Skin Cell Reprogrammed into Neurons Without Genetic Engineering

Two labs in China have independently succeeded in transforming skin cells into neurons using only a cocktail of chemicals, with one group using human cells from humans and the other group using cells from mice. The two studies reinforce the idea that a purely chemical approach is a promising way to scale up cell reprogramming research that may avoid the technical challenges and safety concerns associated with the more popular method of using transcription factors. Both papers appear on August 6 in the journal Cell Stem Cell.

The importance of these studies is that they were able to change skin cells into neurons without using genetic engineering. This has already been done many times by adding new genes to cells, however that approach creates significant risks if they are used for actual human therapy since the DNA has been changed in ways that may have unknown consequences in the long run.

One of the challenges of forcing cells to change identity is that the cells you end up with may look normal but have different internal activities than their naturally forming counterparts. The two papers provide evidence that similar gene expression, action potentials, and synapse formation can be detected in transcription-factor-induced neurons as those generated from the chemical cocktails. (Both groups used mixtures of seven small molecules, but different recipes–outlined in detail in the supplemental information section of each paper–because they focused on different species.)

“We found that the conversion process induced by our chemical strategy is accompanied by the down-regulation of [skin-cell] specific genes and the increased expression of neuronal transcription factors,” said human study co-author Jian Zhao, of the Shanghai Institutes for Biological Sciences and Tongji University. “By coordinating multiple signaling pathways, these small molecules modulate neuronal transcription factor gene expression and thereby promote the neuronal cell transition.” The authors add that the direct conversion bypasses a proliferative intermediate progenitor stage, which circumvents safety issues posed by other reprogramming methods.

Zhao’s paper, co-led with cell biologist Gang Pei, also shows that the pure chemical protocol can be used to make neurons from the skins cells of Alzheimer’s patients. Most of the work using patient stem cells has been done by using transcription factors–molecules that affect which genes are expressed in a cell–to create induced pluripotent stem cells. Chemical cell reprogramming is seen as an alternative for disease modeling or even potential cell replacement therapy of neurological disorders, but the “proof-of-concept” is still emerging.

“In comparison with using transgenic reprogramming factors, the small molecules that are used in this chemical approach are cell permeable; cost-effective; and easy to synthesize, preserve, and standardize; and their effects can be reversible,” says mouse study co-author Hongkui Deng of the Peking University Stem Cell Research Center. “In addition, the use of small molecules can be fine-tuned by adjusting their concentrations and duration, and the approach bypasses the technical challenges and safety concerns of genetic manipulations, which may be promising in their future applications.”

Deng worked for four years with Zhen Chai and Yang Zhao, also of Peking University, to identify the small molecules that could create chemically induced mouse neurons. Researchers had been close for years, but a transcription factor was always necessary to complete the transformation. Through many chemical screens they identified the key ingredient, I-BET151, which works to suppress transcription in skin cells. They then found the right steps and conditions to mature the neurons post-transformation.

The authors of both papers aim to learn more about the biology behind chemically induced reprogramming and to make the protocols more efficient. While their success is promising, there are still a number of hurdles to overcome.

“We hope in the future that the chemical approaches would be more robust in inducing functional mature neurons,” Deng says. “In addition, we are attempting to generate specific neuronal subtypes and patient-specific functional neurons for translational medicine by using pure chemicals.”

Jian Zhao, of the human study, says: “It should be possible to generate different subtypes of neurons with a similar chemical approach but using slightly modified chemical cocktails.” She adds: “It also needs to be explored whether functional neurons could be induced by chemical cocktails in living organisms with neurological diseases or injury.”

References:

1.Wenxiang Hu, Binlong Qiu, Wuqiang Guan, Qinying Wang, Min Wang, Wei Li, Longfei Gao, Lu Shen, Yin Huang, Gangcai Xie, Hanzhi Zhao, Ying Jin, Beisha Tang, Yongchun Yu, Jian Zhao, Gang Pei. Direct Conversion of Normal and Alzheimer?s Disease Human Fibroblasts into Neuronal Cells by Small Molecules. Cell Stem Cell, 2015; 17 (2): 204 DOI: 10.1016/j.stem.2015.07.006

2.Xiang Li, Xiaohan Zuo, Junzhan Jing, Yantao Ma, Jiaming Wang, Defang Liu, Jialiang Zhu, Xiaomin Du, Liang Xiong, Yuanyuan Du, Jun Xu, Xiong Xiao, Jinlin Wang, Zhen Chai, Yang Zhao, Hongkui Deng. Small-Molecule-Driven Direct Reprogramming of Mouse Fibroblasts into Functional Neurons. Cell Stem Cell, 2015; 17 (2): 195 DOI: 10.1016/j.stem.2015.06.003

Higher Carotenoid Intake Associated With Lower Lipid Oxidation and DNA Damage

Lending fruits and vegetables their bright orange, red, and yellow colors, carotenoids are abundant in antioxidants, for which previous studies have associated a lower risk of premature death. A recent study assessed the potential relationships of carotenoid intake with lipid and oxidative stress markers in middle-aged men. Data analysis revealed that higher total carotenoid intake was associated with lower lipid and oxidative stress markers, and in middle-aged men higher beta-carotene intake was also associated with five of the six lower lipid stress markers.

If you decide to obtain beta-carotene from a nutritional supplement be sure and use one that is derived from carrots, algae and other natural sources rather than synthetic beta-carotene which has been associated with some negative effects in a previous study.

A total of 296 apparently healthy middle-aged men with a mean age of 50.5 years and a mean BMI of 25.8 kg/m2 were recruited to participate in the study. Dietary intake, anthropometry, blood pressure, lifestyle features, blood and urine biomarkers were assessed using validated procedures. The lipid markers included NEFA, Castelli index, and TAG:HDL ratio; oxidative stress markers included urinary 8-hydroxy-2-deoxyguanosine (8-OHdG), 8-iso-PGF2 and plasma oxidised-LDL (ox-LDL). The scientists observed a significant inverse association (P< 0?05) between NEFA concentrations and consumption of lutein plus zeaxanthin, alpha-carotene, beta-carotene and total carotenoid, while the Castelli index was negatively associated with daily intake of lycopene, beta-carotene and total carotenoids. Regarding oxidative stress biomarkers, urinary 8-OHdG and ox-LDL concentrations were also inversely associated (P< 0?05) with consumption of lycopene, lutein plus zeaxanthin, alpha-carotene, beta-carotene and total carotenoids, regardless of confounding variables. Moreover, there was a negative association of urinary 8-iso-PGF2 concentration with dietary lutein plus zeaxanthin and with the sum of all carotenoids. In conclusion, higher total daily carotenoid intake based on five investigated carotenoid types (beta-cryptoxanthin, lycopene, lutein plus zeaxanthin, alpha-carotene and beta-carotene) was associated with lower relevant lipid and oxidative stress markers in middle-aged men, with emphasis on beta-carotene that was negatively associated with five of the six lipid and oxidative stress markers evaluated in the present study.

Mystery of Liver Stem Cells Solved

Howard Hughes Medical Institute (HHMI) scientists have identified stem cells in the liver that give rise to functional liver cells. The work solves a long-standing mystery about the origin of new cells in the liver, which must constantly be replenished as cells die off, even in a healthy organ.

“We’ve solved a very old problem,” says Roel Nusse, an HHMI investigator at Stanford University who led the research. “We’ve shown that like other tissues that need to replace lost cells, the liver has stem cells that both proliferate and give rise to mature cells, even in the absence of injury or disease.” Nusse and his colleagues reported their findings August 5, 2015, in the journal Nature.

The liver is made up mostly of hepatocytes, highly specialized cells that carry out the organ’s many tasks, including storing vitamins and minerals, removing toxins, and helping regulate fats and sugars in the bloodstream. As these cells die off, they are replaced by healthy new hepatocytes. The source of those new cells had never been identified, Nusse says.

Stem cells, which replenish their own populations and maintain the ability to develop into more specialized cells, provide new cells in the skin, blood, and other tissues where cells are naturally lost over time. But no stem cells had been found in the liver. Some scientists speculated that mature hepatocytes might maintain their populations by dividing. But Nusse says the mature cells have become so specialized to carry out the work of the liver, they have likely lost the ability to divide.

“Differentiated hepatocytes have amplified their chromosomes,” he explains. That is, the cells have more than the usual two copies of every chromosome. “This enables the cells to make more proteins, but it really compromises their ability to divide.”

Nusse’s lab at Stanford focuses on a family of proteins of called Wnts, which are key regulators of stem cell fate. To find and follow stem cells in a variety of tissues, they have developed mice in which cells that respond to the Wnt signal are labeled with a fluorescent protein. Several years ago, they decided to use the mice to search for stem cells in the liver.

Bruce Wang, a gastroenterologist at the Liver Center at the University of California, San Francisco, led the experiments as a visiting scholar in Nusse’s lab. Wang began by searching for fluorescently labeled, Wnt-responsive cells in the livers of the engineered mice, and he ultimately found them clustered around the liver’s central vein.

Once they knew which cells to focus on, the scientists tracked the fluorescently labeled cells’ behavior. Over time, they noticed that the cells they were tracking divided rapidly, steadily replenishing their own population. This was possible because unlike mature hepatocytes, the labeled cells had only two copies of each chromosome. By following the descendents of the stem cells for up to a year, the scientists discovered that these had changed, taking on the specialized features and amplified genomes of mature hepatocytes. “This fits the definition of stem cells,” Nusse says.

As expected, the liver stem cells required Wnt signals to maintain their stem cell identity. Nusse’s team discovered that endothelial cells lining the central vein, the blood vessel around which the stem cells were clustered, released Wnt molecules into the tissue. Stem cells that migrated out of reach of that signal quickly lost their ability to divide into new stem cells and began to develop into mature hepatocytes. Nusse says this is consistent with how stem cells are known to behave in other tissues.

The lab is now investigating how the newly identified stem cells might contribute to regeneration of liver tissue after injury. It will also be important to explore whether liver cancers tend to originate in these replicating cells, as opposed to more mature hepatocytes, Nusse says.

The above post is reprinted from materials provided by Howard Hughes Medical Institute. Note: Materials may be edited for content and length.

Better to Avoid Melamine Tableware

melamine tableware

With their vibrant colors and breakage resistance, melamine plates, bowls, and cups are becoming popular. A number of previous studies suggest that heat and acid can cause melamine from dinnerware to seep into food ? leading to increased risks of urinary stones and kidney problems. Ming-Tsang Wu, from Kaohsiung Medical University (Taiwan), and colleagues propose that a substitution can dramatically reduce this potential exposure problem. The researchers first measured melamine levels in the urine of study subjects and then substituted stainless steel boxes and silverware for their hot meals. The melamine levels in their urine decreased after using the containers by as much as 92%. The study authors write that:” Regular use of stainless steel-made meals boxes can mitigate melamine exposure from melamine tableware.”

In 2008, the health effects of acute melamine exposure became widely known when a scandal erupted in China over the material’s use in milk powder. About 300,000 people were sickened, and more than 50,000 babies were hospitalized. Although officials largely stamped out the practice of adding melamine to food, most people continue to be exposed to the substance, an industrial chemical also used in other plastics, flooring and whiteboards. Some research has suggested that even small amounts could increase the risk of urinary stones or kidney problems, and one major source of the material is tableware. Ming-Tsang Wu and colleagues wanted to see what kinds of practices could lower people’s exposure.

The researchers first measured melamine levels in the urine of study subjects and then gave them stainless steel boxes and silverware for their hot meals. The melamine levels in their urine decreased after using the containers by 41 to 92 percent. The wide range could be due to subjects’ exposure to other uncontrolled sources of the substance, the researchers say.

Automating the Production of IPS Cells

Ten years ago there was a lot of controversy about the use of human embryonic stem cells in scientific research. The problem was solved with the creation of IPS Cells (induced pluripotent stem cells) which are made by turning adult skin or other cells back into embryonic like stem cells. The process has been time consuming and manual so robotic equipment has now been produced to make it much faster and more efficient.

The New York Stem Cell Foundation designed and has built a revolutionary, high-throughput robotic platform that automates and standardizes the process of transforming patient samples into stem cells. This one-of-a-kind system addresses challenges that face the entire field, and is now an essential resource that NYSCF provides in collaborations with leading academic and industry partners around the world.

In the paper published in Nature Methods, NYSCF scientists demonstrated how the NYSCF Global Stem Cell Array?, for the first time ever, gives researchers the scale to look at diverse populations and draw meaningful conclusions. This breakthrough technology will allow researchers to better understand the underlying causes of disease and, ultimately, create individually tailored treatments for patients.

Induced pluripotent stem cells (iPSCs) are an essential tool for modeling how causal genetic variants impact cellular function in disease, as well as an emerging source of tissue for regenerative medicine. The preparation of somatic cells, their reprogramming and the subsequent verification of iPSC pluripotency are laborious, manual processes limiting the scale and reproducibility of this technology. This process can not be automated using a modular, robotic platform for iPSC reprogramming, high-throughput conversion of skin biopsies into iPSCs and differentiated cells with minimal manual intervention. Automated reprogramming and the pooled selection of polyclonal pluripotent cells results in high-quality, stable iPSCs. These lines display less line-to-line variation than either manually produced lines or lines produced through automation followed by single-colony subcloning. The robotic platform will enable the application of iPSCs to population-scale biomedical problems including the study of complex genetic diseases and the development of personalized medicines.

Scientists Say They Will Soon Extend Human Lifespan Well Beyond 120 Years

Each new paradigm goes through three stages. The first is outright rejection, the second is discussion and the third is when it is accepted as self evident. For development of significant life extension technologies we are now in the second stage. Even five years ago the scientific consensus was that aging research was interesting but unlikely to lead to anything practical. Now Google is funding it’s Calico life extension startup with hundreds of millions of dollars and a number of other billonaires and Silicon Valley startups are also seriously funding or working on anti-aging research.

At Life Code we have taken the approach of using the scientific knowledge that is already available to develop nutraceutical supplements to help extend both the quality and quantity of life now. Combining these with a healthy diet and exercise program will yield even better results. We want to enjoy life as we get older and not end up shuffling around a nursing home with a walker. We also want to be alive when even more effective anti-aging therapies become available whether from our parent biotechnology companies or from others.

An excellent article with the title Live for ever: Scientists say they?ll soon extend life ?well beyond 120? appeared in the Guardian earlier this year. It gives an overview of some of the high profile people involved with life extension research.

Scientists Discover When Aging Begins

When does aging really begin? Two Northwestern University scientists now have a molecular clue. In a study of the transparent roundworm C. elegans, they found that adult cells abruptly begin their downhill slide when an animal reaches reproductive maturity.

A genetic switch starts the aging process by turning off cell stress responses that protect the cell by keeping important proteins folded and functional. The switch is thrown by germline stem cells in early adulthood, after the animal starts to reproduce, ensuring its line will live on.

While the studies were conducted in worms, the findings have implications for humans, the researchers report. The genetic switch and other components identified by the scientists as playing a role in aging are conserved in all animals, including humans, offering targets for future study. (C. elegans has a biochemical environment similar to that of humans and is a popular research tool for the study of the biology of aging and as a model of human disease.)

Knowing more about how the quality control system works in cells could help researchers one day figure out how to provide humans with a better cellular quality of life and therefore delay degenerative diseases related to aging, such as neurodegenerative diseases.

“Wouldn’t it be better for society if people could be healthy and productive for a longer period during their lifetime?” said Richard I. Morimoto, the senior author of the study. “I am very interested in keeping the quality control systems optimal as long as we can, and now we have a target. Our findings suggest there should be a way to turn this genetic switch back on and protect our aging cells by increasing their ability to resist stress.”

Morimoto is the Bill and Gayle Cook Professor of Molecular Biosciences and director of the Rice Institute for Biomedical Research in Northwestern’s Weinberg College of Arts and Sciences.

The study, built on a decade of research, will be published in the July 23 issue of the journal Molecular Cell. Johnathan Labbadia, a postdoctoral fellow in Morimoto’s lab, is the first author of the paper.

In C. elegans, the decline begins eight hours into adulthood — all the switches get thrown to shut off an animal’s cell stress protective mechanisms. Morimoto and Labbadia found it is the germline stem cells responsible for making eggs and sperm that control the switch.

In animals, including C. elegans and humans, the heat shock response is essential for proper protein folding and cellular health. Aging is associated with a decline in quality control, so Morimoto and Labbadia looked specifically at the heat shock response in the life of C. elegans.

“We saw a dramatic collapse of the protective heat shock response beginning in early adulthood,” Morimoto said.

Morimoto and Labbadia found the genetic switch occurs between two major tissues in an organism that determine the future of the species: the germline and the soma (the body tissues of the animal, such as muscle cells and neurons). Once the germline has completed its job and produced eggs and sperm — necessary for the next generation of animals — it sends a signal to cell tissues to turn off protective mechanisms, starting the decline of the adult animal.

“C. elegans has told us that aging is not a continuum of various events, which a lot of people thought it was,” Morimoto said.

“In a system where we can actually do the experiments, we discover a switch that is very precise for aging,” he said. “All these stress pathways that insure robustness of tissue function are essential for life, so it was unexpected that a genetic switch is literally thrown eight hours into adulthood, leading to the simultaneous repression of the heat shock response and other cell stress responses.”

Using a combination of genetic and biochemical approaches, Morimoto and Labbadia found the protective heat shock response declines steeply over a four-hour period in early adulthood, precisely at the onset of reproductive maturity. The animals still appear normal in behavior, but the scientists can see molecular changes and the decline of protein quality control.

In one experiment, the researchers blocked the germline from sending the signal to turn off cellular quality control. They found the somatic tissues remained robust and stress resistant in the adult animals.

“This was fascinating to see,” Morimoto said. “We had, in a sense, a super stress-resistant animal that is robust against all kinds of cellular stress and protein damage. This genetic switch gives us a target for future research.”

Reference: Johnathan Labbadia, Richard I. Morimoto. Repression of the Heat Shock Response Is a Programmed Event at the Onset of Reproduction. Molecular Cell, 2015; DOI: 10.1016/j.molcel.2015.06.027

Agave Extracts Help Improve Gut Microbiota

Summary: Prebiotics are digestion-resistant compounds that feed the “good bacteria” in the GI tract. The agave plant contains inulin, a polysaccharide for which some previous studies suggest a physiologic effect. Kelly Swanson, from the University of Illinois (Illinois, USA), and colleagues enrolled 29 healthy adults in a 3-period crossover double-blind study in which subjects were randomized to 1of 3 groups: 0, 5.0, or 7.5 grams per day of agave inulin; each period was followed by a 7-day washout before crossover. Fecal samples were collected and fermented, then analyzed to determine gut bacteria populations. Data analysis revealed that Bifidobacterium levels increased 4-fold after 5.0 and 7.5 grams per day agave inulin; as well, Desultivibrio levels decreased 40%. Agave inulin consumption also associated with reduced fecal pH and increased butyrate ? suggesting increased saccharolytic fermentation and reduced proteolytic fermentation. The study authors observe that: “Agave inulin supplementation shifted the gastrointestinal microbiota composition and activity in healthy adults.”

Background: Prebiotics resist digestion, providing fermentable substrates for select gastrointestinal bacteria associated with health and well-being. Agave inulin differs from other inulin type fibers in chemical structure and botanical origin. Preclinical animal research suggests these differences affect bacterial utilization and physiologic outcomes. Thus, research is needed to determine whether these effects translate to healthy adults.

Objective: We aimed to evaluate agave inulin utilization by the gastrointestinal microbiota by measuring fecal fermentative end products and bacterial taxa.

Methods: A randomized, double-blind, placebo-controlled, 3-period, crossover trial was undertaken in healthy adults (n = 29). Participants consumed 0, 5.0, or 7.5 g agave inulin/d for 21 d with 7-d washouts between periods. Participants recorded daily dietary intake; fecal samples were collected during days 16?20 of each period and were subjected to fermentative end product analysis and 16S Illumina sequencing.

Results: Fecal Actinobacteria and Bifidobacterium were enriched (P < 0.001) 3- and 4-fold after 5.0 and 7.5 g agave inulin/d, respectively, compared with control. Desulfovibrio were depleted 40% with agave inulin compared with control. Agave inulin tended (P < 0.07) to reduce fecal 4-methyphenol and pH. Bivariate correlations revealed a positive association between intakes of agave inulin (g/kcal) and Bifidobacterium (r = 0.41, P < 0.001). Total dietary fiber intake (total fiber plus 0, 5.0, or 7.5 g agave inulin/d) per kilocalorie was positively associated with fecal butyrate (r = 0.30, P = 0.005), tended to be positively associated with Bifidobacterium (r = 0.19, P = 0.08), and was negatively correlated with Desulfovibrio abundance (r = ?0.31, P = 0.004). Conclusions: Agave inulin supplementation shifted the gastrointestinal microbiota composition and activity in healthy adults. Further investigation is warranted to determine whether the observed changes translate into health benefits in human populations.

Sugary Drinks Linked to Higher Mortality

Summary: If you want to live longer and stay healthy your chances are better if you substantially reduce or eliminate sugar-sweetened beverages from your diet.

Consumption of sugary drinks may lead to an estimated 184,000 adult deaths each year worldwide, according to research published today in the journal Circulation and previously presented as an abstract at the American Heart Association Council on Epidemiology and Prevention in 2013.

“Many countries in the world have a significant number of deaths occurring from a single dietary factor, sugar-sweetened beverages. It should be a global priority to substantially reduce or eliminate sugar-sweetened beverages from the diet,” said Dariush Mozaffarian, M.D., Dr.P.H., senior author of the study and dean of the Friedman School of Nutrition Science & Policy at Tufts University in Boston.

In the first detailed global report on the impact of sugar-sweetened beverages, researchers estimated deaths and disabilities from diabetes, heart disease, and cancers in 2010. In this analysis, sugar sweetened beverages were defined as any sugar-sweetened sodas, fruit drinks, sports/energy drinks, sweetened iced teas, or homemade sugary drinks such as frescas, that contained at least 50 kcal per 8oz serving. 100 percent fruit juice was excluded.

Estimates of consumption were made from 62 dietary surveys including 611,971 individuals conducted between 1980 and 2010 across 51 countries, along with data on national availability of sugar in 187 countries and other information. This allowed capture of geographical, gender and age variation in consumption levels of sugar-sweetened beverages in different populations. Based on meta-analyses of other published evidence on health harms of sugar-sweetened beverages, the investigators calculated the direct impact on diabetes and the obesity-related effects on cardiovascular disease, diabetes and cancer.

In 2010, the researchers estimate that sugar-sweetened beverages consumption may have been responsible for approximately:

? 133,000 deaths from diabetes

? 45,000 deaths from cardiovascular disease

? 6,450 deaths from cancer

“Some population dietary changes, such as increasing fruits and vegetables, can be challenging due to agriculture, costs, storage, and other complexities. This is not complicated. There are no health benefits from sugar-sweetened beverages, and the potential impact of reducing consumption is saving tens of thousands of deaths each year,” Mozaffarian said.

The impact of sugar-sweetened beverages varied greatly between populations. At the extremes, the estimated percentage of deaths was less than 1 percent in Japanese over 65 years old, but 30 percent in Mexican adults younger than 45. Of the 20 most populous countries, Mexico had the highest death rate attributable to sugar-sweetened beverages with an estimated 405 deaths per million adults (24,000 total deaths) and the U.S. ranked second with an estimated 125 deaths per million adults (25,000 total deaths).

About 76 percent of the estimated sugar-sweetened beverage-related deaths occurred in low- or middle-income countries.

In nations of the Caribbean and Latin America, such as Mexico, homemade sugary drinks (e.g. frescas) are popular and consumed in addition to commercially prepared sugar-sweetened beverages. “Among the 20 countries with the highest estimated sugar-sweetened beverage-related deaths, at least 8 were in Latin America and the Caribbean, reflecting the high intakes in that region of the world,” said Gitanjali Singh, Ph.D., lead author of the study and a research assistant professor at the Friedman School.

Overall, in younger adults, the percent of chronic disease attributed to sugar-sweetened beverages was higher than the percent in older adults. “The health impact of sugar-sweetened beverage intake on the young is important because younger adults form a large sector of the workforce in many countries, so the economic impact of sugar-sweetened beverage-related deaths and disability in this age group can be significant. It also raises concerns about the future. If these young people continue to consume high levels as they age, the effects of high consumption will be compounded by the effects of aging, leading to even higher death and disability rates from heart disease and diabetes than we are seeing now,” Singh said.

Loss of Cognitive Function From Eating a High Fat or High Sugar Diet

CORVALLIS, Ore. – A study at Oregon State University indicates that both a high-fat and a high-sugar diet, compared to a normal diet, cause changes in gut bacteria that appear related to a significant loss of “cognitive flexibility,” or the power to adapt and adjust to changing situations.

This effect was most serious on the high-sugar diet, which also showed an impairment of early learning for both long-term and short-term memory.

The findings are consistent with some other studies about the impact of fat and sugar on cognitive function and behavior, and suggest that some of these problems may be linked to alteration of the microbiome – a complex mixture in the digestive system of about 100 trillion microorganisms.

The research was done with laboratory mice that consumed different diets and then faced a variety of tests, such as water maze testing, to monitor changes in their mental and physical function, and associated impacts on various types of bacteria. The findings were published in the journal Neuroscience, in work supported by the Microbiology Foundation and the National Science Foundation.

“It’s increasingly clear that our gut bacteria, or microbiota, can communicate with the human brain,” said Kathy Magnusson, a professor in the OSU College of Veterinary Medicine and principal investigator with the Linus Pauling Institute.

“Bacteria can release compounds that act as neurotransmitters, stimulate sensory nerves or the immune system, and affect a wide range of biological functions,” she said. “We’re not sure just what messages are being sent, but we are tracking down the pathways and the effects.”

Mice have proven to be a particularly good model for studies relevant to humans, Magnusson said, on such topics as aging, spatial memory, obesity and other issues.

In this research, after just four weeks on a high-fat or a high-sugar diet, the performance of mice on various tests of mental and physical function began to drop, compared to animals on a normal diet. One of the most pronounced changes was in what researchers call cognitive flexibility.

“The impairment of cognitive flexibility in this study was pretty strong,” Magnusson said. “Think about driving home on a route that’s very familiar to you, something you’re used to doing. Then one day that road is closed and you suddenly have to find a new way home.”

A person with high levels of cognitive flexibility would immediately adapt to the change, determine the next best route home, and remember to use the same route the following morning, all with little problem. With impaired flexibility, it might be a long, slow, and stressful way home.

This study was done with young animals, Magnusson said, which ordinarily would have a healthier biological system that’s better able to resist pathological influences from their microbiota. The findings might be even more pronounced with older animals or humans with compromised intestinal systems, she said.

What’s often referred to as the “Western diet,” or foods that are high in fat, sugars and simple carbohydrates, has been linked to a range of chronic illnesses in the United States, including the obesity epidemic and an increased incidence of Alzheimer’s disease.

“We’ve known for a while that too much fat and sugar are not good for you,” Magnusson said. “This work suggests that fat and sugar are altering your healthy bacterial systems, and that’s one of the reasons those foods aren’t good for you. It’s not just the food that could be influencing your brain, but an interaction between the food and microbial changes.”