Obese-type Gut Microbiota Induce Neurobehavioral Changes in the Absence of Obesity - Biological Psychiatry

Background

The prevalence of mental illness, particularly depression and dementia, is increased by obesity.
Here, we test the hypothesis that obesity-associated changes in gut microbiota are intrinsically able to impair neurocognitive behavior in mice.

Methods

Conventionally housed, nonobese, adult male C57BL/6 mice maintained on a normal chow diet were
subjected to a microbiome depletion/transplantation paradigm using microbiota isolated from donors on either a high-fat diet (HFD) or control diet. Following re-colonization, mice were subjected to
comprehensive behavioral and biochemical analyses.

Results

The mice given HFD microbiota had significant and selective disruptions in
exploratory, cognitive, and stereotypical behavior compared with mice
with control diet microbiota in the absence of significant differences
in body weight. Sequencing-based phylogenetic analysis confirmed the
presence of distinct core microbiota between groups, with alterations in
α- and β-diversity, modulation in taxonomic distribution, and
statistically significant alterations to metabolically active taxa. HFD
microbiota also disrupted markers of intestinal barrier function,
increased circulating endotoxin, and increased lymphocyte expression of
ionized calcium-binding adapter molecule 1, toll-like receptor 2, and
toll-like receptor 4. Finally, evaluation of brain homogenates revealed
that HFD-shaped microbiota increased neuroinflammation and disrupted
cerebrovascular homeostasis.

Conclusions

Collectively, these data reinforce the link between gut dysbiosis and neurologic dysfunction and suggest that dietary and/or pharmacologic manipulation of gut microbiota could attenuate the neurologic complications of obesity.

Borna disease virus phosphoprotein modulates epigenetic signaling in neurons to control viral replication.

Understanding the modalities
of interaction of neurotropic viruses with their target cells represents
a major challenge that may improve our knowledge of many human
neurological disorders for which viral origin is suspected. Borna
disease virus (BDV) represents an ideal model to analyze the molecular
mechanisms of viral persistence in neurons and its consequences for
neuronal homeostasis. It is now established that BDV ensures its
long-term maintenance in infected cells through a stable interaction of
viral components with the host cell chromatin, in particular with core
histones. This has led to our hypothesis that such an interaction may
trigger epigenetic changes in the host cell. Here, we focused on histone
acetylation, which play key roles in epigenetic regulation of gene
expression, notably for neurons. We performed a comparative analysis of
histone acetylation patterns of neurons infected or not by BDV, which
revealed that infection decreases histone acetylation on selected lysine
residues. We showed that the BDV phosphoprotein (P) is responsible for
these perturbations, even when expressed alone independently of the
viral context, and that this action depends on its phosphorylation by
protein kinase C. We also demonstrated that BDV P inhibits cellular
histone acetyl transferase activities. Finally, by pharmacologically
manipulating cellular acetylation levels, we observed that inhibiting
cellular acetyl transferases reduces viral replication in cell culture.
Our findings reveal that manipulation of cellular epigenetics by BDV
could be a mean to modulate viral replication and thus illustrate a
fascinating example of virus/host cell interaction.

IMPORTANCE:

Persistent
DNA viruses often subvert the mechanisms that regulate cellular
chromatin dynamics, thereby benefitting from the resulting epigenetic
changes to create a favorable milieu for their latent/persistent states.
Here, we reasoned that Borna Disease Virus (BDV), the only RNA virus
known to durably persist in the nucleus of infected cells, notably
neurons, might employ a similar mechanism. In this study, we uncover a
novel modality of virus/cell interaction in which BDV phosphoprotein
inhibits cellular histone acetylation by interfering with histone acetyl
transferase activities. Manipulation of cellular histone acetylation is
accompanied by a modulation of viral replication, revealing the perfect
adaptation of this "ancient" virus to its host that may favor neuronal
persistence and limit cellular damage.

Translational Psychiatry - Serotonin versus catecholamine deficiency: behavioral and neural effects of experimental depletion in remitted depression

Despite immense efforts into development of new antidepressant drugs,
the increases of serotoninergic and catecholaminergic neurotransmission
have remained the two major pharmacodynamic principles of current drug
treatments for depression. Consequently, psychopathological or
biological markers that predict response to drugs that selectively
increase serotonin and/or catecholamine
neurotransmission hold the potential to optimize the prescriber’s
selection among currently available treatment options. The aim of this
study was to elucidate the differential symptomatology and
neurophysiology in response to reductions in serotonergic versus
catecholaminergic neurotransmission in subjects at high risk of
depression recurrence. Using identical neuroimaging procedures with [18F]
fluorodeoxyglucose positron emission tomography after tryptophan
depletion (TD) and catecholamine depletion (CD), subjects with remitted
depression were compared with healthy controls in a double-blind,
randomized, crossover design. Although TD induced significantly more
depressed mood, sadness and hopelessness than CD, CD induced more
inactivity, concentration difficulties, lassitude and somatic anxiety
than TD. CD specifically increased glucose metabolism in the bilateral
ventral striatum and decreased glucose metabolism in the bilateral
orbitofrontal cortex, whereas TD specifically increased metabolism in
the right prefrontal cortex and the posterior cingulate cortex. Although
we found direct associations between changes in brain metabolism and
induced depressive symptoms following CD, the relationship between
neural activity and symptoms was less clear after TD. In conclusion,
this study showed that serotonin and catecholamines have common and
differential roles in the pathophysiology of depression.

Evidence many young children with autism show gut symptoms Medical News Today

Mothers of infants aged up to 3 years who have autism are more likely to report the children have gastrointestinal symptoms of constipation, diarrhea and food allergy or intolerance, finds a study collecting 10 years of prospective data.

Air pollution, stroke, and anxiety | The BMJ

Particulate air pollution is an emerging risk factor for an increasing number of common conditions
The
effects of air pollution on the lungs and heart are now widely
appreciated, with expanding evidence for an important role in cardiac
disease.1 The Global Burden of Disease Study identified fine particulate matter (PM2.5)
in outdoor air and household air pollution from use of solid fuels as
the ninth and fourth leading risk factors, respectively, for disease
worldwide,2 and the World Health Organization attributes one in every eight deaths to air pollution.3
The effects of air pollution are not limited to cardiopulmonary
diseases. Recent evidence suggests a role in diverse outcomes, including
diabetes,4 low birth weight, and preterm birth.5
This research stems from improved understanding of the role of air
pollution in initiating systemic inflammation, a response that may
affect multiple organ systems. Two linked studies (doi:10.1136/bmj.h1295, doi:10.1136/bmj.h1111) add to growing evidence that air pollution is an important risk factor for an increasing number of common diseases.6 7
In the first of the two papers, Shah and colleagues6
systematically reviewed and meta-analysed 103 studies conducted in 28
countries and including 6.2 million events to assess the role of short
term fluctuations in air pollution as a trigger for stroke. Although
evidence from several cohort studies of long term exposure to
particulate matter indicates associations with stroke mortality, such
findings are not universal.8
The
role of air pollution as a possible trigger for stroke has important
implications for disease burden, especially in China where air pollution
and the incidence of (especially haemorrhagic) stroke are high. In
their analysis, Shah and colleagues found that increases in each of the
common gaseous and particulate air pollutants were significantly
associated with admission to hospital for stroke or stroke related
mortality, with associations strongest for strokes on the same day as
exposure; increased ozone was only weakly associated with
cerebrovascular events.

Prenatal exposure to common air pollutants linked to cognitive and behavioral impairment

Neurotoxic PAH (polycyclic aromatic hydrocarbons) are ubiquitous in
the environment, in the home and in the workplace. Emissions from motor
vehicles, oil and coal burning for home heating or power generation,
wildfires and agricultural burning, hazardous waste sites, tobacco smoke
and charred foods are all sources of exposure. PAH readily crosses the
placenta and affects an unborn child's brain; earlier animal studies
showed that prenatal exposure impaired the development of behavior,
learning and memory.


Scientists led by Bradley S. Peterson, MD, director of the Institute
for the Developing Mind at The Saban Research Institute of CHLA, along
with Virginia Rauh, ScD, and Frederica Perera, DrPH, PhD, from Columbia
University's Mailman School of Public Health, conducted a study of
minority youth to test the effects on brain structure of PAH exposure
during the final trimester of pregnancy. They used magnetic resonance
imaging (MRI) to measure the brains of 40 children from a cohort of more
than 600 mother-baby pairs from minority communities in New York City.
The Columbia researchers had previously reported that exposure to
airborne PAH during gestation in this cohort was associated with
multiple neurodevelopmental disturbances, including development delay by
age 3, reduced verbal IQ at age 5, and symptoms of anxiety and
depression at age 7.

Endocrine-disrupting chemicals can adversely affect reproduction of future generations of fish

Bisphenol A (BPA) is a chemical that is used in a variety of consumer
products, such as water bottles, dental composites and resins used to
line metal food and beverage containers. Often, aquatic environments
such as rivers and streams become reservoirs for contaminants, including
BPA. Now, University of Missouri researchers and U.S. Geological Survey
(USGS) scientists have determined that fish exposed to
endocrine-disrupting chemicals will pass adverse reproductive effects
onto their offspring as many as three generations later. These findings
suggest that BPA could have adverse reproductive effects for humans and
their offspring who are exposed to BPA as well.

National Science Foundation (NSF) News - The 'intraterrestrials': New viruses discovered in ocean depths - US National Science Foundation (NSF)

Strange creatures live in the deep sea, but few are odder than the viruses that inhabit deep ocean methane seeps and prey on single-celled microorganisms called archaea.
The least understood of life's three primary domains, archaea thrive in the most extreme environments on the planet: near hot ocean rift vents, in acid mine drainage, in the saltiest of evaporation ponds and in petroleum deposits deep underground.
Virus in the deep blue sea
While searching the ocean's depths for evidence of viruses, scientists have found a remarkable new one, a virus that seemingly infects archaea that live beneath the ocean floor.
The researchers were surprised to discover that the virus selectively targets one of its own genes for mutation, and that this capacity is also shared by archaea themselves.
The findings appear today in a paper in the journal Nature Communications.

Epigenetics and animal virus infections



Epigenetics, modifications of the genome, heritable during cell division, that do not involve changes in DNA sequences include several mechanisms mainly: histone modifications, DNA
methylation and related modifications, non-coding RNAs (ncRNAs) and
others that regulate gene expression.
The past two decades has seen an explosion of interest for revealing mechanisms that
control epigenetic modifications, mainly based on the influence they
have on chromatin structure and their impact in biological processes
such as programmed DNA rearrangements, imprinting, germ line silencing,
developmentally cued stem cell division, and overall chromosomal
stability and identity. It has also become obvious that epigenetics
changes are fundamental in the interplay between viruses and their host
cells. Generally speaking, when retroviruses and DNA viruses integrate
their genomes into the host genome, they can stay latent by silencing
their genes or can be productive by activating them, and viral gene
expression can be regulated just like as the host. In fact, viral DNA
uses host transcription factors as well as epigenetic regulators, in
such a way that the effect of viral epigenetic control of its own gene
expression also extends to regulate host gene expression. At the same
time cells use similar mechanisms, transcription factors and epigenetic
modifications, in order to try to eliminate viral infections. In
summary, epigenetic mechanisms are involved in most of the virus-cell
interactions.
The goal of this special issue is to bring
together key experimental and theoretical research linking
state-of-the-art knowledge of epigenetic mechanisms involved in
regulating virus-cell interactions.

Air pollutants could boost potency of common airborne allergens -- ScienceDaily

A pair of air pollutants linked to climate change could also be major
contributors to the unparalleled rise in the number of people sneezing,
sniffling and wheezing during allergy season. The gases, nitrogen
dioxide and ground-level ozone, appear to provoke chemical changes in
certain airborne allergens that may increase their potency. That, in
combination with changes in global climate could help explain why
allergies are becoming more common.

American Public Health Association - Association Between Assisted Reproductive Technology Conception and Autism in California, 1997–2007

Objectives. We assessed the
association between assisted reproductive technology (ART) and diagnosed
autistic disorder in a population-based sample of California births.
Methods.
We performed an observational cohort study using linked records from
the California Birth Master Files for 1997 through 2007, the California
Department of Developmental Services autism caseload for 1997 through
2011, and the Centers for Disease Control and Prevention’s National ART
Surveillance System for live births in 1997 through 2007. Participants
were all 5 926 251 live births, including 48 865 ART-originated infants
and 32 922 cases of autism diagnosed by the Department of Developmental
Services. We compared births originated using ART with births originated
without ART for incidence of autism.

Results. In the full
population, the incidence of diagnosed autism was twice as high for ART
as non-ART births. The association was diminished by excluding mothers
unlikely to use ART; adjustment for demographic and adverse prenatal and
perinatal outcomes reduced the association substantially, although
statistical significance persisted for mothers aged 20 to 34 years.

Conclusions. The association between ART and autism is primarily explained by adverse prenatal and perinatal outcomes and multiple births.



Read More: http://ajph.aphapublications.org/doi/10.2105/AJPH.2014.302383

Glycans – the sweet difference - On Biology

It's easy to forget that there's much more behind our individuality than
genetics. A guest blog by Professor Vlatka Zoldos looks at the
epigenetics of glycan protein modifications, and how this has been
evolutionarily advantageous.
Glycan structure (tagged onto many proteins) is not determined with a single gene, but rather by a complex dynamic network of many genes. Single nucleotide polymorphisms in any of these genes may affect the final structure of a glycan consisting of several monosaccharides. Moreover, the network responsible for biosynthesis of glycans includes a number of small metabolites that are influenced by various environmental factors. Therefore glycans are not defined simply by a genetic script, but also by various environmental factors that could either be currently present in the environment, or acted sometime in our early environment (during intrauterine development) and left marks in the epigenetic memory.

New knowledge strengthens risk assessment of chemical cocktails in food

A recently completed, four-year research project on cocktail effects in foods, led by the National Food Institute, has established that when two or more chemicals appear together, they often have an additive effect. This means that cocktail effects can be predicted based on information from single chemicals, but also that small amounts of chemicals when present together can have significant negative effects.

Infection and Inflammation in Schizophrenia and Bipolar Disorder: A Genome Wide Study for Interactions with Genetic Variation.

Inflammation and maternal or fetal infections have been suggested as
risk factors for schizophrenia (SZ) and bipolar disorder (BP). It is
likely that such environmental effects are contingent on genetic
background. Here, in a genome-wide approach, we test the hypothesis that
such exposures increase the risk for SZ and BP and that the increase is
dependent on genetic variants. We use genome-wide genotype data, plasma
IgG antibody measurements against Toxoplasma gondii, Herpes simplex
virus type 1, Cytomegalovirus, Human Herpes Virus 6 and the food antigen
gliadin as well as measurements of C-reactive protein (CRP), a
peripheral marker of inflammation. The subjects are SZ cases, BP cases,
parents of cases and screened controls. We look for higher levels of our
immunity/infection variables and interactions between them and common
genetic variation genome-wide. We find many of the antibody measurements
higher in both disorders. While individual tests do not withstand
correction for multiple comparisons, the number of nominally significant
tests and the comparisons showing the expected direction are in
significant excess (permutation p=0.019 and 0.004 respectively). We also
find CRP levels highly elevated in SZ, BP and the mothers of BP cases,
in agreement with existing literature, but possibly confounded by our
inability to correct for smoking or body mass index. In our genome-wide
interaction analysis no signal reached genome-wide significance, yet
many plausible candidate genes emerged. In a hypothesis driven test, we
found multiple interactions among SZ-associated SNPs in the HLA region
on chromosome 6 and replicated an interaction between CMV infection and
genotypes near the CTNNA3 gene reported by a recent GWAS. Our results
support that inflammatory processes and infection may modify the risk
for psychosis and suggest that the genotype at SZ-associated HLA loci
modifies the effect of these variables on the risk to develop SZ.

Diet soda linked to increases in belly fat in older adults -- ScienceDaily

A new study published in the Journal of the American Geriatrics Society
shows that increasing diet soda intake is directly linked to greater
abdominal obesity in adults 65 years of age and older. Findings raise
concerns about the safety of chronic diet soda consumption, which may
increase belly fat and contribute to greater risk of metabolic syndrome
and cardiovascular diseases.

The ISME Journal - The host metabolite D-serine contributes to bacterial niche specificity through gene selection

Escherichia coli comprise a diverse array of both commensals and
niche-specific pathotypes. The ability to cause disease results from
both carriage of specific virulence factors and regulatory control of
these via environmental stimuli. Moreover, host metabolites
further refine the response of bacteria to their environment and can
dramatically affect the outcome of the host–pathogen interaction. Here,
we demonstrate that the host metabolite, D-serine, selectively affects
gene expression in E. coli O157:H7. Transcriptomic profiling
showed exposure to D-serine results in activation of the SOS response
and suppresses expression of the Type 3 Secretion System (T3SS) used to
attach to host cells. We also show that concurrent carriage of both the
D-serine tolerance locus (dsdCXA) and the locus of enterocyte
effacement pathogenicity island encoding a T3SS is extremely rare, a
genotype that we attribute to an ‘evolutionary incompatibility’ between
the two loci. This study demonstrates the importance of co-operation
between both core and pathogenic genetic elements in defining niche
specificity.

Persistent Organic Pollutants Modify Gut Microbiota–Host Metabolic Homeostasis in Mice Through Aryl Hydrocarbon Receptor Activation


  • Background: Alteration of the gut microbiota through
    diet and environmental contaminants may disturb physiological
    homeostasis, leading to various diseases including obesity and type 2
    diabetes. Since most exposure to environmentally-persistent organic
    pollutants (POPs) occurs through the diet, the host gastrointestinal
    tract and commensal gut microbiota are likely to be exposed to POPs.
    Objectives: We report that
    2,3,7,8-tetrachlorodibenzofuran (TCDF), a persistent environmental
    contaminant, profoundly impacts the gut microbiota and host metabolism
    in an aryl hydrocarbon receptor (AHR)-dependent manner.


    Methods: Six-week-old male wild-type and Ahr-/- mice on the C57BL/6J background were treated with 24 µg/kg TCDF in the diet for five days. 16S rRNA gene sequencing, 1H
    nuclear magnetic resonance (NMR) metabolomics, targeted
    ultra-performance liquid chromatography coupled with triplequadrupole
    mass spectrometry (UPLC-TQMS) and biochemical assays were used to
    determine the microbiota compositions and the physiological and
    metabolic effects of TCDF.


    Results: Dietary TCDF altered the gut microbiota by
    shifting the ratio of Firmicutes to Bacteroidetes. TCDF-treated mouse
    cecal contents were enriched with Butyrivibrio spp., but depleted in
    Oscillobacter spp. in comparison with vehicle-treated mice. These
    changes in the gut microbiota were associated with altered bile acid
    metabolism. Further, dietary TCDF inhibited the farnesoid X receptor
    (FXR) signaling pathway, and triggered significant inflammation and host
    metabolic disorders as a result of activation of bacterial
    fermentation, and altering hepatic lipogenesis, gluconeogenesis and
    glycogenolysis, in an AHR-dependent manner.


    Conclusion: These findings provide new insights into
    the biochemical consequences of TCDF exposure involving the alteration
    of the gut microbiota, modulation of nuclear receptor signaling, and
    disruption of host metabolism.

Borrelia burgdorferi/host interactome

A referenced  list of host genes and proteins involved in the spirochaete life cycle

Does Amyloid Kill in Alzheimer’s, Heal in MS?

Beta-amyloid, ...........a suspected culprit in Alzheimer's disease but many amyloid directed trials have failed:-

Steinman’s team questioned whether aβ is a villain at all. This helped them to try an unusual experiment that may pay off in spades—though it may confuse a lot of people along the way.Noticing some aβ in MS lesions, they created a synthetic version of it and gave it systemically to MS-model mice to figure out its purpose there. To his shock, it reversed their paralysis for as long as it was administered. He reported this in Science Translational Medicine in 2012. In 2013, he reported in that same journal that even small, pared down hexa-peptides from aβ—and from other amyloid-forming proteins like Alpha-b crystalline and tau—could reverse paralysis in MS-model mice. Now “we are tackling neuro-inflammation using amyloid hexa-peptides mostly in models of MS, which is a disease of neuro-inflammation,” he told Bioscience Technology. “In that situation, our amyloid structures definitely make mice better. We have also found the absence of such amyloid structures makes mice worse, whether you knock out aβ or Alpha b-crystallin, or tau, or prion. This could be a whole new potential MS therapy.”