Translocation Of Microbial Products Research Articles

Abstract 2441: Higher levels of LPS in blood plasma as potential novel biomarker for cancer risk in Puerto Rican people living with HIV

Abstract Background: People living with HIV (PWH) have a significantly higher risk of developing cancers than people without HIV (PWOH), even with suppressive antiretroviral therapy. Puerto Rico (PR) is considered a high-risk group disproportionately affected by HIV and a priority group for cancer prevention strategies. Dysbiosis of the human microbiota can contribute to persistent inflammation by upregulating TGF-β (microbial-induced oncogenesis biomarker), which can promote the translocation of microbial products into the bloodstream, increasing cancer risk at local and distant sites. However, the relationship between TGF-β, and microbial products such as lipopolysaccharide (LPS) and short-chain fatty acids (SCFA) in relation to HIV infection is poorly understood, therefore we aimed to quantify the levels of LPS and SCFA in the blood plasma of PWH vs. PWOH and investigated their relationship with cancer risk measured by TGF-β. Methods: Blood samples, sociodemographic, and clinical data from 80 adults (50 PWH and 30 PWOH) were collected. PWH were virally suppressed (<50 copies/mL) with a median CD4 count of 699.8 cells/µL. We measured TGF-β, LPS, and soluble CD14 (sCD14. marker of innate immune activation and microbial translocation) using immunoassays. SCFA (acetate, butyrate, and propionate) were measured using gas chromatography followed by mass spectrometry. Differences in the median levels of TGF-β, LPS, and SCFAs were evaluated using a Mann-Whitney test. We assessed the effects of LPS, SCFAs, and HIV infections in relationship with levels of TGF-β using multivariate fixed-effects regression analysis in R-statistical software. Results: PWH had significantly higher levels of TGF-β (4397 pg/mL vs. 1121 pg/mL, p=0.017), higher levels of LPS (38.97 pg/mL vs. 19.26 pg/mL, p<0.001), higher levels of sCD14 (1326 pg/mL vs. 1137 pg/mL, p=0.007), and significantly lower levels of butyrate (84.5 ng/mL vs. 62.0 ng/mL, p<0.001). Higher levels of TGF-b were associated with higher levels of LPS (rho=0.38, p=0.017) and higher levels of sCD14 (rho=0.27, p=0.016) these relationships remain significant after adjusting for HIV status (p<0.001). Conclusion: Our findings suggest that microbial products in blood plasma can contribute to higher cancer risk in Puerto Rican PWH and may represent potential novel biomarkers for cancer prevention. Citation Format: Jurelis Torres Reyes, Tanner L. Shull, Gabriel Borges-Velez, Veronica S. Sanchez Gonzalez, Jeannette L. Salgado Montilla, Josue Perez Santiago. Higher levels of LPS in blood plasma as potential novel biomarker for cancer risk in Puerto Rican people living with HIV [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2441.

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.

Proton Pump Inhibitors For HIV+ Patients - A Word Of Caution.

Madam, HIV (human immunodeficiency virus) is on the rise in Pakistan. A Lancet global health modeling study reports that patient registration with the National Aids Control Program (NACP) has risen from 4500 in 2013 to 24331 in 2019 [1]. In HIV+ patients, the gastrointestinal tract is a common site of infection, often leading to anorexia, dysphagia, vomiting, weight loss, and diarrhoea. A study conducted in 2016 showed that 80% of HIV-infected adults had moderate-severe GERD (gastro-oesophageal reflux disorder) symptoms [2]. Physicians often prescribe proton pump inhibitors (PPIs) to treat GERD and stomach or duodenal ulcers. This class of drugs is the most potent inhibitor of gastric acid secretion and is ,unfortunately, prescribed excessively and often inappropriately, regardless of if the patient is HIV+. A recent study shows that 66.2% of patients in a tertiary care hospital in Karachi, Pakistan receive PPIs without proper indication [3]. However, PPIs being prescribed inappropriately pose severe health risks to individuals that are HIV+. A recent study in 2019 raised the valid concern that the use of PPIs in patients already receiving anti-retroviral (ARV) therapy in HIV+ patients could very well be related to an increased risk of acute kidney infection (AKI) [4]. This is not the only research to show the adverse effect of PPI use in HIV patients. A 2017 study shows statistically significant increased innate immune activation due to the translocation of microbial products in HIV+ patients taking PPIs [5]. This can carry serious future implications for these patients post-treatment because higher levels of innate immune activation markers are associated with immunological failure in HIV-treated patients [6]. These statistics raise a very critical question- is it safe for PPIs to be prescribed so freely without any attention to patients being HIV+ or on ARV therapy? It is suggested that existing and future ARV therapies be planned carefully if PPIs are prescribed, and close attention be paid to a patient’s virologic response. In the case of acute hospital admission, where PPIs are prescribed for preventing stress-induced or GI ulcers, medication reconciliation algorithms that acknowledge the interaction between protease inhibitors (PIs) and PPIs should be used [7]. It would be prudent to use PPIs strictly when prescribed and for lesser periods of time.

Endotoxemia Associated with Liver Disease Correlates with Systemic Inflammation and T Cell Exhaustion in Hepatitis C Virus Infection.

Both acute and chronic hepatitis C virus (HCV) infections are characterized by inflammation. HCV and reduced liver blood filtration contribute to inflammation; however, the mechanisms of systemic immune activation and dysfunction as a result of HCV infection are not clear. We measured circulating inflammatory mediators (IL-6, IP10, sCD163, sCD14), indices of endotoxemia (EndoCab, LBP, FABP), and T cell markers of exhaustion and senescence (PD-1, TIGIT, CD57, KLRG-1) in HCV-infected participants, and followed a small cohort after direct-acting anti-viral therapy. IL-6, IP10, Endocab, LBP, and FABP were elevated in HCV participants, as were T cell co-expression of exhaustion and senescence markers. We found positive associations between IL-6, IP10, EndoCab, LBP, and co-expression of T cell markers of exhaustion and senescence. We also found numerous associations between reduced liver function, as measured by plasma albumin levels, and T cell exhaustion/senescence, inflammation, and endotoxemia. We found positive associations between liver stiffness (TE score) and plasma levels of IL-6, IP10, and LBP. Lastly, plasma IP10 and the proportion of CD8 T cells co-expressing PD-1 and CD57 decreased after initiation of direct-acting anti-viral therapy. Although associations do not prove causality, our results support the model that translocation of microbial products, resulting from decreased liver blood filtration, during HCV infection drives chronic inflammation that results in T cell exhaustion/senescence and contributes to systemic immune dysfunction.

Toll-like receptor 2 activation in monocytes contributes to systemic inflammation and alcohol-associated liver disease in humans.

In the context of gut leakiness and translocation of microbial products in alcohol-associated liver disease (ALD), it is possible that systemic and liver inflammation involve the activation of circulating monocyte through gut-derived factors. We explored the association between monocytes, microbial translocation, systemic inflammation, and ALD. Patients with alcohol use disorder following a rehabilitation program were compared with healthy controls. We determined the circulating number and proportion of monocyte subsets by FACS. The activation of signaling pathways by gut-derived microbes was analyzed by quantitative PCR in isolated monocytes. Cytokines secretion by monocytes and phagocytosis were assessed in vitro. Serum microbial translocation markers and cytokines were measured by ELISA and multiplex assay, respectively. ALD severity and liver inflammatory responses were analyzed in liver biopsies by various methods. In patients with alcohol use disorder, the number of blood monocytes increased compared with controls. Monocytes from patients with alcohol use disorder upregulated IL-1β and IL-8 together with toll-like receptor 2 and downstream AP-1, while fungal sensor CARD9 was downregulated. IL-1β and IL-8 were actively secreted upon stimulation in vitro with the toll-like receptor 2 ligand peptidoglycan. Exposure with Escherichia coli confirmed preserved bacterial phagocytic activity. In contrast, Candida albicans stimulation leads to downregulation of IL-1β and TNFα compared with controls. Systemic cytokines and monocyte changes correlated with microbial translocation. Hepatic IL-1β and IL-8 increased with ALD severity together with liver macrophage activation and upregulation of chemokines involved in monocyte attraction. Our results point to the contribution of activated monocytes to systemic inflammation and ALD. Monocytes likely infiltrate the liver, transform into monocyte-derived macrophages and release IL-1β and IL-8 in response to peptidoglycan and toll-like receptor 2 activation.

Antenatal gut microbiome profiles and effect on pregnancy outcome in HIV infected and HIV uninfected women in a resource limited setting

BackgroundHuman immunodeficiency virus (HIV) severely damages the epithelial cells of the gut lining leading to an inflamed leaky gut, translocation of microbial products, and dysbiosis resulting in systemic immune activation. Also, microbiota composition and maternal gut function can be altered in pregnancy through changes in the immune system and intestinal physiology. The aim of this study was to investigate the gut microbiota in HIV-infected and HIV-uninfected pregnant women and to compare and identify the association between gut microbial composition and adverse birth outcomes.ResultsA total of 94 pregnant women (35 HIV-infected and 59 HIV-uninfected controls) were recruited in Harare from 4 polyclinics serving populations with relatively poor socioeconomic status. Women were of a median age of 28 years (interquartile range, IQR: 22.3–32.0) and 55% of women were 35 weeks gestational age at enrolment (median 35.0 weeks, IQR: 32.5–37.2). Microbiota profiling in these participants showed that species richness was significantly lower in the HIV-infected pregnant women compared to their HIV-uninfected peers and significant differences in β-diversity using Bray–Curtis dissimilarity were observed. In contrast, there was no significant difference in α-diversity between immune-compromised (CD4+ < 350 cells/µL) and immune-competent HIV-infected women (CD4+ ≥ 350 cells/µL) even after stratification by viral load suppression. HIV infection was significantly associated with a reduced abundance of Clostridium, Turicibacter, Ruminococcus, Parabacteroides, Bacteroides, Bifidobacterium, Treponema, Oscillospira, and Faecalibacterium and a higher abundance of Actinomyces, and Succinivibrio. Low infant birth weight (< 2500 g) was significantly associated with high abundances of the phylum Spirochaetes, the families Spirochaeteceae, Veillonellaceae, and the genus Treponema.ConclusionThe results reported here show that the species richness and taxonomy composition of the gut microbiota is altered in HIV-infected pregnant women, possibly reflecting intestinal dysbiosis. Some of these taxa were also associated with low infant birth weight.

Cardiovascular Disease and Thrombosis in HIV Infection.

HIV infection has transitioned from an acute, fatal disease to a chronic one managed by antiretroviral therapy. Thus, the aging population of people living with HIV (PLWH) continues to expand. HIV infection results in a dysregulated immune system, wherein CD4+ T cells are depleted, particularly in the gastrointestinal tract, disrupting the gut epithelial barrier. Long-term HIV infection is associated with chronic inflammation through potentially direct mechanisms caused by viral replication or exposure to viral proteins and indirect mechanisms resulting from increased translocation of microbial products from the intestine or exposure to antiretroviral therapy. Chronic inflammation (as marked by IL [interleukin]-6 and CRP [C-reactive protein]) in PLWH promotes endothelial cell dysfunction and atherosclerosis. PLWH show significantly increased rates of cardiovascular disease, such as myocardial infarction (risk ratio, 1.79 [95% CI, 1.54-2.08]) and stroke (risk ratio, 2.56 [95% CI, 1.43-4.61]). In addition, PLWH have increased levels of the coagulation biomarker D-dimer and have a two to ten-fold increased risk of venous thromboembolism compared with the general population. Several small clinical trials analyzed the effect of different antithrombotic agents on platelet activation, coagulation, inflammation, and immune cell activation. Although some markers for coagulation were reduced, most agents failed to reduce inflammatory markers in PLWH. More studies are needed to understand the underlying mechanisms driving inflammation in PLWH to create better therapies for lowering chronic inflammation in PLWH. Such therapies can potentially reduce atherosclerosis, cardiovascular disease, and thrombosis rates in PLWH and thus overall mortality in this population.

Targeting the Gut Microbiome to Treat Metabolic Dysfunction-Associated Fatty Liver Disease: Ready for Prime Time?

Numerous studies show a modification of the gut microbiota in patients with obesity or diabetes. Animal studies have also shown a causal role of gut microbiota in liver metabolic disorders including steatosis whereas the human situation is less clear. Patients with metabolic dysfunction associated fatty liver disease (MAFLD) also have a modification in their gut microbiota composition but the changes are not fully characterized. The absence of consensus on a precise signature is probably due to disease heterogeneity, possible concomitant medications and different selection or evaluation criteria. The most consistent changes were increased relative abundance of Proteobacteria, Enterobacteriaceae and Escherichia species and decreased abundance of Coprococcus and Eubacterium. Possible mechanisms linking the microbiota and MAFLD are increased intestinal permeability with translocation of microbial products into the portal circulation, but also changes in the bile acids and production of microbial metabolites such as ethanol, short chain fatty acids and amino acid derivatives able to modulate liver metabolism and inflammation. Several interventional studies exist that attempt to modulate liver disease by administering antibiotics, probiotics, prebiotics, synbiotics, postbiotics or fecal transplantation. In conclusion, there are both gaps and hopes concerning the interest of gut microbiome evaluation for diagnosis purposes of MAFLD and for new therapeutic developments that are often tested on small size cohorts.

Aging With Grace for People Living With HIV: Strategies to Overcome Leaky Gut and Cytomegalovirus Coinfection.

:The intestinal epithelial layer acts as a mechanical and functional barrier between the intraluminal microbiota and the immunologically active submucosa. A progressive loss of gut barrier function (leaky gut) leads to enhanced translocation of microbial products, which in turn contributes as endotoxins to inflammaging. Th17 T cell represents the main immune sentinels in the gut epithelium, preventing aggression from commensal and pathogenic microbes. As HIV infection deeply affects gut Th17 function and increases gut permeability, microbial translocation occurs at high level in people living with HIV (PLWH) and has been associated with the development of non-AIDS comorbidities. Although the inflammatory role of endotoxins like lipopolysaccharide produced by Gram-negative bacteria is well-established, fungal products such as β-D-glucan emerge as new contributors. In addition, PLWH are more frequently infected with cytomegalovirus (CMV) than the general population. CMV infection is a well-described accelerator of immune aging, through the induction of expansion of dysfunctional CD8 T-cells as well as through enhancement of gut microbial translocation. We critically review immune mechanisms related to bacterial and fungal translocation, with a focus on the contribution of CMV coinfection in PLWH. Improving gut barrier dysfunction, microbial composition, and reducing microbial translocation constitute emerging strategies for the prevention and treatment of HIV-associated inflammation and may be relevant for age-related inflammatory conditions.

Gut Leakage of Fungal-Related Products: Turning Up the Heat for HIV Infection.

The intestinal epithelial layer serves as a physical and functional barrier between the microbiota in the lumen and immunologically active submucosa. Th17 T-cell function protects the gut epithelium from aggression from microbes and their by-products. Loss of barrier function has been associated with enhanced translocation of microbial products which act as endotoxins, leading to local and systemic immune activation. Whereas the inflammatory role of LPS produced by Gram-negative bacteria has been extensively studied, the role of fungal products such as β-D-glucan remains only partially understood. As HIV infection is characterized by impaired gut Th17 function and increased gut permeability, we critically review mechanisms of immune activation related to fungal translocation in this viral infection. Additionally, we discuss markers of fungal translocation for diagnosis and monitoring of experimental treatment responses. Targeting gut barrier dysfunction and reducing fungal translocation are emerging strategies for the prevention and treatment of HIV-associated inflammation and may prove useful in other inflammatory chronic diseases.

Plasma Biomarkers of Risk of Tuberculosis Recurrence in HIV Co-Infected Patients From South Africa.

There is an urgent need to identify immunological markers of tuberculosis (TB) risk in HIV co-infected individuals. Previously we have shown that TB recurrence in HIV co-infected individuals on ART was associated with markers of systemic inflammation (IL-6, IL1β and IL-1Rα). Here we examined the effect of additional acute inflammation and microbial translocation marker expression on risk of TB recurrence. Stored plasma samples were drawn from the TB Recurrence upon Treatment with HAART (TRuTH) study, in which individuals with previously treated pulmonary TB were screened for recurrence quarterly for up to 4 years. Recurrent TB cases (n = 37) were matched to controls (n = 102) by original trial study arm assignment and ART start date. Additional subsets of HIV infected (n = 41) and HIV uninfected (n = 37) individuals from Improving Recurrence Success (IMPRESS) study were sampled at active TB and post successful treatment completion. Plasma concentrations of soluble adhesion molecules (sMAdCAM, sICAM and sVCAM), lipopolysaccharide binding protein (LBP) and transforming growth factor-beta (TGF-β1, TGF-β2, TGF-β3) were measured by multiplex immunoassays and ELISA. Cytokine data was square root transformed in order to reduce variability. Multivariable analysis adjusted for a number of potential confounders measured at sample time-point: age, BMI, CD4 count, viral load (VL) and measured at baseline: presence or absence of lung cavities, previous history of TB, and WHO disease stage (4 vs 3). The following analytes were associated with increased risk of TB recurrence in the multivariable model: sICAM (aOR 1.06, 95% CI: 1.02-1.12, p = 0.009), LBP (aOR 8.78, 95% CI: 1.23-62.66, p = 0.030) and TGF-β3 (aOR 1.44, 95% CI 1.01-2.05, p = 0.044). Additionally, we observed a positive correlation between LBP and sICAM (r= 0.347, p<0.0001), and LBP and IL-6, identified to be one of the strongest predictors of TB risk in our previous study (r=0.623, p=0.03). These data show that increased risk of TB recurrence in HIV infected individuals on ART is likely associated with HIV mediated translocation of microbial products and the resulting chronic immune activation.

New therapies for inflammatory bowel diseases

Currently, Inflammatory Bowel Disease (IBD) is considered an immune-mediated disease. The most widely accepted etiopathogenic hypothesis is that it is due to an inadequate interaction between the immune system and the microorganisms that form the normal intestinal flora. This abnormal interaction occurs in genetically predisposed subjects under the influence of various environmental factors (such as tobacco, diet, stress, or recurrent bacterial infections), which could act as triggers for alterations in the intestinal epithelial barrier. This would lead to an increase in the permeability of barrier, allowing the translocation of microbial products to the wall of the digestive tract, which would activate an acute cell-mediated immune response[1]. The failure of the anti-inflammatory regulatory mechanisms, together with an excess in the production of pro-inflammatory cytokines, would promote an aberrant immune response that would be self-perpetuating over time, thus giving rise to the chronic inflammation that characterizes IBD[2]. Since the first descriptions of Ulcerative Colitis (UC) and Crohn's Disease (CD), many treatments have been developed, with varying degrees of safety and efficacy. At the end of the 20th century, the first biological, called Infliximab, began to be used. A biological drug is one that has a biotechnological origin and arises from proteins derived from DNA and hybridization processes, which require living organisms as a fundamental part of the production process[3]. Undoubtedly, the appearance of biologics in the therapeutic arsenal of IBD was a very important advance in the treatment of these patients, a true revolution. Until that date, many of the patients who began to be treated with this biologic could only do with corticosteroids or by surgery. These drugs have been shown to be effective in reducing intestinal damage caused by chronic inflammation, the need for surgery and hospital admissions and, consequently, have improved the quality of life of many patients[4]. The demonstrated benefit of these drugs, especially when administered early, as well as their favorable safety profile, have led to their increasingly frequent use in the treatment of patients with IBD. They can be divided into - anti-TNF drugs (blocking the cytokine TNF-α), - Vedolizumab (blocking the integrin α4β7) and - Ustekinumab (blocking Interleukin 12 and 23). Recently, and only for use in UC, Tofacitinib (an inhibitor of the JAK-kinase pathway) has been approved and has demonstrated its efficacy in the treatment of moderate-severe active UC[5]. The management of all these drugs represents a challenge for the digestive specialist who must know their mechanisms of action and use them appropriately in patients with IBD. Anti-TNF drugs, being the oldest, are the ones with which we have the most experience and, therefore, they are usually used in the first line in those cases in which conventional drugs (corticosteroids and / or immunosuppressants) have failed. There are three currently marketed in Spain: Infliximab (for intravenous administration), Adalimumab (for subcutaneous administration) and Golimumab (for subcutaneous administration). Vedolizumab (administered intravenously), and Ustekinumab (administered subcutaneously, after a first intravenous administration) are characterized by having an excellent safety profile and a very low immunogenic potential compared to anti-TNF drugs. There are many lines of research currently underway to try to identify the clinical factors of the patient that would make one drug or another more useful in the first line. Other lines seek to identify genetic factors (it seems that mutations in the HLA DQA1 * 05 haplotype could increase immunogenicity to anti-TNF drugs[6]) and also molecular factors[7].

Regulating Intestinal Microbiota in the Prevention and Treatment of Alcohol-Related Liver Disease.

When alcohol-related liver disease occurs, the number and composition ratio of intestinal microorganisms will accordingly change. The alcohol-induced changes in the intestinal microbiota play a pivotal role in the process of developing the alcohol-related liver disease through the translocation of microbial products due to increased intestinal permeability. In recent years, therapeutic interventions with a concentration on regulating intestinal microbiota have been conducted for patients with alcohol-related liver disease. We aimed to provide a critical review and updates on the prevention and treatment of alcohol-related liver disease through regulating intestinal microbiota. A literature search was performed on the PubMed database for studies published in English about the therapeutic intervention with microbiota using animal models and patients with alcohol-related liver disease (1/2010–4/2020). The accumulating pieces of evidence suggest that the therapeutic use of probiotics, prebiotics, antibiotics, phages, or fecal microbial transplantation may have several influences on alcohol-related liver disease patients. Emergent data unveiled that these interventions can further regulate the composition of intestinal microbiota, minimize the negative impact of microbiota on the liver, and prevent disease progression from mild to severe alcoholic hepatitis, fibrosis, cirrhosis, or even liver cancer. The current review provides updates on the advances of therapeutic interventions with the effects of regulating intestinal microbiota on patients who have alcohol-related liver disease. In addition, the data gaps and research directions on further exploration of the role of intestinal microbiota for the management of the alcohol-related liver disease are also discussed.

Corrigendum to: Gut epithelial impairment, microbial translocation and immune system activation in inflammatory bowel disease-associated spondyloarthritis.

Objectives Gut microbiota has been widely reported to be involved in systemic inflammation through microbial translocation and T cell activation in several diseases. In this work we aimed to investigate bacterial infiltration and epithelial impairment in the gut of patients with IBD-associated SpA (SpA-IBD), as well as the relationship of microbial translocation with immune system activation and their putative role in the pathogenesis of joint inflammation in IBD patients. Methods Tight-junction proteins (TJPs) occludin and claudin-1/-4 and bacteria were assessed by real-time PCR analysis and immunohistochemical staining of the ileum. Intestinal fatty acid binding protein (I-FABP), lipopolysaccharides (LPS), soluble CD14 (sCD14), sclerostin and anti-sclerostin antibodies (anti-sclerostin-IgG) were assayed with ELISAs and peripheral mononuclear blood cells with flow cytometry. LPS and sCD14 were used in vitro to stimulate a human osteoblast cell line. Results Compared with IBD, ileal samples from SpA-IBD patients showed bacterial infiltration, epithelial damage and downregulation of TJPs. In sera, they showed higher serum levels of I-FABP, LPS, sCD14 (the latter correlating with sclerostin and anti-sclerostin-IgG) and higher CD80+/CD163+ and lower CD14+ mononuclear cells. In vitro experiments demonstrated that only the LPS and sCD14 synergic action downregulates sclerostin expression in osteoblast cells. Conclusion SpA-IBD patients are characterized by gut epithelium impairment with consequent translocation of microbial products into the bloodstream, immune system activation and an increase of specific soluble biomarkers. These findings suggest that gut dysbiosis could be involved in the pathogenesis of SpA-IBD and it could hopefully prompt the use of these biomarkers in the follow-up and management of IBD patients.

Treating From the Inside Out: Relevance of Fecal Microbiota Transplantation to Counteract Gut Damage in GVHD and HIV Infection.

The gastrointestinal (GI) tract is a complex and well-balanced milieu of anatomic and immunological barriers. The epithelial surface of the GI tract is colonized by trillions of microorganisms, known as the gut microbiota, which is considered an “organ” with distinctive endocrine and immunoregulatory functions. Dysregulation of the gut microbiota composition, termed dysbiosis, has been associated with epithelial damage and translocation of microbial products into the circulating blood. Dysbiosis, increased gut permeability and chronic inflammation play a major role on the clinical outcome of inflammatory bowel diseases, graft-vs.-host disease (GVHD) and HIV infection. In this review, we focus on GVHD and HIV infection, conditions sharing gut immune damage leading to dysbiosis. The degree of dysbiosis and level of epithelial gut damage predict poor clinical outcome in both conditions. Emerging interventions are therefore warranted to promote gut microbiota homeostasis and improve intestinal barrier function. Interventions such as anti-inflammatory medications, and probiotics have toxicity and/or limited transitory effects, justifying innovative approaches. Fecal microbiota transplantation (FMT) is one such approach where fecal microorganisms are transferred from healthy donors into the GI tract of the recipient to restore microbiota composition in patients with Clostridium difficile-induced colitis or inflammatory bowel diseases. Preliminary findings point toward a beneficial effect of FMT to improve GVHD and HIV-related outcomes through the engraftment of beneficial donor bacteria, notably those producing anti-inflammatory metabolites. Herein, we critically review the potential for FMT in alleviating dysbiosis and gut damage in patients with GVHD or HIV-infection. Understanding the underlying mechanism by which FMT restores gut function will pave the way toward novel scalable and targeted interventions.

The Butyrogenic and Lactic Bacteria of the Gut Microbiota Determine the Outcome of Allogenic Hematopoietic Cell Transplant.

Graft versus host disease (GVHD) is a post-transplant pathology in which donor-derived T cells present in the Peyer’s patches target the cell-surface alloantigens of the recipient, causing host tissue damages. Therefore, the GVHD has long been considered only a purely immunological process whose prevention requires an immunosuppressive treatment. However, since the early 2010s, the impact of gut microbiota on GVHD has received increased attention. Both a surprising fall in gut microbiota diversity and a shift toward Enterobacteriaceae were described in this disease. Recently, unexpected results were reported that further link GVHD with changes in bacterial composition in the gut and disruption of intestinal epithelial tight junctions leading to abnormal intestinal barrier permeability. Patients receiving allogenic hematopoietic stem cell transplant (allo-HCT) as treatment of hematologic malignancies showed a decrease of the overall diversity of the gut microbiota that affects Clostridia and Blautia spp. and a predominance of lactic acid bacteria (LAB) of the Enterococcus genus, in particular the lactose auxotroph Enterococcus faecium. The reduced microbiota diversity (likely including Actinobacteria, such as Bifidobacterium adolescentis that cross feed butyrogenic bacteria) deprives the butyrogenic bacteria (such as Roseburia intestinalis or Eubacterium) of their capacity to metabolize acetate to butyrate. Indeed, administration of butyrate protects against the GVHD. Here, we review the data highlighting the possible link between GVHD and lactase defect, accumulation of lactose in the gut lumen, reduction of Reg3 antimicrobial peptides, narrower enzyme equipment of bacteria that predominate post-transplant, proliferation of En. faecium that use lactose as metabolic fuels, induction of innate and adaptive immune response against these bacteria which maintains an inflammatory process, elevated expression of myosin light chain kinase 210 (MLCK210) and subsequent disruption of intestinal barrier, and translocation of microbial products (lactate) or transmigration of LAB within the liver. The analysis of data from the literature confirms that the gut microbiota plays a major role in the GVHD. Moreover, the most recent publications uncover that the LAB, butyrogenic bacteria and bacterial cross feeding were the missing pieces in the puzzle. This opens new bacteria-based strategies in the treatment of GVHD.

Gut epithelial impairment, microbial translocation and immune system activation in inflammatory bowel disease-associated spondyloarthritis.

Gut microbiota has been widely reported to be involved in systemic inflammation through microbial translocation and T cell activation in several diseases. In this work we aimed to investigate bacterial infiltration and epithelial impairment in the gut of patients with IBD-associated SpA (SpA-IBD), as well as the relationship of microbial translocation with immune system activation and their putative role in the pathogenesis of joint inflammation in IBD patients. Tight-junction proteins (TJPs) occludin and claudin-1/-4 and bacteria were assessed by real-time PCR analysis and immunohistochemical staining of the ileum. Intestinal fatty acid binding protein (I-FABP), lipopolysaccharides (LPS), soluble CD14 (sCD14), sclerostin and anti-sclerostin antibodies (anti-sclerostin-IgG) were assayed with ELISAs and peripheral mononuclear blood cells with flow cytometry. LPS and sCD14 were used in vitro to stimulate a human osteoblast cell line. Compared with IBD, ileal samples from SpA-IBD patients showed bacterial infiltration, epithelial damage and downregulation of TJPs. In sera, they showed higher serum levels of I-FABP, LPS, sCD14 (the latter correlating with sclerostin and anti-sclerostin-IgG) and higher CD80+/CD163+ and lower CD14+ mononuclear cells. In vitro experiments demonstrated that only the LPS and sCD14 synergic action downregulates sclerostin expression in osteoblast cells. SpA-IBD patients are characterized by gut epithelium impairment with consequent translocation of microbial products into the bloodstream, immune system activation and an increase of specific soluble biomarkers. These findings suggest that gut dysbiosis could be involved in the pathogenesis of SpA-IBD and it could hopefully prompt the use of these biomarkers in the follow-up and management of IBD patients.

Gut Microbiome Alterations During HIV/SIV Infection: Implications for HIV Cure.

Gut mucosal damage, associated with Human Immunodeficiency Virus-1 (HIV) infection, is characterized by depletion in CD4+ T cells and persistent immune activation as a result of early epithelial barrier disruption and systemic translocation of microbial products. Unique approaches in studying both HIV infection in human patients and Simian Immunodeficiency Virus (SIV) infection in rhesus macaques have provided critical evidence for the pathogenesis and treatment of HIV/AIDS. While there is vast resemblance between SIV and HIV infection, the development of gut dysbiosis attributed to HIV infection in chronically infected patients has not been consistently reported in SIV infection in the non-human primate model of AIDS, raising concerns for the translatability of gut microbiome studies in rhesus macaques. This review outlines our current understanding of gut microbial signatures across various stages of HIV versus SIV infection, with an emphasis on the impact of microbiome-based therapies in restoring gut mucosal immunity as well as their translational potential to supplement current HIV cure efforts.

IgG Antibodies to GlcNAcβ and Asialo-GM2 (GA2) Glycans as Potential Markers of Liver Damage in Chronic Hepatitis C and the Efficacy of Antiviral Treatment.

Total serum IgG level is a surrogate marker of hepatitis C (HC) severity. Antibodies (Abs) to microbial glycans could be markers of HC severity caused by the translocation of microbial products. The level of anti-glycan (AG) Abs was analysed in serum samples of patients (n = 128) with chronic HC in ELISA using fourteen synthetic glycans present in microbes and adhesins to evaluate the association of Abs with clinical parameters and the efficacy of antiviral treatment. The anti-GlcNAcβ IgG level was significantly higher in patients with fibrosis (P = 0.021) and severe portal inflammation (P < 0.001) regardless of other clinical parameters. The ROC curve analysis showed sensitivity of 0.59, specificity of 0.84, and AUC of 0.71 in discriminating F0 from F1–4 (HCV genotype-1b-infected patients). The level of anti-GA2 Abs before Peg-IFN/RBV treatment was significantly higher in nonsustained viral response (non-SVR) to treatment than in SVR (P = 0.033). ROC analysis showed sensitivity of 0.62, specificity of 0.70, and AUC of 64. Correlations of AG Abs to clinical parameters were found. The quantification of anti-GlcNAcβ Abs deserves attention in assessment of the hepatic damage while anti-GA2 Abs may be a sign of immune response related to the antiviral treatment.

Are Probiotics Effective in Targeting Alcoholic Liver Diseases?

Alcoholic liver disease (ALD) encompasses a broad spectrum of disorders including steatosis, steatohepatitis, fibrosis, and cirrhosis. Despite intensive research in the last two decades, there is currently no Food and Drug Administration-approved therapy for treating ALD. Several studies have demonstrated the importance of the gut-liver axis and gut microbiome on the pathogenesis of ALD. Alcohol may induce intestinal dysbiosis and increased intestinal permeability, which in turn result in increased levels of pathogen-associated molecular patterns such as lipopolysaccharide (LPS) and translocation of microbial products from the gut to the liver (bacterial translocation). LPS is an inflammatory signal that activates toll-like receptor 4 on Kupffer cells, contributing to the inflammation observed in ALD. Recently, probiotics have been shown to be effective in reducing or preventing the progression of ALD. A potential mechanism is that the probiotics transforms the composition of intestinal microbiota, which leads to reductions in alcohol-induced dysbiosis, intestinal permeability, bacterial translocation, endotoxemia, and consequently, the development of ALD. While transformation of intestinal microbiota by probiotics appears to be a promising therapeutic strategy for the treatment of intestinal barrier dysfunction, there is a scarcity of research that studies probiotics in the context of ALD. In this review, we discuss the potential therapeutic applications of probiotics in the treatment of ALD.