Tufts University School of Engineering researchers and collaborators from Texas A&M University have published the first research to use computational modelling to predict and identify the metabolic products of gastrointestinal (GI) tract microorganisms. Understanding these metabolic products, or metabolites, could influence how clinicians diagnose and treat GI diseases, as well as many other metabolic and neurological diseases increasingly associated with compromised GI function.

The human GI tract is colonized by billions of bacteria and other microorganisms, belonging to hundreds of species that are collectively termed ‘microbiota.’ Disruptions in the microbiota composition, and subsequently the metabolites derived from the microbiota, are increasingly correlated not only to GI diseases such as inflammatory bowel disease (IBD) and colitis, but also to insulin resistance and Type 2 diabetes.

‘There is increasing evidence that microbiota-derived metabolites play a significant role in modulating physiological functions of the gut,’ said Professor Kyongbum Lee, senior author on the paper and chair of the Department of Chemical and Biological Engineering in Tuft School of Engineering. ‘Emerging links between the GI tract microbiota and many other parts of the body, including the brain, suggest the tantalizing possibility to influence even cognition and behaviour through relatively benign interventions involving diets or probiotics.’

However, to date, only a handful of metabolites principally produced by microbiota—rather than the host organism itself—have been identified. Identifying microbiota-derived metabolites and understanding their effects on specific host functions could open up new avenues of basic and clinical research to develop safe, targeted therapies involving molecules that, by definition, constitute the natural chemical makeup of the host.

‘Current methods of identifying and quantifying these metabolites are unable to distinguish whether the metabolites are produced by the host or the microbiota,’ said Lee.

The newly reported approach models the microbiome as a single, complex network of reactions. By using computational algorithms for network analysis, virtual pathways can be constructed to determine possible metabolic products. Then, these products can be parsed into host-derived or microbiota-derived metabolites.

The research team focused on aromatic amino acids (AAAs) because their metabolites are involved in many of the more than 2,400 distinct reactions expressed in the microbiota as a whole.

‘In addition, we studied AAA-derived metabolites because AAAs can give rise to a variety of bioactive chemicals, such as salicylic acid, an anti-inflammatory compound, and serotonin, which is a neurotransmitter, obviously important in proper brain function,’ said Lee.

Work previously published in the Proceedings of the National Academy of Sciences from Lee’s collaborator Arul Jayaraman, professor in the Artie McFerrin Department of Chemical Engineering at Texas A&M University who holds a master’s from Tufts School of Engineering, had already demonstrated that indole, a bacterial metabolite derived from the aromatic amino acid tryptophan, caused an anti-inflammatory response in the gut and increased resistance to pathogen colonization that could lead to infection

The algorithmic model in the research published today predicted 49 different metabolites would appear as exclusive to the microbiota. In vivo tests on mice then confirmed the presence of more than half of the predicted metabolites, including two novel metabolites, which play a role in the pathways that regulate microbiota metabolism as well as host immune function.

Next steps for the team include identifying microbiota metabolites whose levels are either significantly elevated or depleted during diseases such as IBD or cancer, to find disease-specific markers and explore possible roles for these metabolites in disease progression.

‘Ultimately, the goal is to apply our models to arrive at a mechanistic understanding of the roles microbiota products may play in human physiology, and in turn, diagnose and treat disease,’ said Lee. ‘I think the potential for impact is immense.’ Tufts University

Some children are more sensitive to their environments, for better and for worse. Now Duke University researchers have identified a gene variant that may serve as a marker for these children, who are among society’s most vulnerable.

“The findings are a step toward understanding the biology of what makes a child particularly sensitive to positive and negative environments,” said Dustin Albert, a research scientist at the Duke Center for Child and Family Policy. “This gives us an important clue about some of the children who need help the most.”

Drawing on two decades worth of data on high-risk first-graders from four locations across the country, the study found that children from high-risk backgrounds who also carried a certain common gene variant were extremely likely to develop serious problems as adults. Left untreated, 75 percent with the gene variant developed psychological problems by age 25, including alcohol abuse, substance abuse and antisocial personality disorder.

The picture changed dramatically, though, when children with the gene variant participated in an intensive program called the Fast Track Project. After receiving support services in childhood, just 18 percent developed psychopathology as adults.

“It’s a hopeful finding,” Albert said. “The children we studied were very susceptible to stress. But far from being doomed, they were instead particularly responsive to help.”

Previous research has suggested that while some children thrive like dandelions in a wide range of circumstances, others are more like orchids who wither or bloom in different environments. The new study suggests that children’s different levels of sensitivity are related to differences in their genomes.

Beginning in 1991, researchers screened nearly 10,000 kindergartners for aggressive behaviour problems, identifying nearly 900 who were at high risk, and assigning half of that group to receive intensive help. It was the largest violence-prevention trial ever supported by the National Institutes of Health and researchers have now followed participants since the early 1990’s.

Previous research has linked participation in Fast Track interventions to lower rates of psychiatric problems, substance abuse and convictions for violent crime in adulthood. The new study looks at the possible biology behind those responses. Albert said these findings could be a first step toward potential personalized treatments for some of society’s most troubled children. Knowledge like this might someday be used to help match children who would benefit with programs they badly need.

Key questions remain though, Albert said.  For starters, while the Fast Track Project was offered to children of all races, the new findings were limited to white children. Specifically, the authors observed strong response to Fast Track among the 60 white children with a common variant of the glucocorticoid receptor gene NR3C1, a gene involved in the body’s stress response.

Although children of other ethnicities benefited from Fast Track, the authors have not yet found a similar genetic clue to help identify which of these children responded most positively to the intervention.

“That doesn’t mean such genetic markers don’t exist among children of other races,” Albert said. “We simply don’t know yet what those markers are. ”That’s one of several important avenues for future research, Albert said, adding that thoughtful examination of the ethical issues involved is needed before the findings can be translated into policy.

“It would be premature to use this finding to screen children to determine who should receive intervention,” Albert said. “A lot more work needs to be done before we decide whether or not to make that leap.” Duke University

A new study from Lund University in Sweden shows that women with low levels of an anti-stress hormone have an increased risk of getting breast cancer. The study is the first of its kind on humans and confirms previous similar observations from animal experiments.
The recent findings on a potential new marker for the risk of developing breast cancer. The study focused on a hormone which circulates freely in the blood, enkephalin, with pain- and anxiety-reducing properties. Enkephalin also reinforces the immune system by directly affecting immune cells.

“This is the first time the role of enkephalin in breast cancer has been studied in humans, and the results were surprisingly clear. Among women with the lowest levels of the hormone, the risk of breast cancer was more than three times that of the women with the highest levels of the hormone. This is one of the strongest correlations between cancer risk and a freely circulating biomarker ever described”, said Olle Melander and Mattias Belting, both professors at Lund University and consultant physicians at Skåne University Hospital.

The findings were possible thanks to a broad approach combining the latest knowledge within cancer and cardiovascular research at Lund University; the study was based on blood samples taken from just over 1 900 women in Malmö.  The women were followed up with regard to breast cancer for an average period of 15 years.

The results were adjusted for age, menopause, hormonal treatment, smoking and other factors which can affect the risk of getting breast cancer.

The current study confirms a statistical correlation between low enkephalin concentrations in the blood and increased risk of breast cancer, and it remains to be seen whether there is a causal relation showing that a low level of the hormone directly affects tumour development. The researchers also point out that geographical location and age, in spite of the adjustments in the study, may be significant. The average age of the women studied was 57.

On the other hand, the study’s results are backed up by a subsequent control study of a group of 1 500 women with a marginally higher average age. In this group, the link between low levels of the hormone and breast cancer was even stronger. Animal studies by other researchers also gave similar indications. These studies established that enkephalin can reinforce the activity of the immune system against cancer cells, as well as having a direct tumour-inhibiting effect.

The researchers at Lund University hope that, after further studies, the results will facilitate prevention and early detection of breast cancer.  For those with an increased risk of breast cancer, potential preventive treatments could take the form of lifestyle interventions to reduce stress and new drugs. The findings fit well with the development towards individualised risk assessment and treatment, on the basis of each woman’s needs. Lund University

In a recent study, Virginia Commonwealth University School of Medicine researchers predicted which cirrhosis patients would suffer inflammations and require hospitalization by analysing their saliva, revealing a new target for research into a disease that accounts for more than 30,000 deaths in the United States each year.

The findings could trigger a change in the way researchers study chronic liver disease and associated microbiota, the network of tiny organisms in the human body such as bacteria and fungi that can either bolster an immune system or weaken it.

The breakdown of defences in the mucosa of the gut has long been a signal of inflammation in those with cirrhosis, which sees healthy liver tissue replaced by scar tissue.

The recent findings suggest that another part of the body also can produce warning signs.

“It has been believed that most of the pathogenesis of cirrhosis starts in the gut, which is what makes this discovery so fascinating,” said Jasmohan S. Bajaj, M.D., associate professor of hepatology in the VCU School of Medicine and Hunter Holmes McGuire Veterans Affairs Medical Center.“The fact that saliva, along with fluid in the gut, can be an indicator of inflammation tells us that we need to further explore the oral cavity and its connections to liver disease.”

The paper describes a study of more than 100 cirrhosis patients from VCU and VA Medical Center, 38 of which had to be hospitalized within 90 days because of flare-ups. Researchers found that the ratio of good-to-bad microbes was similar in the saliva as in the stool of these patients who required hospitalization.

Another part of the same study looked at an additional group of more than 80 people with and without cirrhosis. Those with cirrhosis had impaired salivary defenses, mirroring the immune deficiencies that take place in the gut.

“The data suggest that there may be a change in the overall mucosal-immune interface in cirrhosis patients, allowing a more toxic microbiota to emerge in both the gut and oral cavity,” said Phillip B. Hylemon, Ph.D., professor of microbiology and immunology in the VCU School of Medicine and co-author of the paper.

In addition to using oral microbiota to predict the disease status of cirrhosis patients, Hylemon said the new evidence could provide a useful tool for testing treatment protocols for patients with cirrhosis or other diseases driven by inflammation. Virginia Commonwealth University Scool of Medicine