Source: University of Colorado at Boulder
Thirty years after scientists coined the term “hygiene hypothesis ” to suggest that increased exposure to microorganisms could benefi t health, University of Colorado Boulder researchers have identified an ant i-inflammatory fat in a soil-dwelling bacterium that may be responsible.
The discovery, published Monday in the journal Psychopharmacology, may at l east partly explain how the bacterium, Mycobacterium vaccae, quells stress- related disorders. It also brings the researchers one step closer to develo ping a microbe-based “stress vaccine.”
“We think there is a special sauce driving the protective effects i n this bacterium, and this fat is one of the main ingredients in that speci al 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 impa ired 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 fr iends” – beneficial microbes in soil and the environment – and that mental health is also impacted.
“The idea is that as humans have moved away from farms and an agric ultural or hunter-gatherer existence into cities, we have lost contact with organisms that served to regulate our immune system and suppress inappropr iate inflammation,” said Lowry, who prefers the phrases ‘ol d friends hypothesis’ or ‘farm effect.’ “Th at has put us at higher risk for inflammatory disease and stress-related ps ychiatric 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 anima ls and bacteria-laden dust, grow up to have more stress-resilient immune sy stems and may be at lower risk of mental illness than pet-free city dweller s.
Others have shown that when a particular bacterium, Mycobacterium vaccae, i s injected into rodents, it alters the animals’ behavior in a way s imilar to that of antidepressants and has long-lasting anti-inflammatory ef fects on the brain. Studies suggest exaggerated inflammation boosts risk of trauma- and stressor-related disorders, such as posttraumatic stress disor der (PTSD).
One recent Lowry-authored study, published in the Proceedings of the Nation al Academy of Sciences in 2017, showed that injections of M. vaccae prior t o a stressful event could prevent a “PTSD-like” syndrome in mice, fending off stress-induced colitis and making the animals act less a nxious when stressed again later.
“We knew it worked, but we didn’t know why,” said L owry. “This new paper helps clarify that.”
For the new study, Lowry and his team identified, isolated and chemically s ynthesized a novel lipid, or fatty acid, called 10(Z)-hexadecenoic acid fou nd in Mycobacterium vaccae and used next-generation sequencing techniques t o 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, bi nding to a specific receptor, peroxisome proliferator-activated receptor (P PAR), 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 r esistant to inflammation when stimulated.
“It seems that these bacteria we co-evolved with have a trick up th eir sleeve,” said Lowry. “When they get taken up by immune cells, they release these lipids that bind to this receptor and shut off th e inflammatory cascade.”
Lowry has long envisioned developing a “stress vaccine” fro m 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 stres s.
“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 th e host,” he said.
Simply knowing the mechanism of action by which M. vaccae reaps benefits co uld boost confidence in it as a potential therapeutic. And if further studi es show the novel fat alone has therapeutic effects, that molecule could be come a target for drug development, he said.
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Researchers have since refined that theory, suggesting that it is not lack of exposure to disease-causing germs at play, but rather to “old fr iends” – beneficial microbes in soil and the environment – and that mental health is also impacted. The image is adapted fro m the University of Colorado at Boulder news release.
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 th at 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 evol ved to keep us healthy. It should inspire awe in all of us.”
ABOUT THIS NEUROSCIENCE RESEARCH ARTICLE Source: University of Colorado at Boulder Media Contacts: Lisa Marshall – University of Colorado at Boulder Image Source: The image is adapted from U Colorado/Boulder news release.
Original Research: Closed access “Identification and characterization of a novel anti-inflammatory l ipid isolated from Mycobacterium vaccae, a soil-derived bacterium with immu noregulatory and stress resilience properties”. David G. Smith, Rob erta Martinelli, Gurdyal S. Besra, Petr A. Illarionov, Istvan Szatmari, Pet er Brazda, Mary A. Allen, Wenqing Xu, Xiang Wang, László Nagy, Ro bin D. Dowell, Graham A. W. Rook, Laura Rosa Brunet, Christopher A. Lowry. Psychopharmacology. doi:10.1007/s00213-019-05253-9
Identification and characterization of a novel anti-inflammatory lipid isol ated from Mycobacterium vaccae, a soil-derived bacterium with immunoregulat ory and stress resilience properties
Rationale Mycobacterium vaccae (NCTC 11659) is an environmental saprophytic bacterium with anti-inflammatory, immunoregulatory, and stress resilience properties . Previous studies have shown that whole, heat-killed preparations of M. va ccae prevent allergic airway inflammation in a murine model of allergic ast hma. Recent studies also demonstrate that immunization with M. vaccae preve nts stress-induced exaggeration of proinflammatory cytokine secretion from mesenteric lymph node cells stimulated ex vivo, prevents stress-induced exa ggeration of chemically induced colitis in a model of inflammatory bowel di sease, and prevents stress-induced anxiety-like defensive behavioral respon ses. Furthermore, immunization with M. vaccae induces anti-inflammatory res ponses in the brain and prevents stress-induced exaggeration of microglial priming. However, the molecular mechanisms underlying anti-inflammatory eff ects of M. vaccae are not known.
Objectives Our objective was to identify and characterize novel anti-inflammatory mole cules from M. vaccae NCTC 11659.
Methods We have purified and identified a unique anti-inflammatory triglyceride, 1, 2,3-tri [Z-10-hexadecenoyl] glycerol, from M. vaccae and evaluated its effe cts in freshly isolated murine peritoneal macrophages.
Results The free fatty acid form of 1,2,3-tri [Z-10-hexadecenoyl] glycerol, 10(Z)-h exadecenoic acid, decreased lipopolysaccharide-stimulated secretion of the proinflammatory cytokine IL-6 ex vivo. Meanwhile, next-generation RNA seque ncing revealed that pretreatment with 10(Z)-hexadecenoic acid upregulated g enes associated with peroxisome proliferator-activated receptor alpha (PPAR α) signaling in lipopolysaccharide-stimulated macrophages, in associat ion with a broad transcriptional repression of inflammatory markers. We con firmed using luciferase-based transfection assays that 10(Z)-hexadecenoic a cid activated PPARα signaling, but not PPARγ, PPARδ, or reti noic acid receptor (RAR) α signaling. The effects of 10(Z)-hexadecenoi c acid on lipopolysaccharide-stimulated secretion of IL-6 were prevented by PPARα antagonists and absent in PPARα-deficient mice.
Conclusion Future studies should evaluate the effects of 10(Z)-hexadecenoic acid on st ress-induced exaggeration of peripheral inflammatory signaling, central neu roinflammatory signaling, and anxiety- and fear-related defensive behaviora l responses.