Inflammation Link Allergy, Asthma, and Depression?

The prevalence of depression is consistently higher in persons with asthma than in persons without it, according to experts, and a review of 24 studies also found that allergic rhinitis was associated with higher odds of depression or anxiety.

Over the past two decades, multiple investigators have looked beyond emotional or lifestyle triggers of depression in chronic airway or allergic conditions, focusing instead on eco-biological ones. This has led to inflammation being identified as the common denominator in all three — allergies, asthma, and depression.

As the understanding of how inflammation, as measured by an increase in immune cells, cytokines, and other biomarkers, affects neural signaling continues to improve; potential implications for clinical practice are beginning to emerge, experts say.

Evolutionary ‘Mismatch’

One line of inquiry that implicates inflammation in depression, chronic airway trouble, and allergies, involves the microbiome and how modern living has altered it.

“There’s essentially an evolutionary mismatch in the modern world,” Charles Raison, MD, professor of psychiatry and human ecology at the University of Wisconsin – Madison, told Medscape Medical News in an interview. “We’ve made the world so clean we deprive ourselves — especially in early life when allergies and asthma tend to develop — of contact with microorganisms that train the immune system not to fire off at things they don’t need to fire off about.”

In a review of literature published in 2013 on immune function titled, Inflammation, Sanitation, and Consternation, Raison and his coauthors concluded that measured exposure to certain microorganisms and their antigens could offer both prevention and intervention for depression.

“Our current challenge is to determine who among those with allergies is at highest risk of developing depression, and why,” Christopher Lowry, PhD, a coauthor on the paper with Raison, told Medscape Medical News. Lowry is a professor of integrative physiology and associate chair of faculty affairs at the University of Colorado Boulder.

‘Old Friends’

Raison and Lowry’s collaboration follows on from the “Old Friends” work of Graham Rook, a coauthor of their review study, and an emeritus professor of medical microbiology at the University College London in London, England.

“The association between allergies and depression is embedded in the ‘Old Friends’ or Biodiversity Hypothesis which posits that reduced exposures to diverse microbial environments, which is typical of modern urban lifestyles, increases risk of allergies, anxiety disorders, and depression,” Lowry told Medscape Medical News.

Because the commensal microorganisms in the gut are one of the major types of microbial “Old Friends” that can induce anti-inflammatory and immunoregulatory responses, Lowry said, “Those who lack diverse microbial exposures, including diverse microbial exposures in the gut microbiome, are thought to be at higher risk of inflammatory disease and inflammation-associated conditions.” 

Similarly, “we have shown that this response is greater in persons who grow up in an urban environment, without daily exposure to pets, relative to persons who grow up on a farm, with daily exposure to farm animals,” said Lowry, whose research on the immune effects of exposure to animals was published in the Proceedings of the National Academies of Science.

Other categories of microbial “Old Friends,” according to Lowry, are environmental saprophytes found in soil, mud, and unpurified water, and so-called “Old Infections” such as the hepatitis A virus or Salmonella.

Rook has gone so far as to say that these microbial inputs, “are absolutely crucial in early life, but continue to be important in adulthood and old age.” Raison added, “These microbes don’t cause illnesses, they are the teachers of tolerance, is how we used to say it. When we began to institute a bunch of modern sanitation and medical practices, on the plus side people stopped dying in youth. Huge win. But we didn’t see we were tossing out the good with the bad, and we’ve lost our exposure to these environmental immunoregulatory organisms that suppress inflammation.”

In the past 40 years, incident rates for asthma in the US have doubled according to federal data. A third of persons in the US now have an allergy of some kind, these data also showed. Rates of depression are also at their highest, according to a probability-based Gallup survey of 100,000 adults in the US. In 2023, the survey found that 29% of US adults had been given a diagnosis of depression in their lifetime.

Microbial Population Health Initiative

The “Old Friends” theory was tested in Finland for the decade between 2008 and 2018, when a population health initiative to increase exposures to diverse microbial environments led to a reduction in hospitalizations for asthma by half nationally and a 50% drop in the number of food allergies reported in Finnish schools and daycares. The results were published in 2021 in The Journal of Allergy and Clinical Immunology. Depression rates for this time period in Finland are not currently available.

“This was hot, sexy stuff back 20 years ago, but nobody figured out the magic bullet to end all allergies and asthma, so like a lot of things in mental health, it didn’t come too much,” Raison said. “It’s gone through fads, like the probiotic fad. But another question would be, what if you were to re-expose kids to these kinds of microbes that train the immune system not to be so agitated, would you lower rates of depression and suicide in adults? Those studies were never done.”

Lowry, however, now studies whether the microorganism, Mycobacterium vaccae ATCC 15483, which has been identified as having anti-inflammatory, immunoregulatory, and stress-resilience properties, can be leveraged to protect humans from the effects of inflammation.

In a study that was published earlier this year in Brain, Behavior and Immunity, Lowry and his colleagues found M vaccae reduced biomarkers of neuroinflammation and anxiety-like behavior in animals. It also reduced several indicators of obesity such as plasma leptin concentrations and adipose tissue.

“We hope to conduct clinical trials in the next 2-5 years to determine if treatment with mycobacteria can reduce inflammation and promote stress resilience in humans,” Lowry said. “Future studies should evaluate if mycobacteria or other ‘Old Friends’ can prevent or treat anxiety and depression.”

Inflammation Is Bidirectional

If depression in asthma and allergies is at least partially biological, then there are implications for clinical practice, according to one expert.

“The default for physicians is usually that it’s hard to have a chronic disease, and that’s why their patients are depressed,” Melissa Rosenkranz, PhD, told Medscape Medical News. “But if they understand that there is a biology that underlies it, that the immune dysregulation that’s giving rise to the disease is also contributing to the depression, and that they can do something about that — if we can target those signaling pathways, then we can be treating both simultaneously.”

Rosenkranz is an associate professor of psychiatry at the University of Wisconsin – Madison and is the distinguished chair of contemplative neuroscience at the Center for Healthy Minds. Her field is psycho-neuroimmunology, which focuses on interactions between the mind, brain, and immune system.

Whether inflammation is the mechanism of action or a symptom in both asthma and depression is something she and her colleagues have studied.

“It goes in both directions,” Rosenkranz said. “We’ve done that research.”

Alterations in Neural Signaling

Their first and second studies involved scanning study patients’ brains before and after their airways were challenged with an inflammatory antigen and comparing those results to the before and after scans of the brains of participants exposed to methacholine, which does not irritate, but does constrict, the bronchial passages, making it difficult to breathe. A third study introduced an inflammatory agent to a micro region of the bronchial passages.

“All three studies showed what was happening in the brain was different in the inflammatory context,” Rosenkranz said in the interview.

Specifically, Rosenkranz and her colleagues discovered that the brain’s salience network — the part that prioritizes which stimuli, both internal and external to the body, require the brain’s attention most — responded differently to emotional information when the immune system had been activated. They found that the more the salience network was engaged during psychological stress, the more the inflammatory response in the airway was activated, even without exposure to allergy triggers.

“Our results identify a specific inflammatory pathway linking asthma-related airway inflammation and emotion-related neural function,” Rosenkranz and her coauthors wrote in their study, published in The Journal of Allergy and Clinical Immunology.

An immune pathway common to both depression and the airway inflammatory response in asthma is the T helper cell 17 (TH17) response, according to Rosenkranz, whose work has shown that the TH17 response is amplified in the lung during stress.

Activity in the TH17 pathway is also elevated in people with depression, according to Rosenkranz, and TH17 is also less responsive to common asthma medications and is associated with treatment-resistant depression.

“There are probably multiple pathways through which [inflammation] happens, so I don’t want to claim that this is the only one, but I think it’s one among a few that may provoke inflammation in the brain,” Rosenkranz said. “And inflammation has been shown to be part of the pathophysiology of depression. It’s also part of the cascade that gives rise to Alzheimer’s disease and other forms of dementia.”

Rosenkranz’s latest study is on how an asthma exacerbation can lead to inflammation in the brain, and whether those changes might set the stage for dementia.

“It’s possible that depression is along the same trajectory as dementia,” Rosenkranz said. “As you get on later in life, you see the cognitive decline. With nearly 10% of the population having asthma, this is a really important public health question.”

Rosenkranz said she doesn’t want to be an alarmist. “I’m not suggesting that everybody who has depression has inflammation in their brain,” she said.

As the field searches for an immune-signaling pathway that, if targeted with drugs, could improve asthma, allergies, prevent asthma-related depression, and possibly protect the brain, Rosenkranz said that for now, “Physicians should evaluate the emotional well-being of their patients and work closely with mental health professionals to address mental and physical symptoms in tandem, so that they can best serve their patients.” They need to understand that depression in patients with asthma or allergy could be a symptom of, not a reaction to their diagnosis, she said.

Raison serves as a consultant for Usona Institute and Otsuka and is on the Board of Directors for the Fireside Project. He received grant funding from the Tiny Blue Dot Foundation. Lowry is a cofounder and member of the Scientific Advisory Board of Mycobacteria Therapeutics Corporation (Kioga) and is a member of the faculty of Clinical Care Options, LLC (CCO), Reston, Virginia; the Integrative Psychiatry Institute, Boulder, Colorado; the Institute for Brain Potential, Los Banos, California; and Intelligent Health Ltd, Reading, England. In the previous three years, he has served on the Scientific Advisory Board of Immodulon Therapeutics Ltd., London, England. Rosenkranz had no disclosures to report.