDQ higher than the median. Multivariable analyses showed that LPS association with PDQ, but not B-CAM, was independent of age and level of education. I-FABP, REG3α, and BDG levels were not associated with B-CAM nor PDQ levels in multivariable analyses. CONCLUSION: In this well characterized cohort of ART-treated men living with HIV, bacterial but not fungal translocation was associated with presence of cognitive difficulties. These results need replication in larger samples.

Cognitive impairment and biomarkers of gut microbial translocation in testicular germ cell tumor survivors.

Background: Survivors of testicular germ cell tumors (GCT) may suffer from late cognitive impairment. We hypothesized that disruption of intestinal barrier during chemotherapy and/or radiotherapy may be a contributing factor of cognitive dysfunction within the gut-blood-brain axis. Methods: GCT survivors (N = 142) from National Cancer Institute of Slovakia completed the Functional Assessment of Cancer Therapy Cognitive Function questionnaires during their annual follow-up visit at 9-year median (range 4-32). Biomarkers of gut microbial translocation and dysbiosis high mobility group box-1 (HMGB-1), lipopolysaccharide, d-lactate and sCD14 were measured from peripheral blood obtained during the same visit. Each questionnaire score was correlated with biomarkers. Survivors were treated with orchiectomy only (N = 17), cisplatin-based chemotherapy (N = 108), radiotherapy to the retroperitoneum (N = 11) or both (N = 6). Results: GCT survivors with higher sCD14 (above median) had worse cognitive function perceived by others (CogOth domain) (mean ± SEM; 14.6 ± 0.25 vs 15.4 ± 0.25, p = 0.019), lower perceived cognitive abilities (CogPCA domain) (20.0 ± 0.74 vs 23.4 ± 0.73, p = 0.025) and lower overall cognitive function score (109.2 ± 0.74 vs 116.7 ± 1.90, p = 0.021). There were no significant cognitive declines associated with HMGB-1, d-lactate and lipopolysaccharide. Survivors treated with ≥ 400mg/m2 vs < 400mg/m2 of cisplatin-based chemotherapy had a higher lipopolysaccharide (567.8 µg/L ± 42.7 vs 462.9 µg/L ± 51.9, (p = 0.03). Conclusions: sCD14 is a marker of monocytic activation by lipopolysaccharide and may also serve as a promising biomarker of cognitive impairment in long-term cancer survivors. While chemotherapy and radiotherapy-induced intestinal injury may be the underlying mechanism, further research using animal models and larger patient cohorts are needed to explore the pathogenesis of cognitive impairment in GCT survivors within the gut-brain axis.

Persistent immune activation and altered gut integrity over time in a longitudinal study of Ugandan youth with perinatally acquired HIV.

Introduction: Perinatally acquired HIV infection (PHIV) occurs during a critical window of immune development. We investigated changes in systemic inflammation and immune activation in adolescents with PHIV and those without HIV (HIV-) in Uganda. Methods: A prospective observational cohort study was performed in 2017-2021 in Uganda. All participants were between 10-18 years of age and without active co-infections. PHIVs were on ART with HIV-1 RNA level ≤400 copies/mL. We measured plasma and cellular markers of monocyte activation, T-cell activation (expression of CD38 and HLA-DR on CD4+ and CD8+), oxidized LDL, markers of gut integrity and fungal translocation. Groups were compared using Wilcoxon rank sum tests. Changes from baseline were examined with 97.5% confidence intervals on relative fold change. P values were adjusted for false discovery rate. Results: We enrolled 101 PHIV and 96 HIV-; among these, 89 PHIV and 79 HIV- also had measurements at 96 weeks. At baseline, median (Q1, Q3) age was 13 yrs (11,15), and 52% were females. In PHIV, median CD4+ cell counts were 988 cells/µL (638, 1308), ART duration was 10 yrs (8, 11), and 85% had viral load <50 copies/mL throughout the study, 53% of participants had a regimen switch between visits, 85% of whom switched to 3TC, TDF and DTG. Over 96 weeks, while hsCRP decreased by 40% in PHIV (p=0.12), I-FABP and BDG both increased by 19 and 38% respectively (p=0.08 and ≤0.01) and did not change in HIV- (p≥0.33). At baseline, PHIVs had higher monocyte activation (sCD14) (p=0.01) and elevated frequencies of non-classical monocytes (p<0.01) compared to HIV- which remained stable over time in PHIV but increased by 34% and 80% respectively in HIV-. At both time points, PHIVs had higher T cell activation (p ≤ 0.03: CD4+/CD8+ T cells expressing HLA-DR and CD38). Only in PHIV, at both timepoints, oxidized LDL was inversely associated with activated T cells(p<0.01). Switching to dolutegravir at week 96 was significantly associated an elevated level of sCD163 (ß=0.4, 95% CI=0.14,0.57, p<0.01), without changes in other markers. Conclusion: Ugandan PHIV with viral suppression have some improvement in markers of inflammation over time, however T-cell activation remains elevated. Gut integrity and translocation worsened only in PHIV over time. A deeper understanding of the mechanisms causing immune activation in ART treated African PHIV is crucial.

Circulating markers of microbial translocation and host response to bacteria with risk of colorectal cancer: a prospective, nested case-control study in men.

BACKGROUND: Gut microbial dysbiosis contributes to colorectal cancer (CRC) pathogenesis, possibly mediated in part by increased intestinal permeability to endotoxin lipopolysaccharide (LPS), microbial translocation, and subsequent endotoxemia and inflammation. However, epidemiologic evidence linking circulating markers of microbial translocation with CRC risk is limited. METHODS: We conducted a prospective, nested case-control study of 261 incident CRC cases and 261 controls (matched on age and time of blood draw) among 18,159 men with pre-diagnostic blood specimens in the Health Professionals Follow-Up Study (1993-2009). We examined three complementary markers of microbial translocation and host response to bacteria, including LPS-binding protein (LBP), soluble CD14 (sCD14), and endotoxincore antibody (EndoCAb) immunoglobulin M (IgM), with subsequent risk of CRC. Unconditional logistic regressions were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). FINDINGS: Pre-diagnostic circulating levels of sCD14 were associated with a higher risk of incident CRC. Compared to men in the lowest quartile, the multivariable OR was 1.90 (95% CI, 1.13-3.22) for men in the highest quartile (OR per standard deviation [SD] increase, 1.28; 95%CI 1.06-1.53; Ptrend = 0.01). This positive association remained similar after adjusting for C-reactive protein, interleukin-6, and soluble tumor necrosis factor receptor-2, and within strata of putative CRC risk factors. We also observed a suggestive inverse association between EndoCAb IgM and risk of CRC (OR per SD increase, 0.84; 95%CI 0.69-1.02; Ptrend = 0.09). INTERPRETATION: Microbial translocation and host response to bacteria, as reflected by sCD14, is associated with risk of incident CRC in men. FUNDING: US National Institutes of Health.

sCD14 and Intestinal Fatty Acid Binding Protein Are Elevated in the Serum of Patients With Idiopathic Anaphylaxis.

BACKGROUND: Intestinal epithelial integrity compromise has been identified in gastrointestinal (GI), atopic, and autoimmune diseases. OBJECTIVE: Episodes of idiopathic anaphylaxis (IA) are often accompanied by GI manifestations. We, therefore, sought to determine whether surrogate markers of GI permeability were aberrant in this patient population. METHODS: Serum concentrations of zonulin, intestinal fatty acid binding protein (I-FABP), and soluble CD14 (sCD14) measured in 54 patients with IA were compared with concentrations in healthy controls (HCs); and correlated with clinical and laboratory parameters. RESULTS: The I-FABP was elevated in sera of patients with IA compared with HCs (median 1,378.0 pg/mL vs 479.0 pg/mL, respectively; P < .001). The sCD14 was also elevated compared with HCs (median 2,017.0 ng/mL and 1,189.0 ng/mL, respectively; P < .001), whereas zonulin was comparable between patients with IA and HCs (median 49.6 ng/mL vs 52.4 ng/mL, respectively; P = .40). The I-FABP was elevated in patients with IA who experienced vomiting and/or diarrhea compared with patients with IA who did not (P = .0091). CONCLUSIONS: The I-FABP and sCD14 are elevated in the serum of patients with IA. Elevations in these biomarkers of IA provides evidence that increased GI permeability, as is observed in other allergic conditions such as food allergy, is a common finding in those with IA and offers possible insight into the pathogenesis of this disease.