Accumulating evidence demonstrates that the gut microbiota affects brain function and behavior, including depressive behavior. Antidepressants are the main drugs used for treatment of depression. We ...hypothesized that antidepressant treatment could modify gut microbiota which can partially mediate their antidepressant effects. Mice were chronically treated with one of five antidepressants (fluoxetine, escitalopram, venlafaxine, duloxetine or desipramine), and gut microbiota was analyzed, using 16s rRNA gene sequencing. After characterization of differences in the microbiota, chosen bacterial species were supplemented to vehicle and antidepressant-treated mice, and depressive-like behavior was assessed to determine bacterial effects. RNA-seq analysis was performed to determine effects of bacterial treatment in the brain. Antidepressants reduced richness and increased beta diversity of gut bacteria, compared to controls. At the genus level, antidepressants reduced abundances of Ruminococcus, Adlercreutzia, and an unclassified Alphaproteobacteria. To examine implications of the dysregulated bacteria, we chose one of antidepressants (duloxetine) and investigated if its antidepressive effects can be attenuated by simultaneous treatment with Ruminococcus flavefaciens or Adlercreutzia equolifaciens. Supplementation with R. flavefaciens diminished duloxetine-induced decrease in depressive-like behavior, while A. equolifaciens had no such effect. R. flavefaciens treatment induced changes in cortical gene expression, up-regulating genes involved in mitochondrial oxidative phosphorylation, while down-regulating genes involved in neuronal plasticity. Our results demonstrate that various types of antidepressants alter gut microbiota composition, and further implicate a role for R. flavefaciens in alleviating depressive-like behavior. Moreover, R. flavefaciens affects gene networks in the brain, suggesting a mechanism for microbial regulation of antidepressant treatment efficiency.
Exposure to antibiotics in the first days of life is thought to affect various physiological aspects of neonatal development. Here, we investigate the long-term impact of antibiotic treatment in the ...neonatal period and early childhood on child growth in an unselected birth cohort of 12,422 children born at full term. We find significant attenuation of weight and height gain during the first 6 years of life after neonatal antibiotic exposure in boys, but not in girls, after adjusting for potential confounders. In contrast, antibiotic use after the neonatal period but during the first 6 years of life is associated with significantly higher body mass index throughout the study period in both boys and girls. Neonatal antibiotic exposure is associated with significant differences in the gut microbiome, particularly in decreased abundance and diversity of fecal Bifidobacteria until 2 years of age. Finally, we demonstrate that fecal microbiota transplant from antibiotic-exposed children to germ-free male, but not female, mice results in significant growth impairment. Thus, we conclude that neonatal antibiotic exposure is associated with a long-term gut microbiome perturbation and may result in reduced growth in boys during the first six years of life while antibiotic use later in childhood is associated with increased body mass index.
The gut microbiome has been shown to influence the response of tumors to anti-PD-1 (programmed cell death-1) immunotherapy in preclinical mouse models and observational patient cohorts. However, ...modulation of gut microbiota in cancer patients has not been investigated in clinical trials. In this study, we performed a phase 1 clinical trial to assess the safety and feasibility of fecal microbiota transplantation (FMT) and reinduction of anti-PD-1 immunotherapy in 10 patients with anti-PD-1-refractory metastatic melanoma. We observed clinical responses in three patients, including two partial responses and one complete response. Notably, treatment with FMT was associated with favorable changes in immune cell infiltrates and gene expression profiles in both the gut lamina propria and the tumor microenvironment. These early findings have implications for modulating the gut microbiota in cancer treatment.
•Shank3 KO displays differential abundance of several microbial general and species.•GABA receptor expression correlates with L. reuteri abundance.•L. reuteri modifies social and repetitive behaviors ...in Shank3 KO mice.•L. reuteri modifies GABA receptor expression and oxytocin expression in Shank3 KO mice.
Recent studies have determined that the microbiome has direct effects on behavior, and may be dysregulated in neurodevelopmental conditions. Considering that neurodevelopmental conditions, such as autism, have a strong genetic etiology, it is necessary to understand if genes associated with neurodevelopmental disorders, such as Shank3, can influence the gut microbiome, and if probiotics can be a therapeutic tool. In this study, we have identified dysregulation of several genera and species of bacteria in the gut and colon of both male and female Shank3 KO mice. L. reuteri, a species with decreased relative abundance in the Shank3 KO mice, positively correlated with the expression of gamma-Aminobutyric acid (GABA) receptor subunits in the brain. Treatment of Shank3 KO mice with L. reuteri induced an attenuation of unsocial behavior specifically in male Shank3 mice, and a decrease in repetitive behaviors in both male and female Shank3 KO mice. In addition, L. reuteri treatment affected GABA receptor gene expression and protein levels in multiple brain regions. This study identifies bacterial species that are sensitive to an autism-related mutation, and further suggests a therapeutic potential for probiotic treatment.
Microfluidic chips provide a powerful platform for high-throughput screening of diverse biophysical systems. The most prevalent detection methods are fluorescence based. Developing new readout ...techniques for microfluidics focusing on quantitative information in the low signal regime is desirable. In this work, we combine the well-established immunoassay approach, with magnetic nanoparticles, with a highly sensitive magnetic imaging technique. We offer to integrate a microfluidic array into a scanning superconducting quantum interference device (SQUID) microscope, to image nanoparticles that were moved through the microfluidic device. We demonstrate the technique on protein-protein interactions (PPI). We compare sensitivity to that of a conventional readout, quantify the amount of interactions, and demonstrate 0.1 atto-mole sensitivity. Our work serves as a proof of concept that will promote the development of a new set of eyes, a stable usable microfluidic-scanning SQUID microscopy.
Gestation is accompanied by alterations in the microbial repertoire; however, the mechanisms driving these changes are unknown. Here, we demonstrate a dramatic shift in the gut microbial composition ...of women and mice during late pregnancy, including an increase in the relative abundance of Bifidobacterium. Using in-vivo-transplanted pellets, we found that progesterone, the principal gestation hormone, affects the microbial community. The effect of progesterone on the richness of several bacteria species, including Bifidobacterium, was also demonstrated in vitro, indicating a direct effect. Altogether, our results delineate a model in which progesterone promotes Bifidobacterium growth during late pregnancy.
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•Bifidobacterium abundance increases in the gut during pregnancy in women and mice•Progesterone supplementation alters gut microbial composition in mice and in vitro•Progesterone supplementation increases Bifidobacterium abundance in mice and in vitro•We suggest that progesterone promotes Bifidobacterium growth during late pregnancy
Nuriel-Ohayon et al. demonstrate a dramatic shift in the gut microbial composition of women and mice during late pregnancy, including an increase in the relative abundance of Bifidobacterium. Using in vitro and in vivo experiments, they show that supplementation of progesterone affects the microbial communities, including increasing the relative abundance of Bifidobacterium.
The link between the gut microbiota and social behavior has been demonstrated, however the translational impact of a certain microbiota composition on stable behavioral patterns is yet to be ...elucidated. Here we employed an established social behavior mouse model of dominance (Dom) or submissiveness (Sub). A comprehensive 16S rRNA gene sequence analysis of Dom and Sub mice revealed a significantly different gut microbiota composition that clearly distinguishes between the two behavioral modes. Sub mice gut microbiota is significantly less diverse than that of Dom mice, and their taxa composition uniquely comprised the genera Mycoplasma and Anaeroplasma of the Tenericutes phylum, in addition to the Rikenellaceae and Clostridiaceae families. Conversely, the gut microbiota of Dom mice includes the genus Prevotella of the Bacteriodetes phylum, significantly less abundant in Sub mice. In addition, Sub mice show lower body weight from the age of 2 weeks and throughout their life span, accompanied with lower epididymis white adipose tissue (eWAT) mass and smaller adipocytes together with substantially elevated expression of inflammation and metabolic-related eWAT adipokines. Finally, fecal microbiota transplantation into germ-free mice show that Sub-transplanted mice acquired Sub microbiota and adopted their behavioral and physiological features, including depressive-like and anti-social behaviors alongside reduced eWAT mass, smaller adipocytes, and a Sub-like eWAT adipokine profile. Our findings demonstrate the critical role of the gut microbiome in determining dominance vs. submissiveness and suggest an association between gut microbiota, the eWAT metabolic and inflammatory profile, and the social behavior mode.
Interest in the pathogenesis, detection, and prevention of viral infections has increased broadly in many fields of research over the past year. The development of water treatment technology to ...combat viral infection by inactivation or disinfection might play a key role in infection prevention in places where drinking water sources are biologically contaminated. Laser-induced graphene (LIG) has antimicrobial and antifouling surface effects mainly because of its electrochemical properties and texture, and LIG-based water filters have been used for the inactivation of bacteria. However, the antiviral activity of LIG-based filters has not yet been explored. Here we show that LIG filters also have antiviral effects by applying electrical potential during filtration of the model prototypic poxvirus
. This antiviral activity of the LIG filters was compared with its antibacterial activity, which showed that higher voltages were required for the inactivation of viruses compared to that of bacteria. The generation of reactive oxygen species, along with surface electrical effects, played a role in the mechanism of virus inactivation. This new property of LIG highlights its potential for use in water and wastewater treatment for the electrochemical disinfection of various pathogenic microorganisms, including bacteria and viruses.
It is common practice to perform a lumbar puncture in infants presenting with fever and a bulging fontanelle in order to rule out bacterial meningitis. However, most of these infants have benign, ...self-limiting diseases. The objective was to determine whether there is an association between bulging fontanelle and bacterial meningitis in febrile infants. This retrospective cohort study included febrile children with a bulging fontanelle who underwent lumbar puncture at Meir Medical Center from 2005 through 2015. A total of 764 children ages 2–18 months underwent lumbar puncture during the study period. Among them, 304 had a bulging fontanelle and fever on evaluation and cerebrospinal fluid pleocytosis was found in 115 (37.8%), including 1 case of bacterial meningitis (0.3%). None of the infants described on admission as appearing well on presentation was found to have bacterial meningitis. Of the 764 children who underwent lumbar puncture, 10 infants were diagnosed with bacterial meningitis, and only one (10%) presented with a bulging fontanelle.
Conclusion
: The finding of a bulging fontanelle has very low sensitivity and specificity for bacterial meningitis. Most causes of a bulging fontanelle in febrile infants are self-limiting diseases. The routine approach of performing a lumbar puncture in febrile infants with a bulging fontanelle should be reconsidered.
What is Known:
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It is common to perform a lumbar puncture in febrile infants with a bulging fontanelle, to rule out bacterial meningitis.
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However, there are only few researches regarding the relationship between bulging fontanelle and bacterial meningitis.
What is New:
• The finding of a bulging fontanelle has very low sensitivity and specificity for bacterial meningitis
• The need for routine lumbar puncture in these cases should be reconsidered.
rVSV-Spike (rVSV-S) is a recombinant viral vaccine candidate under development to control the COVID-19 pandemic and is currently in phase II clinical trials. rVSV-S induces neutralizing antibodies ...and protects against SARS-CoV-2 infection in animal models. Bringing rVSV-S to clinical trials required the development of a scalable downstream process for the production of rVSV-S that can meet regulatory guidelines. The objective of this study was the development of the first downstream unit operations for cell-culture-derived rVSV-S, namely, the removal of nucleic acid contamination, the clarification and concentration of viral harvested supernatant, and buffer exchange. Retaining the infectivity of the rVSV-S during the downstream process was challenged by the shear sensitivity of the enveloped rVSV-S and its membrane protruding spike protein. Through a series of screening experiments, we evaluated and established the required endonuclease treatment conditions, filter train composition, and hollow fiber-tangential flow filtration parameters to remove large particles, reduce the load of impurities, and concentrate and exchange the buffer while retaining rVSV-S infectivity. The combined effect of the first unit operations on viral recovery and the removal of critical impurities was examined during scale-up experiments. Overall, approximately 40% of viral recovery was obtained and the regulatory requirements of less than 10 ng host cell DNA per dose were met. However, while 86–97% of the host cell proteins were removed, the regulatory acceptable HCP levels were not achieved, requiring subsequent purification and polishing steps. The results we obtained during the scale-up experiments were similar to those obtained during the screening experiments, indicating the scalability of the process. The findings of this study set the foundation for the development of a complete downstream manufacturing process, requiring subsequent purification and polishing unit operations for clinical preparations of rVSV-S.
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