Antibiotic-induced perturbations in microbial diversity during post-natal development alters amyloid pathology in an aged APP SWE /PS1 ΔE9 murine model of Alzheimer’s disease | Scientific Reports

Recent evidence suggests the commensal microbiome regulates host immunity and influences brain function; findings that have ramifications for neurodegenerative diseases. In the context of Alzheimer’s disease (AD), we previously reported that perturbations in microbial diversity induced by life-long combinatorial antibiotic (ABX) selection pressure in the APPSWE/PS1ΔE9 mouse model of amyloidosis is commensurate with reductions in amyloid-β (Aβ) plaque pathology and plaque-localised gliosis. Considering microbiota-host interactions, specifically during early post-natal development, are critical for immune- and neuro-development we now examine the impact of microbial community perturbations induced by acute ABX exposure exclusively during this period in APPSWE/PS1ΔE9 mice. We show that early post-natal (P) ABX treatment (P14-P21) results in long-term alterations of gut microbial genera (predominantly Lachnospiraceae and S24-7) and reduction in brain Aβ deposition in aged APPSWE/PS1ΔE9 mice. These mice exhibit elevated levels of blood- and brain-resident Foxp3+ T-regulatory cells and display an alteration in the inflammatory milieu of the serum and cerebrospinal fluid. Finally, we confirm that plaque-localised microglia and astrocytes are reduced in ABX-exposed mice. These findings suggest that ABX-induced microbial diversity perturbations during post-natal stages of development coincide with altered host immunity mechanisms and amyloidosis in a murine model of AD.

DNA replication is the target for the antibacterial effects of nonsteroidal anti-inflammatory drugs.

 Evidence suggests that some nonsteroidal anti-inflammatory drugs (NSAIDs) possess antibacterial properties with an unknown mechanism. We describe the in vitro antibacterial properties of the NSAIDs carprofen, bromfenac, and vedaprofen, and show that these NSAIDs inhibit the Escherichia coli DNA polymerase III β subunit, an essential interaction hub that acts as a mobile tether on DNA for many essential partner proteins in DNA replication and repair. Crystal structures show that the three NSAIDs bind to the sliding clamp at a common binding site required for partner binding. Inhibition of interaction of the clamp loader and/or the replicative polymerase α subunit with the sliding clamp is demonstrated using an in vitro DNA replication assay. NSAIDs thus present promising lead scaffolds for novel antibacterial agents targeting the sliding clamp.

Antibiotic-induced perturbations in gut microbial diversity influences neuro-inflammation and amyloidosis in a murine model of Alzheimer’s disease : Scientific Reports

Severe amyloidosis and plaque-localized neuro-inflammation are key pathological features of Alzheimer’s disease (AD). In addition to astrocyte and microglial reactivity, emerging evidence suggests a role of gut microbiota in regulating innate immunity and influencing brain function. Here, we examine the role of the host microbiome in regulating amyloidosis in the APPSWE/PS1ΔE9 mouse model of AD. We show that prolonged shifts in gut microbial composition and diversity induced by long-term broad-spectrum combinatorial antibiotic treatment regime decreases Aβ plaque deposition. We also show that levels of soluble Aβ are elevated and that levels of circulating cytokine and chemokine signatures are altered in this setting. Finally, we observe attenuated plaque-localised glial reactivity in these mice and significantly altered microglial morphology. These findings suggest the gut microbiota community diversity can regulate host innate immunity mechanisms that impact Aβ amyloidosis.

Infant antibiotic use linked to adult diseases -- ScienceDaily

A new study led by researchers at the University of Minnesota has found a
three-way link among antibiotic use in infants, changes in the gut
bacteria, and disease later in life. The imbalances in gut microbes,
called dysbiosis, have been tied to infectious diseases, allergies and
other autoimmune disorders, and even obesity, later in life.

Taking antibiotics during pregnancy increases risk for child becoming obese -- ScienceDaily

A study just released by Columbia University's Mailman School of Public
Health found that children who were exposed to antibiotics in the second
or third trimester of pregnancy had a higher risk of childhood obesity
at age 7. The research also showed that for mothers who delivered their
babies by a cesarean section, whether elective or non-elective, there
was a higher risk for obesity in their offspring.

Obesity risk rises if antibiotics given before age two

The research in the Journal of the American Medical Association (JAMA) Pediatrics is the latest to find a link between weight problems and antibiotics, which can eliminate bacterial infections but also the beneficial intestinal microflora that colonizes the gut.
Experts at the Children's Hospital of Philadelphia looked at health records from nearly 65,000 children who were treated at primary care clinics from 2001 to 2013. Those included in the study were followed for five years.
More than two thirds of the kids studied were exposed to antibiotics before age two. The increase in obesity risk ranged from two to 20 percent and was seen particularly in children who had been treated with antibiotics four or more times by age two.
Those given broad-spectrum antibiotics, which target a range of bacteria, were also at higher risk of weight problems in childhood.

"No association was seen between obesity and narrow-spectrum antibiotics," said the study, which described the use of broad-spectrum antibiotics in children under two as "one factor" in whether a child develops obesity.

Antibiotics, Immunity, and Obesity | The Scientist Magazine®

A brief, low dose of antibiotics shortly after birth can have
long-lasting consequences on gut microbes in mice and lead to obesity
once the rodents reach middle age. These findings, published today
(August 14) in Cell,
suggest that the gut microbiome may influence the development of
metabolic pathways during a critical time window early in life.

Obesity in the United States - dysbiosis from exposure to low-dose antibiotics?

The rapid increase in obesity prevalence in the United States in the last 20 years is unprecedented and not well explained. Here, we explore a hypothesis that the obesity epidemic may be driven by population-wide chronic exposures to low-residue antibiotics that have increasingly entered the American food chain over the same time period. We propose this hypothesis based on two recent bodies of published reports - (1) those that provide evidence for the spread of antibiotics into the American food chain, and (2) those that examine the relationship between the gut microbiota and body physiology. The livestock use of antimicrobial agents has sharply increased in the US over the same 20-year period of the obesity epidemic, especially with the expansion of intensified livestock production, such as the concentrated animal feeding operations. Observational and experimental studies support the idea that changes in the intestinal microbiota exert a profound effect on body physiology. We propose that chronic exposures to low-residue antimicrobial drugs in food could disrupt the equilibrium state of intestinal microbiota and cause dysbiosis that can contribute to changes in body physiology. The obesity epidemic in the United States may be partly driven by the mass exposure of Americans to food containing low-residue antimicrobial agents. While this hypothesis cannot discount the impact of diet and other factors associated with obesity, we believe studies are warranted to consider this possible driver of the epidemic.

Broad-Spectrum Antibiotic Use in Infancy Tied to Obesity: Medscape

 Infants who were given multiple courses of broad-spectrum antibiotics had a 20% increased risk of becoming obese toddlers, according to new research presented last week in a poster at Obesity 2013: The Obesity Society Annual Scientific Meeting.

The landscape of host transcriptional response programs commonly perturbed by bacterial pathogens: towards host-oriented broad-spectrum drug targets.

The emergence of drug-resistant pathogen strains and new infectious agents pose major challenges to public health. A promising approach to combat these problems is to target the host's genes or proteins, especially to discover targets that are effective against multiple pathogens, i.e., host-oriented broad-spectrum (HOBS) drug targets. An important first step in the discovery of such drug targets is the identification of host responses that are commonly perturbed by multiple pathogens.

RESULTS:

In this paper, we present a methodology to identify common host responses elicited by multiple pathogens. First, we identified host responses perturbed by each pathogen using a gene set enrichment analysis of publicly available genome-wide transcriptional datasets. Then, we used biclustering to identify groups of host pathways and biological processes that were perturbed only by a subset of the analyzed pathogens. Finally, we tested the enrichment of each bicluster in human genes that are known drug targets, on the basis of which we elicited putative HOBS targets for specific groups of bacterial pathogens. We identified 84 up-regulated and three down-regulated statistically significant biclusters. Each bicluster contained a group of pathogens that commonly dysregulated a group of biological processes. We validated our approach by checking whether these biclusters correspond to known hallmarks of bacterial infection. Indeed, these biclusters contained biological process such as inflammation, activation of dendritic cells, pro- and anti- apoptotic responses and other innate immune responses. Next, we identified biclusters containing pathogens that infected the same tissue. After a literature-based analysis of the drug targets contained in these biclusters, we suggested new uses of the drugs Anakinra, Etanercept, and Infliximab for gastrointestinal pathogens Yersinia enterocolitica, Helicobacter pylori kx2 strain, and enterohemorrhagic Escherichia coli and the drug Simvastatin for hematopoietic pathogen Ehrlichia chaffeensis.

CONCLUSIONS:

Using a combination of automated analysis of host-response gene expression data and manual study of the literature, we have been able to suggest host-oriented treatments for specific bacterial infections. The analyses and suggestions made in this study may be utilized to generate concrete hypothesis on which gene sets to probe further in the quest for HOBS drug targets for bacterial infections. All our results are available at the following supplementary website: http://bioinformatics.cs.vt.edu/murali/supplements/2013-kidane-plos-one.

mBiosphere: Rethinking the antibiotic: disarm pathogens, don’t kill them

It may be time to re-think the antibiotic. Traditional antibiotics act by killing the infecting
 organism, much the way an army would seek to do to it’s enemies. But if an army could somehow disarm its foes, taking away every last weapon, wouldn’t that accomplish the same end? 

Ecological Populations of Bacteria Act as Socially Cohesive Units of Antibiotic Production and Resistance

In animals and plants, social structure can reduce conflict within populations and bias aggression toward competing populations; however, for bacteria in the wild it remains unknown whether such population-level organization exists. Here, we show that environmental bacteria are organized into socially cohesive units in which antagonism occurs between rather than within ecologically defined populations. By screening approximately 35,000 possible mutual interactions among Vibrionaceae isolates from the ocean, we show that genotypic clusters known to have cohesive habitat association also act as units in terms of antibiotic production and resistance. Genetic analyses show that within populations, broad-range antibiotics are produced by few genotypes, whereas all others are resistant, suggesting cooperation between conspecifics. Natural antibiotics may thus mediate competition between populations rather than solely increase the success of individuals.

Early life antibiotic-driven changes in microbiota enhance susceptibility to allergic asthma.

Allergic asthma rates have increased steadily in developed countries, arguing for an environmental aetiology. To assess the influence of gut microbiota on experimental murine allergic asthma, we treated neonatal mice with clinical doses of two widely used antibiotics--streptomycin and vancomycin--and evaluated resulting shifts in resident flora and subsequent susceptibility to allergic asthma. Streptomycin treatment had little effect on the microbiota and on disease, whereas vancomycin reduced microbial diversity, shifted the composition of the bacterial population and enhanced disease severity. Neither antibiotic had a significant effect when administered to adult mice. Consistent with the 'hygiene hypothesis', our data support a neonatal, microbiota-driven, specific increase in susceptibility to experimental murine allergic asthma.

Human and soil bacteria swap antibiotic-resistance genes

Antibiotics in early life alter the murine colonic microbiome and adiposity : Nature : Nature Publishing Group

Antibiotics administered in low doses have been widely used as growth promoters in the agricultural industry since the 1950s, yet the mechanisms for this effect are unclear. Because antimicrobial agents of different classes and varying activity are effective across several vertebrate species, we proposed that such subtherapeutic administration alters the population structure of the gut microbiome as well as its metabolic capabilities. We generated a model of adiposity by giving subtherapeutic antibiotic therapy to young mice and evaluated changes in the composition and capabilities of the gut microbiome. Administration of subtherapeutic antibiotic therapy increased adiposity in young mice and increased hormone levels related to metabolism. We observed substantial taxonomic changes in the microbiome, changes in copies of key genes involved in the metabolism of carbohydrates to short-chain fatty acids, increases in colonic short-chain fatty acid levels, and alterations in the regulation of hepatic metabolism of lipids and cholesterol. In this model, we demonstrate the alteration of early-life murine metabolic homeostasis through antibiotic manipulation.

hot on the heels of this ........................................

MNT: Childhood Obesity Linked With Antibiotic Use In Infants Under 6 Months Old

MNT: Childhood Obesity Linked With Antibiotic Use In Infants Under 6 Months Old

New research, by experts at the NYU School of Medicine and the NYU Wagner School of Public Service, suggests that exposing babies to antibiotics may predispose them to being overweight in childhood.The study, which analyzed over 10,000 children and was published in the International Journal of Obesity, found that kids who weighed more for their height were those who were exposed to antibiotics from birth to 5 months of age.

National Science Foundation (NSF) News - Study Is First to Show Transgenerational Effect of Antibiotics - US National Science Foundation (NSF)

In a paper published in Nature's open access journal Scientific Reports, researchers at the University of Nevada, Reno, report that male pseudoscorpions treated with the antibiotic tetracycline suffer significantly reduced sperm viability and pass this toxic effect on to their untreated sons. They suggest a similar effect could occur in humans and other species.

MicrobeWorld - Antibiotics linked to asthma in mouse study

A new study conducted on mice suggests that antibiotics taken in childhood could play a part in the development and severity of allergic asthma.The study published Friday in the journal EMBO reports that antibiotics may damage bacteria that live in the gut, disturbing the bacterial community and possibly causing a more severe form of asthma.

Honey Helps Heal Wounds: Scientific American Podcast

Honey's antibacterial properties have been used for centuries. Now, scientists are discovering just how it works—and that it might be even better than antibiotics. researchers found that honey—in particular that made from bees foraging on manuka flowers—inhibits the development of streptococcus pyogenes.

Do our medicines boost pathogens?

Scientists of the Institute of Tropical Medicine (ITG) discovered a parasite that not only had developed resistance against a common medicine, but at the same time had become better in withstanding the human immune system. With some exaggeration: medical practice helped in developing a superbug. For it appears the battle against the drug also armed the bug better against its host. "To our knowledge it is the first time such a doubly armed organism appears in nature", says researcher Manu Vanaerschot, who obtained a PhD for his detective work at ITG and Antwerp University. "It certainly makes you think."