Gut bacteria can reverse autism-related social behavior in mice

oxy.JPGThe absence of a one specific species of gut bacteria causes social deficits in mice, researchers at Baylor College of Medicine report June 16, 2016 in Cell. By adding this bacteria species back to the guts of affected mice, the researchers were able to reverse some of their behavioral deficits, which are reminiscent of symptoms of autism spectrum disorders (ASDs) in humans. The investigators are now looking to explore the effects of probiotics on neurodevelopmental disorders in future work.

“Other research groups are trying to use drugs or electrical brain stimulation as a way to reverse some of the behavioral symptoms associated with neurodevelopmental disorders — but here we have, perhaps, a new approach,” says senior author Mauro Costa-Mattioli, a neuroscientist at Baylor College of Medicine. “Whether it would be effective in humans, we don’t know yet, but it is an extremely exciting way of affecting the brain from the gut.”

The inspiration for the paper came from human epidemiological studies that have found that maternal obesity during pregnancy could increase children’s risk of developing neurodevelopmental disorders, including ASDs. In addition, some individuals with ASD also report recurring gastrointestinal problems. With emerging research showing how diet can change the gut microbiome and how gut microbes can influence the brain, Costa-Mattioli and his co-authors suspected there could be a connection.

To begin, the researchers fed approximately 60 female mice a high-fat diet that was the rough equivalent of consistently eating fast food multiple times a day. They bred the mice daily and waited for them to bear young. The offspring stayed with their mother for three weeks and then were weaned onto a normal diet. After a month, these offspring showed behavioral deficits, such as spending less time in contact with their peers and not initiating interactions.

“First we wanted to see if there was a difference in the microbiome between the offspring of mouse mothers fed a normal diet versus those of mothers fed a high-fat diet. So, we used 16S ribosomal RNA gene sequencing to determine the bacterial composition of their gut. We found a clear difference in the microbiota of the two maternal diet groups,” says first author Shelly Buffington, a postdoctoral fellow in Costa-Mattioli’s lab. “The sequencing data was so consistent that by looking at the microbiome of an individual mouse we could predict whether its behavior would be impaired.”

Buffington next tested whether the specific differences in the microbiome were causative factors underlying the social impairments in offspring of mothers fed a high-fat diet. Because mice eat each other’s excrement, the researchers housed the animals together so that they would acquire microbiota from their cagemates. When socially impaired three-week-old mice born to mothers on a high-fat diet were paired with normal mice, a full restoration of the gut microbiome and a concurrent improvement in behavior was observed within four weeks. The investigators concluded that one or more beneficial bacterial species might be important for normal social behavior. Fecal-transplant experiments in mice without microbiota (germ-free mice) provided causal evidence that an imbalanced microbial ecology in the mice born to mothers on a high-fat diet is responsible for their social deficits.

The investigators next wanted to know the specific bacterial species that could be affecting the social behavior of the mice. Whole-genome shotgun sequencing revealed one type of bacteria, Lactobacillus reuteri, which was reduced more than nine-fold in the microbiome of mice born to mothers on the high-fat diet.

“We cultured a strain of Lactobacillus (L.) reuteri originally isolated from human breast milk and introduced it into the water of the high-fat-diet offspring. We found that treatment with this single bacterial strain was able to rescue their social behavior,” Buffington says. Other ASD-related behaviors, such as anxiety, were not restored by the reconstitution of the bacteria. Interestingly, the authors found that L. reuteri also promoted the production of the “bonding hormone” oxytocin, which is known to play a crucial role in social behavior and has been associated with autism in humans.

The authors wondered whether the reward circuitry in the socially impaired mice was dysfunctional. “We found that in response to social interaction there was a lack of synaptic potentiation in a key reward area of the brain that could be seen in the normal control mice,” Costa-Mattiol says. “When we put the bacteria back in the maternal-high-fat-diet offspring, we could also restore the changes in synaptic function in the reward circuitry.”

The researchers believe that their work, which uses a human bacteria species to promote oxytocin levels and improve social behavioral deficits in deficient mice, could be explored as a probiotic intervention for the treatment of neurodevelopmental disorders in humans. “This is where the science is unexpectedly leading us. We could potentially see this type of approach developing quite quickly not only for the treatment of ASD but also for other neurodevelopmental disorders; anyway, this is my gut feeling,” Costa-Mattioli says.


Story Source:

The above post is reprinted from materials provided by Cell Press. Note: Materials may be edited for content and length.


Journal Reference:

  1. Buffington et al. Microbial reconstitution reverses maternal diet-induced social and synaptic deficits in offspring. Cell, 2016 DOI: 10.1016/j.cell.2016.06.001

Cell Press. “A single species of gut bacteria can reverse autism-related social behavior in mice.” ScienceDaily. ScienceDaily, 16 June 2016. <www.sciencedaily.com/releases/2016/06/160616140723.htm>.

Nicotinamide Riboside converting 60yr old to 20yr old cells in mice, an anti-aging miracle (metabolic and brain issues)

Mitochondria, organelles on the right, interact with the cell’s nucleus to ensure a healthy, functioning cell.

cell

Researchers have discovered a cause of aging in mammals that may be reversible.

Aging Process

The essence of this finding is a series of molecular events that enable communication inside cells between the nucleus and mitochondria. As communication breaks down, aging accelerates. By administering a molecule naturally produced by the human body, scientists restored the communication network in older mice. Subsequent tissue samples showed key biological hallmarks that were comparable to those of much younger animals.

“The aging process we discovered is like a married couple—when they are young, they communicate well, but over time, living in close quarters for many years, communication breaks down,” said Harvard Medical School Professor of Genetics David Sinclair, senior author on the study. “And just like with a couple, restoring communication solved the problem.”

This study was a joint project between Harvard Medical School, the National Institute on Aging, and the University of New South Wales, Sydney, Australia, where Sinclair also holds a position.

The findings are published Dec. 19 in Cell.

Communication breakdown between Mitochondria and Nucleus

Mitochondria are often referred to as the cell’s “powerhouse,” generating chemical energy to carry out essential biological functions. These self-contained organelles, which live inside our cells and house their own small genomes, have long been identified as key biological players in aging. As they become increasingly dysfunctional overtime, many age-related conditions such as Alzheimer’s disease and diabetes gradually set in.

Researchers have generally been skeptical of the idea that aging can be reversed, due mainly to the prevailing theory that age-related ills are the result of mutations in mitochondrial DNA—and mutations cannot be reversed.

Sinclair and his group have been studying the fundamental science of aging—which is broadly defined as the gradual decline in function with time—for many years, primarily focusing on a group of genes called sirtuins. Previous studies from his lab showed that one of these genes, SIRT1, was activated by the compound resveratrol, which is found in grapes, red wine and certain nuts.

Sirt1 protein, red, circles the cell's chromosomes, blue. Image by Ana GomesSirt1 protein, red, circles the cell’s chromosomes, blue. Image by Ana Gomes

Ana Gomes, a postdoctoral scientist in the Sinclair lab, had been studying mice in which this SIRT1 gene had been removed. While they accurately predicted that these mice would show signs of aging, including mitochondrial dysfunction, the researchers were surprised to find that most mitochondrial proteins coming from the cell’s nucleus were at normal levels; only those encoded by the mitochondrial genome were reduced.

“This was at odds with what the literature suggested,” said Gomes.

How Nicotinamide Riboside Works = NAD, NR and Sirtuin Enzymes

There’s basically three important pieces of this puzzle. NAD+, Nicotinamine Riboside (NR) and Sirtuin Enzymes, all of which relate to the nucleus, mitochondria, and most importantly, the communication between the two in every cell.

It all begins with the mitochondria. Mitochondria have long been known as the “power houses” of our cells, as they are responsible for energy production in each specific cell; and therefore, throughout our entire body.

The nucleus, on the other hand, is the controller of the cell. The nucleus ensures that everything inside of the cell is going well, that all of the “employees” at “Cell Corporation” are doing their jobs effectively.

The problem, as Sinclair and Cantó, et al. discovered, occurs when communication between these two important organelles breaks down. When that happens, the cells begin to suffer the effects of age, producing less energy and not working as efficiently as possible. This failure manifests itself in aging – both in the skin, and in the skeletal and muscle structure.

That is to say, when the nucleus and mitochondria don’t communicate properly, everything falls apart.

This is where the three puzzle pieces fit in. This communication is promoted by an enzyme called Sirutin 1, or SIRT1. This enzyme is responsible, essentially, for ensuring outside molecules don’t interrupt the traffic between the nucleus and the cell wall.

SIRT1, in turn, is activated by a chemical called NAD+. NAD+ is what’s known as a co-substrate, which is basically an activator – a compound that ensures the activation of a certain molecule. NAD+ is the most important part of this whole equation.

Luckily for us, NAD+ is a naturally occurring molecule in our body. Without it, our cells would die quickly.

Note: Energy (Sun,Exercise,protein and healthy fats-rich food,negated by  toxins and stress and lack of sleep)

The sirtuins are a family of highly conserved NAD(+)-dependent deacetylases that act as cellular sensors to detect energy availability and modulate metabolic processes. Two sirtuins that are central to the control of metabolic processes are mammalian sirtuin 1 (SIRT1) and sirtuin 3 (SIRT3), which are localized to the nucleus and mitochondria, respectively. Both are activated by high NAD(+) levels, a condition caused by low cellular energy status. By deacetylating a variety of proteins that induce catabolic processes while inhibiting anabolic processes, SIRT1 and SIRT3 coordinately increase cellular energy stores and ultimately maintain cellular energy homeostasis. Defects in the pathways controlled by SIRT1 and SIRT3 are known to result in various metabolic disorders. Consequently, activation of sirtuins by genetic or pharmacological means can elicit multiple metabolic benefits that protect mice from diet-induced obesity, type 2 diabetes, and nonalcoholic fatty liver disease.

Sirtuins are comprised of 7 proteins, and each has different target proteins. Sirtuin 1 (SIRT1) plays important roles in maintaining metabolic functions and immune responses, and SIRT3 protects cells from oxidative stress-induced cell death. Both SIRT1 and SIRT3 are regulated by metabolic status and aging. Hence, SIRT1 and SIRT3 have been researched in metabolic diseases, such as type 2 diabetes mellitus (DM), fatty liver, and heart diseases.

Unluckily, NAD+ levels decline as we age, resulting in wrinkles, bone deterioration, and muscle decline.

dysfunctional mitochondriaThis is where Sinclair and Cantó, et al.’s research comes in. They identified a new vitamin that can stoke the production of NAD+ — without the side effects of other NAD+ precursors like Nicotinic Acid, which causes severe flushing.

This NAD+ producer is nicotinamide riboside.

In both studies, the mice who were supplemented with NR showed powerful anti-aging effects, metabolic energy increases and improvements in cell repair and upkeep. This suggests that supplementation with this new vitamin is a possible key to halting the effects of aging.

Even more interesting, Cantó, et al. suggest that NR can also be used to “ameliorate metabolic and age-related disorders”. This can be applied to problems that arise from our metabolism and aging problems, like arthritis and type 2 diabetes.

It is important to note that these two studies have only been used on mice. There is a bit of a gap as far humans go. Specifically, the amount of NR necessary to induce a change is, at the current moment, nebulous.

Get your NR here

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Final anti-aging tips: Avoid medications/drugs if possible, get sunshine, take fresh air,clean water, whole foods, avoid sugar/soda/processed foods and get good sleep. Avoid anxiety and dwelling on problems, be happy and dance.