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Contains fulltext : 235749.pdf (Publisher’s version ) (Open Access) Exposure to antibiotic treatment has been associated with increased vulnerability to various psychiatric disorders. However, a research gap exists in understanding how adolescent antibiotic therapy affects behavior and cognition. Many antibiotics that target bacterial translation may also affect mitochondrial translation resulting in impaired mitochondrial function. The brain is one of the most metabolically active organs, and hence is the most vulnerable to impaired mitochondrial function. We hypothesized that exposure to antibiotics during early adolescence would directly affect brain mitochondrial function, and result in altered behavior and cognition. We administered amoxicillin, chloramphenicol, or gentamicin in the drinking water to young adolescent male wild-type mice. Next, we assayed mitochondrial oxidative phosphorylation complex activities in the cerebral cortex, performed behavioral screening and targeted mass spectrometry-based acylcarnitine profiling in the cerebral cortex. We found that mice exposed to chloramphenicol showed increased repetitive and compulsive-like behavior in the marble burying test, an accurate and sensitive assay of anxiety, concomitant with decreased mitochondrial complex IV activity. Our results suggest that only adolescent chloramphenicol exposure leads to impaired brain mitochondrial complex IV function, and could therefore be a candidate driver event for increased anxiety-like and repetitive, compulsive-like behaviors.

Contains fulltext : 196136.pdf (Publisher’s version ) (Closed access) The human intestinal microbiota, comprising trillions of microorganisms, exerts a substantial effect on the host. The microbiota plays essential roles in the function and development of several physiological processes, including those in the brain. A disruption in the microbial composition of the gut has been associated with many metabolic, inflammatory, neurodevelopmental, and neurodegenerative disorders. Nutrition is one of several key factors that shape the microbial composition during infancy and throughout life, thereby affecting brain structure and function. This review examines the effect of the gut microbiota on brain function. The ability of external factors, such as diet, to influence the microbial composition implies a certain vulnerability of the gut microbiota. However, it also offers a potential therapeutic strategy for ameliorating symptoms of mental and physical disorders. Therefore, this review examines the potential effect of nutritional components on gut microbial composition and brain function.

BackgroundThe impact of the gut microbiota on host physiology and behavior has been relatively well established. Whether changes in microbial composition affect brain structure and function is largely elusive, however. This is important as altered brain structure and function have been implicated in various neurodevelopmental disorders, like attention-deficit/hyperactivity disorder (ADHD). We hypothesized that gut microbiota of persons with and without ADHD, when transplanted into mice, would differentially modify brain function and/or structure. We investigated this by colonizing young, male, germ-free C57BL/6JOlaHsd mice with microbiota from individuals with and without ADHD. We generated and analyzed microbiome data, assessed brain structure and function bymagnetic resonance imaging(MRI), and studied mouse behavior in a behavioral test battery.ResultsPrincipal coordinate analysis showed a clear separation of fecal microbiota of mice colonized with ADHD and control microbiota. With diffusion tensor imaging, we observed a decreased structural integrity of both white and gray matter regions (i.e., internal capsule, hippocampus) in mice that were colonized with ADHD microbiota. We also found significant correlations between white matter integrity and the differentially expressed microbiota. Mice colonized with ADHD microbiota additionally showed decreased resting-state functional MRI-based connectivity between right motor and right visual cortices. These regions, as well as the hippocampus and internal capsule, have previously been reported to be altered in several neurodevelopmental disorders. Furthermore, we also show that mice colonized with ADHD microbiota were more anxious in the open-field test.ConclusionsTaken together, we demonstrate that altered microbial composition could be a driver of altered brain structure and function and concomitant changes in the animals’ behavior. These findings may help to understand the mechanisms through which the gut microbiota contributes to the pathobiology of neurodevelopmental disorders.

Introduction:There is an increasing interest to elucidate the health effects of short-chain fatty acids (SCFAs) on metabolism, obesity and brain function. Obesity is often associated with the development of non-alcoholic steatohepatitis (NASH) and cognitive impairment. We herein investigated potential health effects of the SCFA propionic acid (PA) on NASH development and brain function including cognition and behavior readouts.Materials and Methods:During 17 weeks of run-in, LDLR-/-.Leiden mice received either high-fat diet (HFD) to establish obesity or chow as control. Obese mice were matched into groups (n = 15/group) and treated with propionic acid (PA + HFD), or a reference fatty acid (caproic acid; CA + HFD), or HFD without supplements (HFD). Cognitive and behavioral effects, as well as metabolic and inflammatory risk factors, were assessed prior to and after 12 weeks of treatment. At endpoint, liver and adipose tissue pathology were histologically and biochemically analyzed.Results:PA, but not reference CA, reduced body weight and this effect was independent of food intake. PA also reduced fasting insulin levels and plasma cholesterol levels relative to the start of intervention. In addition, PA reduced total and subcutaneous fat mass, but did not affect WAT inflammation. Histopathological analysis of the liver demonstrated that PA reduced macrovesicular steatosis, hypertrophy and inflammation. Consistent herewith, PA reduced the inflammatory marker serum amyloid A and tended to increase intrahepatic ketone bodies (β-hydroxybutyrate), and lowered the hepatic collagen content. PA treatment did not affect normal behavior in the open field test but mice showed impaired spatial memory, i.e. the latency to find the platform in the Morris water maze was increased. In line with these findings, synaptophysin expression in the hippocampus and vasoactivity in both the cortex and hippocampus and mitochondrial activity in the cerebellum was decreased by PA. The reference fatty acid CA exerted no effects on the above readouts.Discussion:Overall, PA exerted pronounced positive effects on metabolic risk factors (insulin, cholesterol, adipose mass) and attenuated the development of NASH and liver fibrosis. The observed higher levels of intrahepatic ketone bodies suggest that lipid β-oxidation is increased which may contribute to the health effects in the liver and reduced fat mass. Contrarily, PA negatively affected spatial memory, which could be a result of reduced synaptophysin expression and decreased mitochondrial function in the brain leading to impaired neurotransmitter signaling and cognitive performance.

The obesity epidemic increases the interest to elucidate impact of short‐chain fatty acids on metabolism, obesity, and the brain. We investigated the effects of propionic acid (PA) and caproic acid (CA) on metabolic risk factors, liver and adipose tissue pathology, brain function, structure (by MRI), and gene expression, during obesity development in Ldlr−/−.Leiden mice. Ldlr−/−.Leiden mice received 16 weeks either a high‐fat diet (HFD) to induce obesity, or chow as reference group. Next, obese HFD‐fed mice were treated 12 weeks with (a) HFD + CA (CA), (b) HFD + PA (PA), or (c) a HFD‐control group. PA reduced the body weight and systolic blood pressure, lowered fasting insulin levels, and reduced HFD‐induced liver macrovesicular steatosis, hypertrophy, inflammation, and collagen content. PA increased the amount of glucose transporter type 1‐positive cerebral blood vessels, reverted cerebral vasoreactivity, and HFD‐induced effects in microstructural gray and white matter integrity of optic tract, and somatosensory and visual cortex. PA and CA also reverted HFD‐induced effects in functional connectivity between visual and auditory cortex. However, PA mice were more anxious in open field, and showed reduced activity of synaptogenesis and glutamate regulators in hippocampus. Therefore, PA treatment should be used with caution even though positive metabolic, (cerebro) vascular, and brain structural and functional effects were observed.The obesity epidemic increases the interest to elucidate impact of short‐chain fatty acids on metabolism, obesity, and the brain. We investigated the effects of propionic acid (PA) and caproic acid (CA) on metabolic risk factors, liver and adipose tissue pathology, brain function, structure (by MRI), and gene expression, during obesity development in Ldlr−/−.Leiden mice. Ldlr−/−.Leiden mice received 16 weeks either a high‐fat diet (HFD) to induce obesity, or chow as reference group. Next, obese HFD‐fed mice were treated 12 weeks with (a) HFD + CA (CA), (b) HFD + PA (PA), or (c) a HFD‐control group. PA reduced the body weight and systolic blood pressure, lowered fasting insulin levels, and reduced HFD‐induced liver macrovesicular steatosis, hypertrophy, inflammation, and collagen content. PA increased the amount of glucose transporter type 1‐positive cerebral blood vessels, reverted cerebral vasoreactivity, and HFD‐induced effects in microstructural gray and white matter integrity of optic tract, and somatosensory and visual cortex. PA and CA also reverted HFD‐induced effects in functional connectivity between visual and auditory cortex. However, PA mice were more anxious in open field, and showed reduced activity of synaptogenesis and glutamate regulators in hippocampus. Therefore, PA treatment should be used with caution even though positive metabolic, (cerebro) vascular, and brain structural and functional effects were observed.

Metabolic syndrome, leaky guts, and infection Metabolic syndrome often accompanies obesity and hyperglycemia and is associated with a breakdown in the integrity of the intestinal barrier and increased risk of systemic infection. Thaiss et al. found that mice with systemic infection of a Salmonella analog, Citrobacter rodentium , also exhibited hyperglycemia. Deletion of the glucose transporter GLUT2 altered sensitivity to chemically induced epithelial permeability and protected mice from pathogen invasion. The authors also found a correlation in humans between glycated hemoglobin (an indicator of hyperglycemia) and serum levels of pathogen recognition receptor ligands. Science , this issue p. 1376

Resistance to ciprofloxacin in Escherichia coli is increasing parallel to increased use of fluoroquinolones both in The Netherlands and in other European countries. The objective was to investigate the contribution of active efflux and expression of outer membrane proteins (OMPs) in a collection of clinical E. coli isolates collected at a clinical microbiology department in a Dutch hospital. Forty-seven E. coli isolates a wide range of ciprofloxacin minimum inhibitory concentrations and known mutations in the quinolone resistance determining region were included. A fluorometric determination of bisbenzimide efflux was used two different efflux pump inhibitors and compared to quantitative reverse transcription-polymerase chain reaction (qRT-PCR) for the expression levels of acrA, acrB, tolC, yhiV, and mdfA efflux pump genes and the OMPs ompF and ompX. Six isolates (12.7%) showed increased efflux. Although in 35 isolates (76%), overexpression of ≥1 efflux pump genes using qRT-PCR was present. Only the combined overexpression of acrAB-TolC and mdfA correlated with the phenotypic efflux assay using glucose/carbonyl cyanide m-chlorophenylhydrazone with glucose. Thus, efflux was involved in ciprofloxacin resistance in a limited number of E. coli isolates collected at a clinical microbiology department in a Dutch hospital complementing other resistance mechanisms.

SummaryAll domains of life feature diverse molecular clock machineries that synchronize physiological processes to diurnal environmental fluctuations. However, no mechanisms are known to cross-regulate prokaryotic and eukaryotic circadian rhythms in multikingdom ecosystems. Here, we show that the intestinal microbiota, in both mice and humans, exhibits diurnal oscillations that are influenced by feeding rhythms, leading to time-specific compositional and functional profiles over the course of a day. Ablation of host molecular clock components or induction of jet lag leads to aberrant microbiota diurnal fluctuations and dysbiosis, driven by impaired feeding rhythmicity. Consequently, jet-lag-induced dysbiosis in both mice and humans promotes glucose intolerance and obesity that are transferrable to germ-free mice upon fecal transplantation. Together, these findings provide evidence of coordinated metaorganism diurnal rhythmicity and offer a microbiome-dependent mechanism for common metabolic disturbances in humans with aberrant circadian rhythms, such as those documented in shift workers and frequent flyers.

SummaryAutophagy is an important defense mechanism against mycobacteria, the causative agents of tuberculosis. The molecular mechanisms that link mycobacterial recognition to autophagy remain unclear. Our analysis in zebrafish and human macrophage models of mycobacterial infection reveals that the DNA damage-regulated autophagy modulator DRAM1 functions downstream of pathogen recognition by the Toll-like receptor (TLR)/interleukin-1 receptor (IL1R)-MYD88-NF-κB innate immune sensing pathway to activate selective autophagy. Mycobacterial infection of human macrophages and zebrafish embryos induced DRAM1 expression in a MYD88 and NF-κB-dependent manner. DRAM1 knockdown increased mycobacterial infection, whereas overexpression lowered infection by hyperactivating autophagy. DRAM1-mediated selective autophagic defenses require the cytosolic DNA sensor STING and the selective autophagy receptor p62/SQSTM1. Contrary to its known role in autophagy-mediated cell death and cancer, this DRAM1 function is p53 independent. We propose that DRAM1 mediates autophagic defense against a broader range of intracellular pathogens, since DRAM1 expression was also induced by the common bacterial endotoxin lipopolysaccharide.