A feature of maternal sleep apnea during gestation causes autism-relevant neuronal and behavioral phenotypes in offspring.

Mounting epidemiologic and scientific evidence indicates that many psychiatric disorders originate from a complex interplay between genetics and early life experiences, particularly in the womb. Despite decades of research, our understanding of the precise prenatal and perinatal experiences that increase susceptibility to neurodevelopmental disorders remains incomplete. Sleep apnea (SA) is increasingly common during pregnancy and is characterized by recurrent partial or complete cessations in breathing during sleep. SA causes pathological drops in blood oxygen levels (intermittent hypoxia, IH), often hundreds of times each night. Although SA is known to cause adverse pregnancy and neonatal outcomes, the long-term consequences of maternal SA during pregnancy on brain-based behavioral outcomes and associated neuronal functioning in the offspring remain unknown. We developed a rat model of maternal SA during pregnancy by exposing dams to IH, a hallmark feature of SA, during gestational days 10 to 21 and investigated the consequences on the offspring's forebrain synaptic structure, synaptic function, and behavioral phenotypes across multiples stages of development. Our findings represent a rare example of prenatal factors causing sexually dimorphic behavioral phenotypes associated with excessive (rather than reduced) synapse numbers and implicate hyperactivity of the mammalian target of rapamycin (mTOR) pathway in contributing to the behavioral aberrations. These findings have implications for neuropsychiatric disorders typified by superfluous synapse maintenance that are believed to result, at least in part, from largely unknown insults to the maternal environment.

Prevention of enteric bacterial infections and modulation of gut microbiota with conjugated linoleic acids producing Lactobacillus in mice.

Probiotics are recognized for outcompeting pathogenic bacteria by competitive receptor-mediated colonization and secretion of functional metabolites which are antimicrobial against certain microbes as well as improving host's gut health and immunity. Recently, we have constructed a bioactive Lactobacillus casei (LC) strain, LC+mcra , by inserting mcra (myosin cross-reactive antigen) gene, which stimulates the conversion of conjugated linoleic acids. In this study, we evaluated the modulation of gut microbiome and protective roles of LC+mcra against pathogenic Salmonella enterica serovar Typhimurium (ST) and enterohemorrhagic E. coli (EHEC) infections in BALB/cJ mice. We observed that LC+mcra colonized efficiently in mice gut intestine and competitively reduced the infection with ST and EHEC in various locations of small and large intestine, specifically cecum, jejunum, and ileum (p < 0.05). Positive modulation of the cecal microbiota, for example, higher relative abundances of Firmicutes, lower relative abundances of Proteobacteria, and increased bacterial species diversity/richness, was detected in ST-challenged mice pretreated with LC+mcra based on 16S metagenomic sequencing. Cytokine gene expression analysis indicated that mice pretreated with LC+mcra associated with attenuated bacterial pathogen-induced gut inflammation. Furthermore, mice fed daily with LC+mcra for one week could protect themselves from the impairments caused by enteric infections with ST or EHEC. These impairments include weight loss, negative hematological changes, intestinal histological alterations, and potential death. This in vivo study suggests that daily consumption of novel conjugated linoleic acids over-producing probiotic effectively improves intestinal microbiota composition and prevents/combats foodborne enteric bacterial infections with pathogenic Salmonella and diarrheagenic E. coli.

Linoleic Acids Overproducing Lactobacillus casei Limits Growth, Survival, and Virulence of Salmonella Typhimurium and Enterohaemorrhagic Escherichia coli.

Probiotics, particularly lactic acid bacteria, are biologic agents which limit the growth, virulence, and survival/colonization of various enteric bacterial pathogens and serve as potential alternatives to antibiotics. Mechanisms that contribute to this antimicrobial effect include producing bioactive metabolites/acids, increasing nutrient and receptor-mediated competition, and modulating gut microbiome ecology. However, these functions of common probiotic strains are limited due to the finite quantity of metabolites they produce and their total number in the gut ecosystem. Conjugated linoleic acids (CLAs), critical metabolites of Lactobacillus, have multiple beneficial effects on human health including anti-carcinogenesis, anti-inflammation, anti-oxidation, and anti-pathogenicity. In this study, we aim to overexpress the myosin cross-reactive antigen gene (mcra) in Lactobacillus casei (LC) to enhance the production of CLA and investigate its effectiveness against enteric bacterial pathogens, specifically Salmonella enterica serovar Typhimurium (ST) and enterohaemorrhagic Escherichia coli (EHEC). By inserting mcra in L. casei, we generated LC-CLA and found the total linoleic acid production by an individual bacterial cell was raised by 21-fold. The adherence ability of LC-CLA on human epithelial cells increased significantly and LC-CLA competitively excluded both ST and EHEC in a mixed-culture condition. Furthermore, LC-CLA significantly altered the physicochemical properties, biofilm formation abilities, interactions with host cells of both ST and EHEC, and triggered anti-inflammatory activities of host cells. These findings offer insights on applying a genetically engineered probiotic to control gut intestinal infections caused by ST and EHEC and prevent foodborne enteric illness in human.