Susceptibility to disease develops during childhood

April 29, 2019

Science Daily/University of Zurich

Traumatized children and children who develop multiple allergies tend to suffer in adulthood from chronic inflammatory diseases and psychiatric disorders. Researchers at the Universities of Zurich and Lausanne have demonstrated this in a study in which they identified five classes of early immune-system programming.

The human immune system forms during childhood: The "hygiene hypothesis" provides a widely regarded perspective on this. It postulates that improved hygiene, changes in agriculture and urbanization have caused our immune systems to come in contact with certain microbes less often or later in life than before. It is presumed that these developments have adversely resulted in an increased incidence of chronic inflammatory diseases, allergies and mental disorders such as depression.

Taking the hygiene hypothesis as a starting point, an interdisciplinary group of researchers at the Universities of Zurich and Lausanne analyzed epidemiological data from a cohort of almost 5,000 people who were born in the mid-20th century. They concentrated on the co-incidence of allergies, viral and bacterial diseases, and psychosocial stress in childhood. On the basis of early morbidity patterns, the scientists identified five different groups of people that they characterized by biomarkers (white blood cell counts, inflammatory markers) and, in a further step, by their association patterns with chronic inflammatory diseases and psychiatric disorders during adulthood.

One in five people have a very resistant immune system

 The main group, which comprised almost 60% of the total cohort analyzed, possessed an ordinary, "neutral" immune system. Their disease burden during childhood was comparatively low. Childhood disease burden was even lower for the second-largest group comprising more than 20% of the total cohort: that group exhibited an especially resistant, "resilient" immune system. Even symptoms of common childhood diseases like measles, mumps or rubella, which were not preventable in the mid-20th century, appeared far less frequently in this group than in the "neutral" group.

The "resilient" group is juxtaposed by three smaller groups. The "atopic" group (7% of total cohort) exhibited incidents of multiple allergic diseases. The roughly same-sized "mixed" group (approximately 9%) was characterized by single allergic disorders such as drug allergies, for example, and by bacterial and rash-inducing childhood diseases like scarlet fever, pertussis or rubella. The smallest of the five groups (approximately 5%) comprised people who were traumatized in childhood. They were more susceptible to allergic diseases, but responded comparatively resiliently to common childhood viral diseases.

Hygiene hypothesis taken a step further

Comparative analyses revealed that the "neutral" and "resilient" groups were larger among people with earlier birth years than they were among individuals with later birth years. The exact opposite was true for the "atopic" group, which increased the later the birth year. "Our study thus corroborates the hygiene hypothesis," lead author Vladeta Ajdacic-Gross from the University of Zurich says, "but at the same time goes beyond it."

Differences between the groups also manifested themselves in later health. People belonging to the "resilient" group were better protected in adulthood not just against chronic inflammatory diseases, but also against mental disorders. Members of the "atopic" and "mixed" groups, on the other hand, were susceptible to elevated somatic and psychiatric health risks in later age. The "traumatized" group likewise exhibited a greater predisposition to psychiatric illness in adulthood as well as a higher risk of suffering from chronic inflammatory diseases, the latter only among women, however. "The findings of the study indicate that the human immune system acts like a switchboard between somatic and psychic processes," Ajdacic-Gross explains. "They help us understand why many people who do not have a history of psychosocial trauma get afflicted by mental disorders and, conversely, why traumatized people show a predisposition to chronic inflammatory diseases."

https://www.sciencedaily.com/releases/2019/04/190429134130.htm

Healthy, stress-busting fat found hidden in dirt

Healthy, stress-busting fat found hidden in dirt

May 29, 2019

Science Daily/University of Colorado at Boulder

Thirty years after scientists coined the term "hygiene hypothesis" to suggest that increased exposure to microorganisms could benefit health, CU Boulder researchers have identified an anti-inflammatory fat in a soil-dwelling bacterium that may be responsible.

The discovery, published Monday in the journal Psychopharmacology, may at least partly explain how the bacterium, Mycobacterium vaccae, quells stress-related disorders. It also brings the researchers one step closer to developing a microbe-based "stress vaccine."

"We think there is a special sauce driving the protective effects in this bacterium, and this fat is one of the main ingredients in that special sauce," said senior author and Integrative Physiology Professor Christopher Lowry.

British scientist David Strachan first proposed the controversial "hygiene hypothesis" in 1989, suggesting that in our modern, sterile world, lack of exposure to microorganisms in childhood was leading to impaired immune systems and higher rates of allergies and asthma. Researchers have since refined that theory, suggesting that it is not lack of exposure to disease-causing germs at play, but rather to "old friends" -- beneficial microbes in soil and the environment that we have long lived alongside -- and that mental health is also impacted.

"The idea is that as humans have moved away from farms and an agricultural or hunter-gatherer existence into cities, we have lost contact with organisms that served to regulate our immune system and suppress inappropriate inflammation," said Lowry. "That has put us at higher risk for inflammatory disease and stress-related psychiatric disorders."

Lowry has published numerous studies demonstrating a link between exposure to healthy bacteria and mental health. One showed that children raised in a rural environment, surrounded by animals and bacteria-laden dust, grow up to have more stress-resilient immune systems and may be at lower risk of mental illness than pet-free city dwellers.

Others have shown that when a particular soil-dwelling bacterium, Mycobacterium vaccae, is injected into rodents, it alters the animals' behavior in a way similar to that of antidepressants and has long-lasting anti-inflammatory effects on the brain. (Studies suggest exaggerated inflammation boosts risk of trauma and stressor related disorders, such as posttraumatic stress disorder.)

One Lowry-authored study, published in the Proceedings of the National Academy of Sciences in 2016, showed that injections of M. vaccae prior to a stressful event could prevent a "PTSD-like" syndrome in mice, fending off stress-induced colitis and making the animals act less anxious when stressed again later.

"We knew it worked, but we didn't know why," said Lowry. "This new paper helps clarify that."

For the new study, Lowry and his team identified, isolated and chemically synthesized a novel lipid, or fatty acid, called 10(Z)-hexadecenoic acid found in Mycobacterium vaccae and used next-generation sequencing techniques to study how it interacted with macrophages, or immune cells, when the cells were stimulated.

They discovered that inside cells, the lipid acted like a key in a lock, binding to a specific receptor, peroxisome proliferator-activated receptor (PPAR), and inhibiting a host of key pathways which drive inflammation. They also found that when cells were pre-treated with the lipid they were more resistant to inflammation when stimulated.

"It seems that these bacteria we co-evolved with have a trick up their sleeve," said Lowry. "When they get taken up by immune cells, they release these lipids that bind to this receptor and shut off the inflammatory cascade."Lowry has long envisioned developing a "stress vaccine" from M. vaccae, which could be given to first responders, soldiers and others in high-stress jobs to help them fend off the psychological damage of stress."This is a huge step forward for us because it identifies an active component of the bacteria and the receptor for this active component in the host," he said.

Simply knowing the mechanism of action by which M. vaccae reaps benefits could boost confidence in it as a potential therapeutic. And if further studies show the novel fat alone has therapeutic effects, that molecule could become a target for drug development, he said.

Overall, the study offers further proof that our "old friends" have a lot to offer.

"This is just one strain of one species of one type of bacterium that is found in the soil but there are millions of other strains in soils," Lowry said. "We are just beginning to see the tip of the iceberg in terms of identifying the mechanisms through which they have evolved to keep us healthy. It should inspire awe in all of us."

https://www.sciencedaily.com/releases/2019/05/190529094003.htm