The increased use of opioids by women of reproductive age has resulted in a dramatic rise in the number of infants exposed to opioids in utero. Although perinatal opioid exposure (POE) has been associated with an elevated risk of infection and hospitalization later in life, the mechanisms by which opioids influence immune development and maturation are not fully elucidated. Alterations in the intestinal microbiota composition, which lead to changes in immune training and maturation, could be at play. Chronic opioid use in adults is associated with a proinflammatory and pathogenic microbiota composition; therefore, we hypothesized here that in utero morphine exposure could negatively affect intestinal microbiota composition, leading to alterations in immune system function. We report that a clinically-relevant model of perinatal opioid exposure, in rats, induces profound intestinal microbiota dysbiosis that is maintained into adulthood. Furthermore, microbial maturity was reduced in morphine-exposed offspring. This suggests that the increased risk of infection observed in children exposed to opioids during gestation may be a consequence of microbiota alterations with a downstream impact on immune system development. Further investigation of how perinatal morphine induces dysbiosis will be critical to the development of early life interventions designed to ameliorate the increased risk of infection observed in these children.

The intestinal microbiota is increasingly recognized as a crucial player in the development and maintenance of various chronic conditions, including obesity and associated metabolic diseases. While most research focuses on the fecal microbiota due to its easier accessibility, the small intestine, as a major site for nutrient sensing and absorption, warrants further investigation to determine its microbiota composition and functions. Here, we conducted a clinical research project in 30 age- and sex-matched participants with (n = 15) and without (n = 15) obesity. Duodenojejunal fluid was obtained by aspiration during endoscopy. Phenotyping included clinical variables related to metabolic status, lifestyle, and psychosocial factors using validated questionnaires. We performed metagenomic analyses of the oral, duodenojejunal, and fecal microbiome, alongside metabolomic data from duodenojejunal fluid and feces, integrating these data with clinical and lifestyle information. Our results highlight significant associations between duodenojejunal microbiota composition and usual dietary intake, as well as clinical phenotypes, with larger effect sizes than the associations between these variables and fecal microbiota. Notably, we found that the duodenojejunal microbiota of patients with obesity exhibited higher diversity and showed distinct differences in the abundance of several duodenojejunal microbiota species compared with individuals without obesity. Our findings support the relevance of studying the role of the small intestinal microbiota in the pathogenesis of nutrition-related diseases.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

ABSTRACTBackground and aimObesity is a major public health issue worldwide. Obesity is associated with chronic inflammation that contribute to long-term complications, including insulin resistance, type 2 diabetes and non-alcoholic fatty liver disease. We hypothesized that obesity may also influence the sensitivity to food contaminants, such as fumonisin B1 (FB1), a mycotoxin produced mainly by theFusarium verticillioides. FB1, a common contaminant of corn, is the most abundant and best characterized member of the fumonisins family. This toxin provokes severe mycotoxicosis in animals, which leads to hepatotoxicity and alterations in the immune response and intestinal barrier permeability. We investigated here whether diet-induced obesity could modulate the sensitivity to oral FB1 exposure, with emphasis on gut health and hepatotoxicity.MethodsThe metabolic effects of FB1 were assessed in obese and non-obese male C57BL/6J mice. For 15 weeks, mice received a high-fat diet (HFD) or normal chow diet (CHOW). During the last three weeks, mice were exposed or not to FB1 (10 mg/kg body weight/day) through drinking water.ResultsAs expected, HFD feeding induced significant body weight gain, glucose intolerance, and hepatic steatosis. FB1-exposed mice displayed a higher sphinganine/sphingosine ratio, a well-known FB1 biomarker of exposure, due to inhibition of ceramide synthases activity by FB1. Combined exposure to HFD and FB1 resulted in body weight loss and a decrease in fasting blood glucose level. This co-exposition also induces gut dysbiosis, an increase in plasma FB1 level, a decrease in liver weight and hepatic steatosis. Moreover, plasma transaminase levels were significantly increased and associated with liver inflammation in HFD/FB1-treated mice. Liver gene expression analysis revealed that the combined exposure to HFD and FB1 was associated with reduced expression of genes involved in lipogenesis and increased expression of immune response and cell cycle-associated genes.ConclusionThese results suggest that, in the context of obesity, FB1 exposure promotes gut dysbiosis and severe liver inflammation. To our knowledge, this study provides the first example of obesity-induced hepatitis in response to a food contaminant.

At birth, mammals experience a massive colonization by microorganisms. We previously reported that newborn mice gestated and born germ-free (GF) have increased microglial labeling and alterations in developmental neuronal cell death in the hippocampus and hypothalamus, as well as greater forebrain volume and body weight when compared to conventionally colonized (CC) mice. To test whether these effects are solely due to differences in postnatal microbial exposure, or instead may be programmed in utero, we cross-fostered GF newborns immediately after birth to CC dams (GF→CC) and compared them to offspring fostered within the same microbiota status (CC→CC, GF→GF). Because key developmental events (including microglial colonization and neuronal cell death) shape the brain during the first postnatal week, we collected brains on postnatal day (P) 7. To track gut bacterial colonization, colonic content was also collected and subjected to 16S rRNA qPCR and Illumina sequencing. In the brains of GF→GF mice, we replicated most of the effects seen previously in GF mice. Interestingly, the GF brain phenotype persisted in GF→CC offspring for almost all measures. In contrast, total bacterial load did not differ between the CC→CC and GF→CC groups on P7, and bacterial community composition was also very similar, with a few exceptions. Thus, GF→CC offspring had altered brain development during at least the first 7 days after birth despite a largely normal microbiota. This suggests that prenatal influences of gestating in an altered microbial environment programs neonatal brain development.

Staphylococcus aureus is a predominant cause of chronic lung infections. While the airway environment is rich in highly sialylated mucins, the interaction of S. aureus with sialic acid is poorly characterized. Using S. aureus USA300 as well as clinical isolates, we demonstrate that quorum-sensing dysfunction, a hallmark of S. aureus adaptation, correlates with a greater ability to consume free sialic acid, providing a growth advantage in an air-liquid interface model and in vivo. Furthermore, RNA-seq experiment reveals that free sialic acid triggers transcriptional reprogramming promoting S. aureus chronic lifestyle. To support the clinical relevance of our results, we show the co-occurrence of S. aureus , sialidase-producing microbiota and free sialic acid in the airway of patients with cystic fibrosis. Our findings suggest a dual role for sialic acid in S. aureus airway infection, triggering virulence reprogramming and driving S. aureus adaptive strategies through the selection of quorum-sensing dysfunctional strains.

The significant increase in food allergy incidence is correlated with dietary changes in modernized countries. Here, we investigated the impact of dietary emulsifiers on food allergy by employing an experimental murine model. Mice were exposed to drinking water containing 1.0% carboxymethylcellulose (CMC) or Polysorbate-80 (P80) for 12 weeks, a treatment that was previously demonstrated to induce significant alterations in microbiota composition and function leading to chronic intestinal inflammation and metabolic abnormalities. Subsequently, the ovalbumin food allergy model was applied and characterized. As a result, we observed that dietary emulsifiers, especially P80, significantly exacerbated food allergy symptoms, with increased OVA-specific IgE induction and accelerated type 2 cytokine expressions, such as IL-4, IL-5, and IL-13, in the colon. Administration of an antibiotic regimen completely reversed the emulsifier-induced exacerbated susceptibility to food allergy, suggesting a critical role played by the intestinal microbiota in food allergy and type 2 immune responses.

Summary: Dietary emulsifiers carboxymethylcellulose (CMC) and polysorbate-80 (P80) disturb gut microbiota, promoting chronic inflammation. Mice with minimal microbiota are protected against emulsifiers’ effects, leading us to hypothesize that these compounds might provoke select pathobionts to promote inflammation. Gnotobiotic wild-type (WT) and interleukin-10 (IL-10)−/− mice were colonized with Crohn’s-disease-associated adherent-invasive E. coli (AIEC) and subsequently administered CMC or P80. AIEC colonization of GF and altered Schaedler flora (ASF) mice results in chronic intestinal inflammation and metabolism dysregulations when consuming the emulsifier. In IL-10−/− mice, AIEC mono-colonization results in severe intestinal inflammation in response to emulsifiers. Exposure of AIEC to emulsifiers in vitro increases its motility and ability to adhere to intestinal epithelial cells. Transcriptomic analysis reveals that emulsifiers directly induce expression of clusters of genes that mediate AIEC virulence and promotion of inflammation. To conclude, emulsifiers promote virulence and encroachment of pathobionts, providing a means by which these compounds may drive inflammation in hosts carrying such bacteria.