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Antibiotic use in neonates can have detrimental effects on the developing gut microbiome, increasing the risk of morbidity. A majority of preterm neonates receive antibiotics after birth without clear evidence to guide this practice. Here microbiome, metabolomic, and immune marker results from the routine early antibiotic use in symptomatic preterm Neonates (REASON) study are presented. The REASON study is the first trial to randomize symptomatic preterm neonates to receive or not receive antibiotics in the first 48 h after birth. Using 16S rRNA sequencing of stool samples collected longitudinally for 91 neonates, the effect of such antibiotic use on microbiome diversity is assessed. The results illustrate that type of nutrition shapes the early infant gut microbiome. By integrating data for the gut microbiome, stool metabolites, stool immune markers, and inferred metabolic pathways, an association was discovered between Veillonella and the neurotransmitter gamma-aminobutyric acid (GABA). These results suggest early antibiotic use may impact the gut-brain axis with the potential for consequences in early life development, a finding that needs to be validated in a larger cohort. Trial Registration This project is registered at clinicaltrials.gov under the name “Antibiotic ‘Dysbiosis’ in Preterm Infants” with trial number NCT02784821.

Abstract Rationale The principal underlying inhaled antibiotic treatment in bronchiectasis is that airway bacterial load drives inflammation, and therefore antibiotic treatment will reduce symptoms. Objectives To determine the relationship between bacterial load and clinical outcomes, assess the stability of bacterial load over time, and test the hypothesis that response to inhaled antibiotics would be predicted by baseline bacterial load. Methods We performed three studies. Studies 1 and 2 were prospective studies including adults with bronchiectasis. Study 3 was a post hoc analysis of a randomized trial of inhaled aztreonam. A priori patients were divided into low (<105 cfu/g), moderate (105–106 cfu/g), and high bacterial load (≥107 cfu/g) using quantitative sputum culture. Measurements and Main Results Bacterial load was a stable trait associated with worse quality of life and more airway inflammation in studies 1, 2, and 3. In study 3, patients with high bacterial load showed an improvement in the primary endpoint (Quality of Life–Bronchiectasis–Respiratory Symptoms Score at Week 4) in favor of aztreonam (mean difference of 9.7 points; 95% confidence interval, 3.4–16.0; P = 0.003). The proportion of patients who achieved an increase above the minimum clinically important difference was higher in the aztreonam group at Week 4 (63% vs. 37%; P = 0.01) and at Week 12 (62% vs. 38%; P = 0.01) only in high bacterial load patients. Conclusions Improvement of quality of life with inhaled aztreonam was only evident in patients with high bacterial load. Bacterial load may be a useful biomarker of severity of disease and treatment response.

Autism spectrum disorder (ASD) is a neurological and developmental condition that begins in infancy or earlier and lasts through the individual's lifetime. The aetiology and mechanisms of ASD are not yet fully understood, and current treatment comprises mainly education and rehabilitation, without significant improvement in the core symptoms. Recent studies suggest that microbiota change in children with ASD after the ingestion of probiotics may improve the balance of microbiota and thus ASD symptoms. The objectives of this study are to evaluate the efficacy of probiotics on the symptoms of children with ASD and the possible mechanisms involved. This is a prospective controlled trial. A total of 160 children with ASD will be stratified and allocated to placebo and probiotics groups randomised according to the severity of their ASD symptoms. The probiotics group will be given probiotics supplements orally twice a day for 3 months and the control group will be given a placebo at the same amount, in addition to the baseline therapy of education and rehabilitation. All the children will be evaluated systematically by using different scales, questionnaires before, during, and after 3 months' treatment, as well as 3 months after discontinuation. The potential impact of probiotics on immunity and inflammation, metabolism, and metagenome will also be investigated. Our previous study showed that the abundance of intestinal flora was greatly different in children with ASD, and that Bifidobacterium was associated with the severity of ASD. In the present study, we will investigate the impact of probiotics supplementation on the symptoms of Children with ASD, with the purpose of evaluating the possible therapeutic effects of additives on ASD and of providing a reference for clinical treatment. The results will help to disclose as yet unknown relationship between probiotics and ASD. This study has been registered with Chinese Clinical Trial Registry (ChiCTR-2000037941).

Background. Tuberculous meningitis (TBM) is the most devastating form of tuberculosis, yet very little is known about the pathophysiology. We hypothesized that the genotype of leukotriene A₄ hydrolase (encode by LTA4H), which determines inflammatory eicosanoid expression, influences intracerebral inflammation, and predicts survival from TBM. Methods. We characterized the pretreatment clinical and intracerebral inflammatory phenotype and 9-month survival of 764 adults with TBM. All were genotyped for single-nucleotide polymorphism rs17525495, and inflammatory phenotype was defined by cerebrospinal fluid (CSF) leukocyte and cytokine concentrations. Results. LTA4H genotype predicted survival of human immunodeficiency virus (HIV)=uninfected patients, with TT-genotype patients significantly more likely to survive TBM than CC-genotype patients, according to Cox regression analysis (univariate P = .040 and multivariable P = .037). HIV-uninfected, TT-genotype patients had high CSF proinflammatory cytokine concentrations, with intermediate and lower concentrations in those with CT and CC genotypes. Increased CSF cytokine concentrations correlated with more-severe disease, but patients with low CSF leukocytes and cytokine concentrations were more likely to die from TBM, HIV infection independently predicted death due to TBM (hazard ratio, 3.94; 95% confidence interval, 2.79-5.56) and was associated with globally increased CSF cytokine concentrations, independent of LTA4H genotype. Conclusions. LTA4H genotype and HIV infection influence pretreatment inflammatory phenotype and survival from TBM. LTA4H genotype may predict adjunctive corticosteroid responsiveness in HIV-uninfected individuals.

Background. Damaging inflammation is thought to contribute to the high morbidity and mortality of tuberculous meningitis (TBM), but the link between inflammation and outcome remains unclear. Methods. We performed prospective clinical and routine laboratory analyses of a cohort of adult patients with TBM in Indonesia. We also examined the LTA4H promoter polymorphism, which predicted cerebrospinal fluid (CSF) leukocyte count and survival of Vietnamese patients with TBM. Patients were followed for >1 year. Results. We included 608 patients with TBM, of whom 67.1% had bacteriological confirmation of disease and 88.2% had severe (ie, grade II or III) disease. One-year mortality was 43.7% and strongly associated with decreased consciousness, fever, and focal neurological signs. Human immunodeficiency virus (HIV) infection, present in 15.3% of patients, was associated with higher mortality and different CSF characteristics, compared with absence of HIV infection. Among HIV-uninfected patients, mortality was associated with higher CSF neutrophil counts (hazard ratio [HR], 1.10 per 10% increase; 95% confidence interval [CI], 1.04-1.16), low CSF to blood glucose ratio (HR, 1.16 per 01.0 decrease; 95% CI, 1.04–1.30), CSF culture positivity (HR, 1.37; 95% CI, 1.02–1.84), and blood neutrophilia (HR, 1.06 per 10⁹ neutrophils/L increase; 95% CI, 1.03–1.10). The LTA4H promoter polymorphism correlated with CSF mononuclear cell count but not with mortality (P = .915). Conclusions. A strong neutrophil response and fever may contribute to or be a result of (immuno) pathology in TBM. Aggressive fever control might improve outcome, and more-precise characterization of CSF leukocytes could guide possibel host-directed therapeutic strategies in TBM.

Periodontitis is a prevalent chronic inflammatory disease due to the host response (IL-1β, IL-6, TNF-α and IL-17A) to oral bacteria such as Porphyromonas gingivalis . The newer members of the IL-1 family, IL-36s (IL-36α/IL-36β/IL-36γ/IL-36Ra/IL-38) are known to be involved in host defense against P. gingivalis in oral epithelial cells (OECs) and are considered as key inflammatory mediators in chronic diseases. The aim of this study was to investigate the potential role of IL-36s in periodontitis. We showed here that IL-36γ mRNA gingival expression is higher in periodontitis patients, whereas IL-36β and IL-36Ra mRNA expression are lower compared to healthy controls. Interestingly, the elevated IL-36γ expression in patients is positively correlated with the RANKL / OPG ratio, an index of bone resorption. In vitro, IL-36γ expression was induced through TLR2 activation in primary OECs infected with P. gingivalis but not in gingival fibroblasts, the most widespread cell type in gingival connective tissue. In OECs, recombinant IL-36γ enhanced the expression of inflammatory cytokines ( IL-1β , IL-6, TNF-α and IL-36γ ), of TLR2 and importantly, the RANKL / OPG ratio. These findings suggest that IL-36γ could be a pivotal inflammatory player in periodontitis by perpetuating gingival inflammation and its associated alveolar bone resorption and could be a relevant therapeutic target.

Background: In healthy adults, probiotic supplementation alone does not increase Urolithin A (UroA) and rarely increases butyrate, both microbiome-derived metabolites that influence key biological functions involved in regulating gastrointestinal symptoms. Accordingly, this clinical trial evaluated key biological functions of a multi-species synbiotic with 24 probiotic strains and a polyphenol-based prebiotic using capsule-in-capsule delivery technology. Methods: We conducted a randomized, placebo-controlled trial among healthy participants (n = 32). Participants were administered a daily synbiotic (53.6 billion AFU multi-species probiotic and 400 mg Indian pomegranate extract; DS-01) or matching placebo for 91 days. Samples were obtained at baseline Day 0, and Days 7, 14, 49, and 91. Endpoints included changes in fecal microbiome composition, urinary UroA, fecal butyrate, serum CRP, and safety. Results: The synbiotic significantly increased alpha-diversity of Bifidobacterium and Lactobacillus spp. at all timepoints, including at end-of-study (Day 91, p < 0.0001) and increased native beneficial microbes. UroA production was significantly increased in the synbiotic arm at short-term (Day 7, 12-fold, p < 0.02) and long-term (Day 91, 49-fold, p < 0.001) timepoints. A higher proportion of synbiotic participants were capable of converting polyphenols into UroA (Day 91, 100% vs. 44.4%; p < 0.01). Mechanistically, synbiotic participants showed an increased abundance of Lactobacillus species involved in UroA precursor metabolism and UroA-producing Gordonibacter species. The synbiotic also significantly increased fecal butyrate levels (p < 0.03), and butyrate-producing species, in low-baseline butyrate producers, through Day 91, and was associated with reduced systemic inflammation. Conclusions: This multi-species synbiotic significantly increases diversity and abundance of key beneficial bacteria, enhances UroA production and butyrate levels, and is associated with lowered systemic inflammation. This is the first synbiotic to increase both UroA and butyrate.

Mutations in the nucleotide-binding oligomerization domain protein 12 (NLRP12) cause recurrent episodes of serosal inflammation. Here we show that NLRP12 efficiently sequesters HSP90 and promotes K48-linked ubiquitination and degradation of NOD2 in response to bacterial muramyl dipeptide (MDP). This interaction is mediated by the linker-region proximal to the nucleotide-binding domain of NLRP12. Consequently, the disease-causing NLRP12 R284X mutation fails to repress MDP-induced NF-κB and subsequent activity of the JAK/STAT signaling pathway. While NLRP12 deficiency renders septic mice highly susceptible towards MDP, a sustained sensing of MDP through NOD2 is observed among monocytes lacking NLRP12. This loss of tolerance in monocytes results in greater colonization resistance towards Citrobacter rodentium . Our data show that this is a consequence of NOD2-dependent accumulation of inflammatory mononuclear cells that correlates with induction of interferon-stimulated genes. Our study unveils a relevant process of tolerance towards the gut microbiota that is exploited by an attaching/effacing enteric pathogen. Mutations in nucleotide-binding oligomerization domain protein 12 (NLRP12) are known to effect inflammatory processes. Here the authors show that NLRP12-mediated proteasomal degradation of NOD2 in monocytes promotes bacterial tolerance and colonisation in a model of enteric infection.

Infant colic is a distressing condition of unknown etiology. An aberrant gastrointestinal microbiota has been associated, and Lactobacillus reuteri supplementation has been shown to reduce crying and/or fussing time (‘crying time’) in some infants with colic. The relationship between L . reuteri gut colonization and crying time has not been examined. We investigated the relationship between L . reuteri colonization and fecal microbiota (microbial diversity and Escherichia coli ), intestinal inflammation, and crying time in infants with colic, using a subset of 65 infants from the Baby Biotics trial, which randomized healthy term infants aged <13 weeks with infant colic to receive probiotic L . reuteri DSM 17938 (1 × 10 8 colony forming units) or placebo daily for 28 days. We observed an overall reduction in median crying time, regardless of L . reuteri colonization status (n = 14 colonized). There were no differences in E . coli colonization rates or densities, microbial diversity or intestinal inflammation by L . reuteri colonization status. We found that L . reuteri density positively correlated with crying time, and E . coli density negatively correlated with microbial diversity. As density of L . reuteri was associated with increased crying time, L . reuteri supplementation may not be an appropriate treatment for all infants with colic.

Myeloproliferative neoplasms (MPNs) are a class of rare hematological malignancies that result in the overproduction of myeloid lineage cells. These malignancies result in increased cytokine production and inflammation, which correlate with worsened symptom burden and prognosis. Other than bone marrow transplantation, there is no cure for myeloproliferative neoplasms. As such, treatments focus on reducing thrombotic risk, inflammation, and symptom burden. Because current pharmacological treatments carry significant side effects, there is a need to explore low-risk therapies that may modulate inflammation and alleviate symptom burden. One potential way to achieve this is adherence to a Mediterranean (MED) diet, which is rich in anti-inflammatory foods, reduces inflammatory biomarkers, and beneficially alters the gut microbiome. We performed a 15-week clinical trial of 28 individuals with MPN who were randomized to dietary counseling based on either a Mediterranean diet or standard U.S. Guidelines for Americans. Our primary objective was to determine whether MPN patients could adopt a Mediterranean eating pattern when supported with dietician counseling. As exploratory endpoints, we investigated the impact of diet and inflammation on the gut microbiome. Using shotgun metagenomic sequencing, we found that microbiome diversity and composition were stable throughout the study duration in both cohorts. Furthermore, we discovered significant differences in the microbiomes between MPN subtypes, such as increased beta-dispersion in subjects with myelofibrosis. Lastly, we found several significant correlations between the abundance of multiple bacterial taxa and cytokine levels. Together, this study provides insight into the interaction between diet, inflammation, and the gut microbiome. The gut microbiome serves as an interface between the host and the diet. Diet and the gut microbiome both play important roles in managing inflammation, which is a key aspect of myeloproliferative neoplasm (MPN). Studies have shown that a Mediterranean (MED) diet can reduce inflammation. Therefore, we longitudinally characterized the gut microbiomes of MPN patients in response to Mediterranean or standard 2020 US Guidelines for Americans dietary counseling to determine whether there were microbiome-associated changes in inflammation. We did not find significant changes in the gut microbiome associated with diet, but we did find several associations with inflammation. This research paves the way for future studies by identifying potential mechanistic targets implicated in inflammation within the MPN gut microbiome.