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Maternal asthma status, prenatal exposures, and infant gut microbiota perturbation are associated with heightened risk of atopy and asthma risk in childhood, observations hypothetically linked by intergenerational microbial transmission. Using maternal vaginal (n = 184) and paired infant stool (n = 172) samples, we identify four compositionally and functionally distinct Lactobacillus-dominated vaginal microbiota clusters (VCs) that relate to prenatal maternal health and exposures and infant serum immunoglobulin E (IgE) status at 1 year. Variance in bacteria shared between mother and infant pairs relate to VCs, maternal allergy/asthma status, and infant IgE levels. Heritable bacterial gene pathways associated with infant IgE include fatty acid synthesis and histamine and tryptophan degradation. In vitro, vertically transmitted Lactobacillus jensenii strains induce immunosuppressive phenotypes on human antigen-presenting cells. Murine supplementation with L. jensenii reduces lung eosinophils, neutrophilic expansion, and the proportion of interleukin-4 (IL-4)

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.

Background In infants, distinct nasopharyngeal bacterial microbiotas differentially associate with the incidence and severity of acute respiratory tract infection and childhood asthma development. Objective We hypothesized that distinct nasal airway microbiota structures also exist in children with asthma and relate to clinical outcomes. Methods Nasal secretion samples (n = 3122) collected after randomization during the fall season from children with asthma (6-17 years, n = 413) enrolled in a trial of omalizumab (anti-IgE) underwent 16S rRNA profiling. Statistical analyses with exacerbation as the primary outcome and rhinovirus infection and respiratory illnesses as secondary outcomes were performed. Using A549 epithelial cells, we assessed nasal isolates of Moraxella, Staphylococcus, and Corynebacterium species for their capacity to induce epithelial damage and inflammatory responses. Results Six nasal airway microbiota assemblages, each dominated by Moraxella, Staphylococcus, Corynebacterium, Streptococcus, Alloiococcus, or Haemophilus species, were observed. Moraxella and Staphylococcus species–dominated microbiotas were most frequently detected and exhibited temporal stability. Nasal microbiotas dominated by Moraxella species were associated with increased exacerbation risk and eosinophil activation. Staphylococcus or Corynebacterium species–dominated microbiotas were associated with reduced respiratory illness and exacerbation events, whereas Streptococcus species–dominated assemblages increased the risk of rhinovirus infection. Nasal microbiota composition remained relatively stable despite viral infection or exacerbation; only a few taxa belonging to the dominant genera exhibited relative abundance fluctuations during these events. In vitro, Moraxella catarrhalis induced significantly greater epithelial damage and inflammatory cytokine expression (IL-33 and IL-8) compared with other dominant nasal bacterial isolates tested. Conclusion Distinct nasal airway microbiotas of children with asthma relate to the likelihood of exacerbation, rhinovirus infection, and respiratory illnesses during the fall season.

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.

Neonates at risk of childhood atopy and asthma exhibit perturbation of the gut microbiome, metabolic dysfunction and increased concentrations of 12,13-diHOME in their faeces. However, the mechanism, source and contribution of this lipid to allergic inflammation remain unknown. Here, we show that intra-abdominal treatment of mice with 12,13-diHOME increased pulmonary inflammation and decreased the number of regulatory T (Treg) cells in the lungs. Treatment of human dendritic cells with 12,13-diHOME altered expression of PPARγ-regulated genes and reduced anti-inflammatory cytokine secretion and the number of Treg cells in vitro. Shotgun metagenomic sequencing of neonatal faeces indicated that bacterial epoxide hydrolase (EH) genes are more abundant in the gut microbiome of neonates who develop atopy and/or asthma during childhood. Three of these bacterial EH genes (3EH) specifically produce 12,13-diHOME, and treatment of mice with bacterial strains expressing 3EH caused a decrease in the number of lung Treg cells in an allergen challenge model. In two small birth cohorts, an increase in the copy number of 3EH or the concentration of 12,13-diHOME in the faeces of neonates was found to be associated with an increased probability of developing atopy, eczema or asthma during childhood. Our data indicate that elevated 12,13-diHOME concentrations impede immune tolerance and may be produced by bacterial EHs in the neonatal gut, offering a mechanistic link between perturbation of the gut microbiome during early life and atopy and asthma during childhood.

Research on the neonatal microbiome has been performed mostly on hospital-born infants, who often undergo multiple birth-related interventions. Both the hospital environment and interventions around the time of birth may affect the neonate microbiome. In this study, we determine the structure of the microbiota in feces from babies born in the hospital or at home, and from vaginal samples of their mothers. We included 35 vaginally-born, breast-fed neonates, 14 of whom delivered at home (4 in water), and 21 who delivered in the hospital. Feces from babies and mothers and maternal vaginal swab samples were collected at enrollment, the day of birth, followed by days 1, 2, 7, 14, 21, and 28. At the time of birth, the diversity of the vaginal microbiota of mothers delivering in the hospital was lower than in mothers delivering at home, and showed higher proportion of Lactobacillus. Among 20 infants not exposed to perinatal maternal antibiotics or water birth, fecal beta diversity differed significantly by birth site, with hospital-born infants having lower Bacteroides, Bifidobacterium, Streptococcus, and Lactobacillus, and higher Clostridium and Enterobacteriaceae family (LDA > 3.0), than babies born at home. At 1 month of age, feces from infants born in the hospital also induced greater pro-inflammatory gene expression (TLR4, IL-8, occludin and TGFβ) in human colon epithelial HT-29 cells. The results of this work suggest that hospitalization (perinatal interventions or the hospital environment) may affect the microbiota of the vaginal source and the initial colonization during labor and birth, with effects that could persist in the intestinal microbiota of infants 1 month after birth. More research is needed to determine specific factors that alter bacterial transmission between mother and baby and the long-term health implications of these differences for the developing infant.

RationaleThe potential role of the airway microbiota in dictating immune responses and infection outcomes in HIV-associated pneumonia is largely unknown.ObjectivesTo investigate whether microbiologically and immunologically distinct subsets of patients with HIV and pneumonia exist and are related to mortality.MethodsBronchoalveolar 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 resultsBased 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.ConclusionsThese 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.

HIV disease progression appears to be driven by increased immune activation. Given observations that fetal exposure to infectious pathogens in utero can result in reduced immune responses, or tolerance, to those pathogens postnatally, we hypothesized that fetal exposure to HIV may render the fetus tolerant to the virus, thus reducing damage caused by immune activation during infection later in life. To test this hypothesis, fetal rhesus macaques (Macaca mulatta) were injected with the attenuated virus SIVmac1A11 in utero and challenged with pathogenic SIVmac239 1 year after birth. SIVmac1A11-injected animals had significantly reduced plasma RNA viral loads (P < 0.02) up to 35 weeks after infection. Generalized estimating equations analysis was performed to identify immunologic and clinical measurements associated with plasma RNA viral load. A positive association with plasma RNA viral load was observed with the proportion of CD8(+) T cells expressing the transcription factor, FoxP3, and the proportion of CD4(+) T cells producing the lymphoproliferative cytokine, IL-2. In contrast, an inverse relationship was found with the frequencies of circulating CD4(+) and CD8(+) T cells displaying intermediate expression of the proliferation marker, Ki-67. Animals exposed to simian immunodeficiency virus (SIV) in utero appeared to have enhanced SIV-specific immune responses, a lower proportion of CD8(+) T cells expressing the exhaustion marker PD-1, and more circulating TH17 cells than controls. Although the development of tolerance was not demonstrated, these data suggest that rhesus monkeys exposed to SIVmac1A11 in utero had distinct immune responses associated with the control of viral replication after postnatal challenge.

SummaryGut 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.

Background. Interferon α (IFN-α) and ribavirin can induce a sustained virologic response (SVR) in some but not all hepatitis C virus (HCV)-infected patients. The mechanism of effective treatment is unclear. One possibility is that IFN-α differentially improves the functional capacity of classic myeloid dendritic cells (mDCs) by altering expression of surface molecules or cytokines. Others have proposed that antigen-presenting cell activation could be paradoxically detrimental during HCV infection because of the production by monocytes of substances inhibitory or toxic to plasmacytoid dendritic cells. Methods. We examined responses to in vitro IFN-α treatment of peripheral blood leukocyte samples from a retrospective treatment cohort of nearly 200 HCV-seropositive patients who had undergone antiviral therapy with ribavirin and pegylated IFN.We analyzed the variable responses of antigen-presenting cell subsets to drug. Results. We found that patients achieving SVR were no more likely to have robust mDC activation in response to IFN-α than those who did not achieve SVR. Rather, patients achieving SVR were distinguished by restrained monocyte activation in the presence of IFN-α, a factor that was second in importance only to IL28B genotype in its association with SVR. Conclusions. These results suggest that interindividual variability in the response of monocytes to IFN-α is an important determinant of treatment success with IFN-α-based regimens. © 2013 The Author.