Common origin behind major childhood allergies

Several major childhood allergies may all stem from the community of bacteria living in our gut, according to a new study led by researchers at the University of British Columbia and BC Children's Hospital.

The research, published in Nature Communications, identifies gut microbiome features and early life influences that are associated with children developing any of four common allergies -- eczema, asthma, food allergy and/or hay fever. The findings could lead to methods of predicting whether a child will develop allergies, and ways to prevent them from developing at all.

"We're seeing more and more children and families seeking help at the emergency department due to allergies," said Dr. Stuart Turvey, professor in the department of pediatrics at UBC and an investigator at BC Children's Hospital Research Institute, and co-senior author on the study. "Hundreds of millions of children worldwide suffer from allergies, including one in three children in Canada, and it's important to understand why this is happening and how it can be prevented."

The study is one of the first to examine four distinct school-aged pediatric allergies at once. While these allergic diseases each have unique symptoms, the Turvey lab was curious whether they might have a common origin linked to the infant gut microbiota composition.

"These are technically different diagnoses, each with their own list of symptoms, so most researchers tend to study them individually," says Dr. Charisse Petersen, co-senior author on the paper and postdoctoral fellow in the Turvey lab. "But when you look at what is going wrong at a cellular level, they actually have a lot in common."

For the study, researchers examined clinical assessments from 1,115 children who were tracked from birth to age five. Roughly half of the children (523) had no evidence of allergies at any time, while more than half (592) were diagnosed with one or more allergic disorders by an expert physician. The researchers evaluated the children's microbiomes from stool samples collected at clinical visits at three months and one year of age.

The stool samples revealed a bacterial signature that was associated with the children developing any of the four allergies by five years of age. The bacterial signature is a hallmark of dysbiosis, or an imbalanced gut microbiota, that likely resulted in a compromised intestinal lining and an elevated inflammatory response within the gut.

"Typically, our bodies tolerate the millions of bacteria living in our guts because they do so many good things for our health. Some of the ways we tolerate them are by keeping a strong barrier between them and our immune cells and by limiting inflammatory signals that would call those immune cells into action," says Courtney Hoskinson, a PhD candidate at UBC and first author on the paper. "We found a common breakdown in these mechanisms in babies prior to the development of allergies."

Many factors can shape the infant gut microbiota, including diet, how we are born, where we live, and our exposure to antibiotics. For example, antibiotics may wipe out sensitive bacteria, while breastfeeding tends to replenish and provide necessary food for bacteria in the infant gut. The researchers examined how these types of influences affected the balance of gut microbiota and the development of allergies.

"There are a lot of potential insights from this robust analysis," says Dr. Turvey. "From these data we can see that factors such as antibiotic usage in the first year of life are more likely to result in later allergic disorders, while breastfeeding for the first six months is protective. This was universal to all the allergic disorders we studied."

Now the researchers hope to leverage the findings to inform treatments that correct an imbalanced gut microbiota and could potentially prevent allergies from developing.

"Developing therapies that change these interactions during infancy may therefore prevent the development of all sorts of allergic diseases in childhood, which often last a lifetime," says Dr. Turvey.

The research is part of the Canadian Healthy Infant Longitudinal Development (CHILD) Cohort Study that recruited families through BC Children's Hospital and BC Women's Hospital + Health Centre and other pediatric hospitals across Canada. Since launching in 2008, the team of Canadian researchers has tracked the health, growth and environments of kids from birth and made important discoveries about how asthma and allergies develop.

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New evidence: Immune system cells in the gut linked to stress-induced depression

In experiments with mice and humans, a team led by Johns Hopkins Medicine researchers says it has identified a particular intestinal immune cell that impacts the gut microbiome, which in turn may affect brain functions linked to stress-induced disorders such as depression. Targeting changes mediated by these immune cells in the gut, with drugs or other therapies, could potentially bring about new ways to treat depression.

The findings of the study were published March 20, 2023 in the journal Nature Immunology.

"The results of our study highlight the previously unrecognized role of intestinal gamma delta T cells (γδ T cells) in modifying psychological stress responses, and the importance of a protein receptor known as dectin-1, found on the surface of immune cells, as a potential therapeutic target for the treatment of stress-induced behaviors," says Atsushi Kamiya, M.D., Ph.D., professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine and the study's senior author.

Dectin-1 binds to certain antigens, or proteins, to signal immune cells to activate in specific ways. This receptor, the researchers say, may be involved in the microbiome alteration and immune-inflammatory responses in the colon of mice, which suggests that it may be involved in stress responses via γδ T cells in the intestinal immune system.

On the basis of previous studies suggesting that immune inflammatory responses in the gut are related to depression, Kamiya and his team designed experiments to focus on understanding stress-induced behaviors produced by an imbalance in the gut microbiota -- types of microorganisms found in a specific environment, such as bacteria, fungi and viruses.

To this end, the team examined the effects of chronic social defeat stress (CSDS) on the gut microbiota in mice. CSDS is a standard rodent test to study stress-induced disorders such as depression. In a series of experiments, the researchers simulated potential stress inducing environments that could mimic similar responses in human environments. After each exposure, the mice were assessed and classified as stress-resilient (stress did not diminish social interactions) or stress-susceptible (stress increased social avoidance).

Fecal samples were then collected and put through genetic analysis to identify the diversity of bacteria in the gut microbiota of the mice. The analysis showed that the intestinal organisms were less diverse in stress-susceptible mice than in stress-resilient mice. It specifically revealed that there were less Lactobacillus johnsonii (L. johnsonii) -- a type of probiotic, or "good" bacteria -- in stress-susceptible mice compared to stress-resilient mice.

"We found that stress increased the γδ T cells, which in turn increased social avoidance," says Xiaolei Zhu, M.D., Ph.D., assistant professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine and the study's lead author. "However, when the stressed mice were given L. johnsonii, social avoidance decreased and the γδ T cells went to normal levels, suggesting that CSDS-induced social avoidance behavior may be the result of lower levels of the bacteria and γδ T cell changes."

Looking for potential natural approaches for prevention of depression rooted somehow in the gut, the researchers explored how changes in dectin-1 on CSDS-induced elevation of γδ T cells responded to pachyman. A compound extracted from wild mushrooms, pachyman is used as a natural anti-inflammatory agent and for treating depression in Eastern medicine. For this experiment, mice were fed a dose of pachyman, which was shown in previous research to affect immune function. Data from flow cytometry analysis -- a technology used to measure the physical and chemical characteristics of a population of cells -- provided evidence that dectin-1 binds to pachyman, inhibiting CSDS-induced γδ17 T cell activity and easing social avoidance behavior.

To gain insight into how the alterations in the gut microbiota could impact the human brain, the researchers investigated the makeup of gut organisms in people with major depressive disorder (MDD) compared to people without MDD. From June 2017 to September 2020, 66 participants, ages 20 or older, were recruited at Showa University Karasuyama Hospital, Keio University Hospital and Komagino Hospital in Tokyo, Japan. Of the study participants, 32 had MDD (17 women and 15 men). The other 34 participants (18 women and 16 men) who did not have MDD formed the control group.

Stool samples were collected from all study participants, who had comprehensive evaluations including psychiatric history and standard screening assessments for depression and anxiety. In these assessments, higher scores indicate greater depressive symptoms. Genetic analysis of the stool samples showed no difference in the diversity of intestinal bacteria between the subjects with MDD and the control group. However, the relative abundance of Lactobacillus was inversely related to higher depression and anxiety scores in the MDD group, meaning that the more Lactobacillusfound in the gut, the lower the potential for depression and anxiety, the researchers say.

"Despite the differences of intestinal microbiota between mice and humans, the results of our study indicate that the amount of Lactobacillus in the gut may potentially influence stress responses and the onset of depression and anxiety," says Kamiya.

The investigators say more research is needed to further understand how γδ T cells in the intestinal immune system may impact the neurological functions in the brain and the role of dectin-1 in other cell types along the gut-brain connection under stress conditions.

"These early-stage findings show that, in addition to probiotic supplements, targeting drugs to such types of receptors in the gut immune system may potentially yield novel approaches to prevent and treat stress-induced psychiatric symptoms such as depression," says Kamiya.

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Exploring factors that may underlie how domestic cats can live in groups

A new analysis explores relationships between domestic cats' hormone levels, gut microbiomes, and social behaviors, shedding light on how these solitary animals live in high densities. Hikari Koyasu of Azabu University in Kanagawa, Japan, and colleagues present these findings in the open-access journal PLOS ONE on July 27, 2022.

Most feline species display solitary and territorial behavior, but domestic cats often live in high densities, raising the question of what strategies cats use to establish cohabitating groups. Social behaviors of cats can be influenced by hormones and the mix of different microbe species living in their guts -- known as the gut microbiome. Studying these factors could help illuminate the group dynamics of cohabitating cats.

In that vein, Koyasu and colleagues conducted a two-week-long study of three different groups of five cats living together in a shelter. They used video cameras to observe the cats' behavior, measured hormone levels in their urine, and collected feces to evaluate the mix of microbial species in the cats' microbiomes.

Statistical analysis of the data revealed that cats with high levels of the hormones cortisol and testosterone had less contact with other cats, and those with high testosterone were more likely to try to escape. Meanwhile, cats with low cortisol and testosterone were more tolerant in their interactions with other cats. The researchers also found greater similarity of gut microbiomes between cats who had more frequent contact with each other, and they found links between the gut microbiome, social behavior, and cortisol levels.

Meanwhile, contrary to the researchers' expectations from research on animals that typically live in groups, cats with high levels of the hormone oxytocin did not display bonding behaviors described as "socially affiliative." This suggests that oxytocin might function differently for typically solitary animals living in groups than for animals that typically live in groups.

The researchers outline possible directions for future research to further deepen understanding of cohabitating cat dynamics, such as a follow-up study that observes cats for several months, rather than just two weeks, and investigations to tease out causal relationships between hormones and social behaviors.

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Cleveland Clinic study links gut microbiome and aggressive prostate cancer

Cleveland Clinic researchers have shown for the first time that diet-associated molecules in the gut are associated with aggressive prostate cancer, suggesting dietary interventions may help reduce risk. Findings from the study were published in Cancer Epidemiology, Biomarkers & Prevention.

While more research will be necessary, the study's lead author Nima Sharifi, M.D., says findings from the team's analysis of nearly 700 patients may have clinical implications for diagnosing and preventing lethal prostate cancer.

"We found that men with higher levels of certain diet-related molecules are more likely to develop aggressive prostate cancer," said Dr. Sharifi, director of Cleveland Clinic's Genitourinary Malignancies Research Center. "As we continue our research in this area, our hope is that one day these molecules can be used as early biomarkers of prostate cancer and help identify patients who can modify their disease risk by making dietary and lifestyle changes."

In this study, Dr. Sharifi and his collaborators -- including Stanley Hazen, M.D., Ph.D., and Eric Klein, M.D. -- analyzed data from patients previously enrolled in the National Cancer Institute's Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial.

They studied baseline levels of certain dietary nutrients and metabolites (byproducts produced when a substance is broken down in the gut) found in patients' blood serum prior to prostate cancer diagnosis. They compared serum levels between healthy patients and those who later received a prostate cancer diagnosis and died from the disease.

The researchers found that men with elevated levels of a metabolite called phenylacetylglutamine (PAGln) were approximately two or three times more likely to be diagnosed with lethal prostate cancer. This metabolite is produced when microbes in the gut break down phenylalanine, an amino acid found in many plant- and animal-based protein sources like meat, beans and soy.

In addition to PAGln, researchers also discovered that elevated levels of two nutrients abundant in animal products, including red meat, egg yolks and high-fat dairy products, called choline and betaine, also were linked with increased risk for aggressive prostate cancer.

While these nutrients and gut metabolites have been studied previously in heart disease and stroke, this is the first time that gut microbiome metabolites have been studied clinically in relation to prostate cancer outcomes.

Dr. Hazen was the first to identify PAGln's association with increased cardiovascular disease risk. The findings were published in 2020 in Cell. "Interestingly, we found that PAGln binds to the same receptors as beta blockers, which are drugs commonly prescribed to help lower blood pressure and subsequent risk of cardiac events," said Dr. Hazen, director of Cleveland Clinic's Center for Microbiome & Human Health and chair of Lerner Research Institute's Department of Cardiovascular & Metabolic Sciences. "This suggests that part of beta blockers' potent efficacy may be due to blocking the metabolite's activity."

"New insights are emerging from large-scale clinical datasets that show use of beta blockers is also associated with lower mortality due to prostate cancer," said Dr. Sharifi, who is a staff physician in Lerner Research Institute's Department of Cancer Biology. "We will continue to work together to investigate the possible mechanisms linking PAGln activity and prostate cancer disease processes in hopes of identifying new therapeutic targets for our patients."

The research team also will continue to explore the reliability of using choline, betaine and PAGln as biomarkers of aggressive prostate cancer and how dietary interventions can be used to modulate their levels and reduce patients' subsequent disease risk.

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