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Elevated infant fecal concentrations of the bacterial-derived lipid 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME) increase the risk for childhood atopy and asthma. However, the mechanisms by which this lipid contributes to disease development are largely unknown. We hypothesized that macrophages, which are key to both antimicrobial and antigen responses, are functionally and epigenetically modified by 12,13-diHOME leading to short- and long-term dysfunction with consequences for both antimicrobial and antigenic responses. Macrophages exposed to 12,13-diHOME are skewed toward inflammatory IL-1βhighCD206low cells, a phenomenon that is further amplified in the presence of common microbial-, aero-, and food-allergens. These IL-1βhighCD206low macrophages also exhibit reduced bacterial phagocytic capacity. In primary immune cell coculture assays involving peanut allergen stimulation, 12,13-diHOME promotes both IL-1β and IL-6 production, memory B cell expansion, and increased IgE production. Exposure to 12,13-diHOME also induces macrophage chromatin remodeling, specifically diminishing access to interferon-stimulated response elements resulting in reduced interferon-regulated gene expression upon bacterial lipopolysaccharide stimulation. Thus 12,13-diHOME reprograms macrophage effector function, B-cell interactions and promotes epigenetic modifications that exacerbate inflammatory response to allergens and mutes antimicrobial response along the interferon axis. These observations offer plausible mechanisms by which this lipid promotes early-life pathogenic microbiome development and innate immune dysfunction associated with childhood allergic sensitization.

Abstract Chronic lung disease (CLD) is a common co-morbidity for HIV-positive children and adolescents on antiretroviral therapy (ART) in sub-Saharan Africa. In this population, distinct airway microbiota may differentially confer risk of CLD. In a cross-sectional study of 202 HIV-infected children aged 6–16 years in Harare, Zimbabwe, we determined the association of sputum microbiota composition (using 16S ribosomal RNA V4 gene region sequencing) with CLD defined using clinical, spirometric, or radiographic criteria. Forty-two percent of children were determined to have CLD according to our definition. Dirichlet multinomial mixtures identified four compositionally distinct sputum microbiota structures. Patients whose sputum microbiota was dominated by Haemophilus, Moraxella or Neisseria (HMN) were at 1.5 times higher risk of CLD than those with Streptococcus or Prevotella (SP)-dominated microbiota (RR = 1.48, p = 0.035). Cell-free products of HMN sputum microbiota induced features of epithelial disruption and inflammatory gene expression in vitro, indicating enhanced pathogenic potential of these CLD-associated microbiota. Thus, HIV-positive children harbor distinct sputum microbiota, with those dominated by Haemophilus, Moraxella or Neisseria associated with enhanced pathogenesis in vitro and clinical CLD.

Abstract Pneumonia is common and frequently fatal in HIV-infected patients, due to rampant, systemic inflammation and failure to control microbial infection. While airway microbiota composition is related to local inflammatory response, gut microbiota has been shown to correlate with the degree of peripheral immune activation (IL6 and IP10 expression) in HIV-infected patients. We thus hypothesized that both airway and gut microbiota are perturbed in HIV-infected pneumonia patients, that the gut microbiota is related to peripheral CD4+ cell counts, and that its associated products differentially program immune cell populations necessary for controlling microbial infection in CD4-high and CD4-low patients. To assess these relationships, paired bronchoalveolar lavage and stool microbiota (bacterial and fungal) from a large cohort of Ugandan, HIV-infected patients with pneumonia were examined, and in vitro tests of the effect of gut microbiome products on macrophage effector phenotypes performed. While lower airway microbiota stratified into three compositionally distinct microbiota as previously described, these were not related to peripheral CD4 cell count. In contrast, variation in gut microbiota composition significantly related to CD4 cell count, lung microbiota composition, and patient mortality. Compared with patients with high CD4+ cell counts, those with low counts possessed more compositionally similar airway and gut microbiota, evidence of microbial translocation, and their associated gut microbiome products reduced macrophage activation and IL-10 expression and increased IL-1β expression in vitro. These findings suggest that the gut microbiome is related to CD4 status and plays a key role in modulating macrophage function, critical to microbial control in HIV-infected patients with pneumonia.

Gut microbial dysbiosis in infancy is associated with childhood atopy and the development of asthma. Here, the authors show that gut microbiota perturbation is evident in the very earliest stages of postnatal life, continues throughout infancy, and can be partially rescued by Lactobacillus supplementation in high-risk for asthma infants.

Gut microbes can profoundly modulate mucosal barrier-promoting Th17 cells in mammals. A salient feature of HIV/simian immunodeficiency virus (SIV) immunopathogenesis is the loss of Th17 cells, which has been linked to increased activity of the immunomodulatory enzyme, indoleamine 2,3-dioxygenase 1 (IDO 1). The role of gut microbes in this system remains unknown, and the SIV-infected rhesus macaque provides a well-described model for HIV-associated Th17 loss and mucosal immune disruption. We observed a specific depletion of gut-resident Lactobacillus during acute and chronic SIV infection of rhesus macaques, which was also seen in early HIV-infected humans. This depletion in rhesus macaques correlated with increased IDO1 activity and Th17 loss. Macaques supplemented with a Lactobacillus-containing probiotic exhibited decreased IDO1 activity during chronic SIV infection. We propose that Lactobacillus species inhibit mammalian IDO1 and thus may help to preserve Th17 cells during pathogenic SIV infection, providing support for Lactobacillus species as modulators of mucosal immune homeostasis.

ABSTRACT Significant gut microbiota heterogeneity exists among ulcerative colitis (UC) patients, though the clinical implications of this variance are unknown. We hypothesized that ethnically distinct UC patients exhibit discrete gut microbiotas with unique metabolic programming that differentially influence immune activity and clinical status. Using parallel 16S rRNA and internal transcribed spacer 2 sequencing of fecal samples (UC, 30; healthy, 13), we corroborated previous observations of UC-associated bacterial diversity depletion and demonstrated significant Saccharomycetales expansion as characteristic of UC gut dysbiosis. Furthermore, we identified four distinct microbial community states (MCSs) within our cohort, confirmed their existence in an independent UC cohort, and demonstrated their coassociation with both patient ethnicity and disease severity. Each MCS was uniquely enriched for specific amino acid, carbohydrate, and lipid metabolism pathways and exhibited significant luminal enrichment of the metabolic products of these pathways. Using a novel ex vivo human dendritic cell and T-cell coculture assay, we showed that exposure to fecal water from UC patients caused significant Th2 skewing in CD4+ T-cell populations compared to that of healthy participants. In addition, fecal water from patients in whom their MCS was associated with the highest level of disease severity induced the most dramatic Th2 skewing. Combined with future investigations, these observations could lead to the identification of highly resolved UC subsets based on defined microbial gradients or discrete microbial features that may be exploited for the development of novel, more effective therapies. IMPORTANCE Despite years of research, the etiology of UC remains enigmatic. Diagnosis is difficult and the patient population heterogeneous, which represents a significant barrier to the development of more effective, tailored therapy. In this study, we demonstrate the clinical utility of the gut microbiome in stratifying UC patients by identifying the existence of four distinct interkingdom pathogenic microbiotas within the UC patient population that are compositionally and metabolically distinct, covary with clinical markers of disease severity, and drive discrete CD4+ T-cell expansions ex vivo. These findings offer new insight into the potential value of the gut microbiome as a tool for subdividing UC patients, opening avenues to the development of more personalized treatment plans and targeted therapies.

Elevated infant fecal concentrations of the bacterial‐derived lipid 12,13‐dihydroxy‐9Z‐octadecenoic acid (12,13‐diHOME) increase the risk for childhood atopy and asthma. However, the mechanisms by which this lipid contributes to disease development are largely unknown. We hypothesized that macrophages, which are key to both antimicrobial and antigen responses, are functionally and epigenetically modified by 12,13‐diHOME leading to short‐ and long‐term dysfunction with consequences for both antimicrobial and antigenic responses. Macrophages exposed to 12,13‐diHOME are skewed toward inflammatory IL‐1βhighCD206low cells, a phenomenon that is further amplified in the presence of common microbial‐, aero‐, and food‐allergens. These IL‐1βhighCD206low macrophages also exhibit reduced bacterial phagocytic capacity. In primary immune cell coculture assays involving peanut allergen stimulation, 12,13‐diHOME promotes both IL‐1β and IL‐6 production, memory B cell expansion, and increased IgE production. Exposure to 12,13‐diHOME also induces macrophage chromatin remodeling, specifically diminishing access to interferon‐stimulated response elements resulting in reduced interferon‐regulated gene expression upon bacterial lipopolysaccharide stimulation. Thus 12,13‐diHOME reprograms macrophage effector function, B‐cell interactions and promotes epigenetic modifications that exacerbate inflammatory response to allergens and mutes antimicrobial response along the interferon axis. These observations offer plausible mechanisms by which this lipid promotes early‐life pathogenic microbiome development and innate immune dysfunction associated with childhood allergic sensitization. [ABSTRACT FROM AUTHOR]

Laparoscopic sleeve gastrectomy (LSG), the most common bariatric surgical procedure, leads to durable weight loss and improves obesity-related comorbidities. However, it induces abnormalities in bone metabolism. One unexplored potential contributor is the gut microbiome, which influences bone metabolism and is altered after surgery. We characterized the relationship between the gut microbiome and skeletal health in severe obesity and after LSG. In a prospective cohort study, 23 adults with severe obesity underwent skeletal health assessment and stool collection preoperatively and 6 mo after LSG. Gut microbial diversity and composition were characterized using 16S rRNA gene sequencing, and fecal concentrations of short-chain fatty acids (SCFA) were measured with LC-MS/MS. Spearman's correlations and PERMANOVA analyses were applied to assess relationships between the gut microbiome and bone health measures including serum bone turnover markers (C-terminal telopeptide of type 1 collagen [CTx] and procollagen type 1 N-terminal propeptide [P1NP]), areal BMD, intestinal calcium absorption, and calciotropic hormones. Six months after LSG, CTx and P1NP increased (by median 188% and 61%, P  < .01) and femoral neck BMD decreased (mean −3.3%, P  < .01). Concurrently, there was a decrease in relative abundance of the phylum Firmicutes. Although there were no change in overall microbial diversity or fecal SCFA concentrations after LSG, those with greater within-subject change in gut community microbial composition (β-diversity) postoperatively had greater increases in P1NP level (ρ = 0.48, P  = .02) and greater bone loss at the femoral neck (ρ = −0.43, P  = .04). In addition, within-participant shifts in microbial richness/evenness (α-diversity) were associated with changes in IGF-1 levels (ρ = 0.56, P  < .01). The lower the postoperative fecal butyrate concentration, the lower the IGF-1 level (ρ = 0.43, P  = .04). Meanwhile, the larger the decrease in butyrate concentration, the higher the postoperative CTx (ρ = −0.43, P  = .04). These findings suggest that LSG-induced gut microbiome alteration may influence skeletal outcomes postoperatively, and microbial influences on butyrate formation and IGF-1 are possible mechanisms. [ABSTRACT FROM AUTHOR]

Author(s): Kei E Fujimura [1]; Alexandra R Sitarik [2]; Suzanne Havstad [2]; Din L Lin [1]; Sophia Levan [1]; Douglas Fadrosh [1]; Ariane R Panzer [1]; Brandon LaMere [1]; Elze [...]

Context: The adverse skeletal effects of Roux-en-Y gastric bypass (RYGB) are partly caused by intestinal calcium absorption decline. Prebiotics, such as soluble corn fiber (SCF), augment colonic calcium absorption in healthy individuals. Objective: We tested the effects of SCF on fractional calcium absorption (FCA), biochemical parameters, and the fecal microbiome in a post- RYGB population. Methods: Randomized, double-blind, placebo-controlled trial of 20 postmenopausal women with history of RYGB a mean 5 years prior; a 2-month course of 20 g/day SCF or maltodextrin placebo was taken orally. The main outcome measure was between-group difference in absolute change in FCA (primary outcome) and was measured with a gold standard dual stable isotope method. Other measures included tolerability, adherence, serum calciotropic hormones and bone turnover markers, and fecal microbial composition via 16S rRNA gene sequencing. Results: Mean FCA ± SD at baseline was low at 5.5 ± 5.1%. Comparing SCF to placebo, there was no between-group difference in mean (95% CI) change in FCA (+3.4 [–6.7, +13.6]%), nor in calciotropic hormones or bone turnover markers. The SCF group had a wider variation in FCA change than placebo (SD 13.4% vs 7.0%). Those with greater change in microbial composition following SCF treatment had greater increase in FCA (r² = 0.72, P = 0.05). SCF adherence was high, and gastrointestinal symptoms were similar between groups. Conclusion: No between-group differences were observed in changes in FCA or calciotropic hormones, but wide CIs suggest a variable impact of SCF that may be due to the degree of gut microbiome alteration. Daily SCF consumption was well tolerated. Larger and longer-term studies are warranted. [ABSTRACT FROM AUTHOR]

Summary: Empagliflozin (EMPA) is a promising novel antidiabetic drug; however, doubts have been raised regarding its use and the increased risk of urinary bladder carcinoma. In this study, we evaluated urothelium expression of cytokeratins (CKs) and Ki‐67 proliferative activity in the urinary bladder of diabetic (DM + EMPA) and non‐diabetic rats after EMPA administration. By routine histology, dysplastic changes were detected in the urothelium of diabetic as well as non‐diabetic animals after EMPA administration. Moreover, the expression of CK‐7 and CK‐8 was significantly decreased (P <.05) while that of CK‐20 as well as Ki‐67 was significantly increased (P <.05) in EMPA per se and DM + EMPA urothelium groups compared to that of control and diabetics. The dysplastic changes together with the increased proliferative activity in urothelium after EMPA administration provide a cellular evidence that supports the former clinical concerns. [ABSTRACT FROM AUTHOR]

Gut microbiota dysbiosis and metabolic dysfunction in infancy precedes childhood atopy and asthma development. Here we examined gut microbiota maturation over the first year of life in infants at high risk for asthma (HR), and whether it is modifiable by early-life Lactobacillus supplementation. We performed a longitudinal comparison of stool samples collected from HR infants randomized to daily oral Lactobacillus rhamnosus GG (HRLGG) or placebo (HRP) for 6 months, and healthy (HC) infants. Meconium microbiota of HRP participants is distinct, follows a delayed developmental trajectory, and is primarily glycolytic and depleted of a range of anti-inflammatory lipids at 6 months of age. These deficits are partly rescued in HRLGG infants, but this effect was lost at 12 months of age, 6 months after cessation of supplementation. Thus we show that early-life gut microbial development is distinct, but plastic, in HR infants. Our findings offer a novel strategy for early-life preventative interventions. [ABSTRACT FROM AUTHOR]

Rationale: The potential role of the airway microbiota in dictating immune responses and infection outcomes in HIV-associated pneumonia is largely unknown.Objectives: To investigate whether microbiologically and immunologically distinct subsets of patients with HIV and pneumonia exist and are related to mortality.Methods: Bronchoalveolar lavage samples from Ugandan patients with HIV and pneumonia (n = 182) were obtained at study enrollment (following antibiotic treatment); patient demographics including 8- and 70-day mortality were collected. Lower airway bacterial community composition was assessed via amplification and sequencing of the V4 region of the 16S ribosomal RNA gene. Host immune response gene expression profiles were generated by quantitative polymerase chain reaction using RNA extracted from bronchoalveolar lavage fluid. Liquid and gas chromatography mass spectrometry was used to profile serum metabolites.Measurements and Main Results: Based on airway microbiome composition, most patients segregated into three distinct groups, each of which were predicted to encode metagenomes capable of producing metabolites characteristically enriched in paired serum samples from these patients. These three groups also exhibited differences in mortality; those with the highest rate had increased ceftriaxone administration and culturable Aspergillus, and demonstrated significantly increased induction of airway T-helper cell type 2 responses. The group with the lowest mortality was characterized by increased expression of T-cell immunoglobulin and mucin domain 3, which down-regulates T-helper cell type 1 proinflammatory responses and is associated with chronic viral infection.Conclusions: These data provide evidence that compositionally and structurally distinct lower airway microbiomes are associated with discrete local host immune responses, peripheral metabolic reprogramming, and different rates of mortality. [ABSTRACT FROM AUTHOR]

Objective: To investigate changes occurring in the morphometric parameters of chorionic villi and their vessels as well as in adhesive molecules expression in placenta of ART pregnancies.Methods: Case-control study including a total of 52 placentas of non-complicated pregnancies of women delivered by spontaneous conception (SC) (n = 26) compared with those of ART (n = 26). Histological and morphometric assessment of fetal chorionic villi as well as the expression of various adhesive molecules (ICAM-1, VCAM-1 and PECAM-1) were performed in fetal plasma and placenta.Results: Although we did not observe any obvious changes in the histological structure of placenta of ART pregnancies, it showed a significant (p < 0.05) decrease in the syncytiotrophoblast cytoplasmic area accompanied with a significant increase (p < 0.05) in the vessel area and syncytiotrophoblast nuclear area without remarkable change in the total villous area or total syncytiotrophoblast % area. In addition, almost all levels of the assayed adhesive molecules were significantly increased (p < 0.05) in placenta as well as in fetal plasma of ART pregnancies compared with SC.Conclusion: We suggested in the current study that the altered adhesive molecules expression accompanying the increased vessel area and decreased syncytial cytoplasm area may indicate a subclinical endothelial stress in placenta of non-complicated ART pregnancies. [ABSTRACT FROM AUTHOR]

Hydroxychloroquine (HCQ) has been demonstrated to reduce the risk to develop diabetes mellitus (DM). However no previous experimental study had investigated its effect on the structure of the endocrine pancreas, islets of Langerhans (IOL), in insulin resistance (IR). In addition, the mechanism by which HCQ can prevent DM is not well understood. In this study, we hypothesized that the possible favorable outcome of HCQ may be partly achieved by its molecular effect on the endothelial stress markers as well as on the imparied balance of the adipokines that usually accompanies IR. A total of 54 rats were divided equally into; control, high fat diet (HFD) and HFD + HCQ groups (received standard chow, HFD and HFD + HCQ respectively). After 12 weeks, samples from pancreas as well as visceral adipose tissue (VAT) were histologically studied for the consequent changes. In the HFD group, there were mild degenerative changes and expansion of the IOL accompanied with a significantly increased (p < 0.05) β-cell area%, mass, proliferation and neogenesis as well as a significantly decreased (p < 0.05) α-cell area% compared with the other groups. On combining HCQ with HFD, reversal of these changes along with correction of the impaired adipokines levels (leptin, adiponectin, resistin, visfatin and lipocalin-2) and significant decrease (p < 0.05) of the vascular endothelial stress markers (sE-selectin, sICAM and sVICAM) were manifested compared with the HFD group. Therefore, HCQ favorable effects in IR may be attributed to relieving of the endothelial stress as well as normalization of the skewed balance of adipokines. [ABSTRACT FROM AUTHOR]

Summary Gut microbes can profoundly modulate mucosal barrier-promoting Th17 cells in mammals. A salient feature of HIV/simian immunodeficiency virus (SIV) immunopathogenesis is the loss of Th17 cells, which has been linked to increased activity of the immunomodulatory enzyme, indoleamine 2,3-dioxygenase 1 (IDO 1). The role of gut microbes in this system remains unknown, and the SIV-infected rhesus macaque provides a well-described model for HIV-associated Th17 loss and mucosal immune disruption. We observed a specific depletion of gut-resident Lactobacillus during acute and chronic SIV infection of rhesus macaques, which was also seen in early HIV-infected humans. This depletion in rhesus macaques correlated with increased IDO1 activity and Th17 loss. Macaques supplemented with a Lactobacillus -containing probiotic exhibited decreased IDO1 activity during chronic SIV infection. We propose that Lactobacillus species inhibit mammalian IDO1 and thus may help to preserve Th17 cells during pathogenic SIV infection, providing support for Lactobacillus species as modulators of mucosal immune homeostasis. [ABSTRACT FROM AUTHOR]

Fungal toxins in nutrition can cause organ dysfunction or even failure. Aflatoxin B 1 (AFB 1 )-induced renal impairment is not sufficiently studied regarding its extent and prevention. The aim of this experiment was to study the effect of AFB 1 on renal cortical tissue and whether its possible harmful effect could be prevented by the conventional economical antioxidant, vitamin E. Forty rats were divided into four groups; I–IV. Group I represented the control while the others received vitamin E (Vit E), AFB 1 and AFB 1 + Vit E, respectively. Renal cortex specimens were taken from each group after 25 days. Then, specimens were prepared for histological study by hematoxlyin and eosin (H&E), Masson's trichrome, caspase-3 as well as for ultrastructural examination and oxidative stress parameters evaluation. Data were morphometrically and statistically analyzed. In AFB 1 -treated group, focal tubulo-interstitial affection in the form of tubular cytoplasmic vacuolation, mitochondrial disruption, numerous lysosomes, marked increase in collagen deposition and in caspase-3 expression were observed. Glomerular impairment in the form of fusion of podocytes enlarged foot processes and thickening of the glomerular basement membrane (GBM) with loss of its trilaminar appearance were detected. In the group treated by AFB 1 + Vit E, there were minimal affection of the histological structure of the renal cortex as well as significant increase in the anti-oxidative parameters which were significantly decreased in the AFB 1 -treated group. Therefore, Vit E could be considered in wide experimental studies to be a first choice antioxidant of high cost-effectiveness in prevention of fungal toxins pro-oxidant-induced renal impairment. [ABSTRACT FROM AUTHOR]

The article focuses on the examination of nonhuman primate responses to infection by simian immunodeficiency virus (SIV). It mentions that fetal rhesus macaques (Macaca mulatta) were injected with the attenuated virus SIVmac1A11 in utero and had significantly reduced plasma RNA viral loads; immunologic and clinical measurements associated with plasma RNA viral load were identified by generalized estimating equations analysis; and impact of Ki-67int cells on viral load.

Inflammatory reactions in the CNS, resulting from a loss of control and involving a network of non-neuronal and neuronal cells, are major contributors to the onset and progress of several major neurodegenerative diseases. Therapeutic strategies should therefore keep or restore the well-controlled and finely-tuned balance of immune reactions, and protect neurons from inflammatory damage. In our study, we selected plants of the Malaysian rain forest by an ethnobotanic approach, and investigated them in cell-based-assay-systems and in living brain tissue cultures in order to identify anti-inflammatory and neuroprotective effects. We found that extracts from the tropical plant Knema laurina (Black wild nutmeg) exhibited highly antiinflammatory and neuroprotective effects in cell culture experiments, reduced NO- and IL-6-release from activated microglia cells dose-dependently, and protects living brain tissue from microglia-mediated inflammatory damage. On the intracellular level, the extract inhibited ERK-1/2-phosphorylation, I-kappaB-phosphorylation and subsequently NF-kappaB-translocation in microglia cells. Knema laurina belongs to the family of Myristicaceae, which have been used for centuries for treatment of digestive and inflammatory diseases and is also a major food plant of the Giant Hornbill. Moreover, extract from Knema laurina promotes also neurogenesis in living brain tissue after oxygen-glucose deprivation. In conclusion, extract from Knema laurina not only controls and limits inflammatory reaction after primary neuronal damage, it promotes moreover neurogenesis if given hours until days after stroke-like injury in levels comparable to the best neurotrophic factors known today. [ABSTRACT FROM AUTHOR]