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Study may explain how infections reduce autism symptoms
An immune molecule sometimes produced during infection can influence the social behavior of mice.
For many years, some parents have noticed that their autistic children's behavioral symptoms diminished when they had a fever.
This phenomenon has been documented in at least two large-scale studies over the past 15 years, but it was unclear why fever would have such an effect.
A new study from MIT and Harvard Medical School sheds light on the cellular mechanisms that may underlie this phenomenon. In a study of mice, the researchers found that in some cases of infection, an immune molecule called IL-17a is released and suppresses a small region of the brain's cortex that has previously been linked to social behavioral deficits in mice.
"People have seen this phenomenon before [in people with autism], but it's the kind of story that is hard to believe, which I think stems from the fact that we did not know the mechanism," says Gloria Choi, the Samuel A. Goldblith Career Development Assistant Professor of Applied Biology and an assistant professor of brain and cognitive sciences at MIT. "Now the field, including my lab, is trying hard to show how this works, all the way from the immune cells and molecules to receptors in the brain, and how those interactions lead to behavioral changes."
Although findings in mice do not always translate into human treatments, the study may help to guide the development of strategies that could help to reduce some behavioral symptoms of autism or other neurological disorders, says Choi, who is also a member of MIT's Picower Institute for Learning and Memory.
Choi and Jun Huh, an assistant professor of immunology at Harvard Medical School, are the senior authors of the study, which appears in Nature today. The lead authors of the paper are MIT graduate student Michael Douglas Reed and MIT postdoc Yeong Shin Yim.
Choi and Huh have previously explored other links between inflammation and autism. In 2016, they showed that mice born to mothers who experience a severe infection during pregnancy are much more likely to show behavioral symptoms such as deficits in sociability, repetitive behaviors, and abnormal communication. They found that this is caused by exposure to maternal IL-17a, which produces defects in a specific brain region of the developing embryos. This brain region, S1DZ, is part of the somatosensory cortex and is believed to be responsible for sensing where the body is in space.
"Immune activation in the mother leads to very particular cortical defects, and those defects are responsible for inducing abnormal behaviors in offspring," Choi says.
A link between infection during pregnancy and autism in children has also been seen in humans. A 2010 study that included all children born in Denmark between 1980 and 2005 found that severe viral infections during the first trimester of pregnancy translated to a threefold increase in risk for autism, and serious bacterial infections during the second trimester were linked with a 1.42-fold increase in risk. These infections included influenza, viral gastroenteritis, and severe urinary tract infections.
In the new study, Choi and Huh turned their attention to the often-reported link between fever and reduction of autism symptoms.
"We wanted to ask whether we could use mouse models of neurodevelopmental disorders to recapitulate this phenomenon," Choi says. "Once you see the phenomenon in animals, you can probe the mechanism."
The researchers began by studying mice that exhibited behavioral symptoms due to exposure to inflammation during gestation. They injected these mice with a bacterial component called LPS, which induces a fever response, and found that the animals' social interactions were temporarily restored to normal.
Further experiments revealed that during inflammation, these mice produce IL-17a, which binds to receptors in S1DZ — the same brain region originally affected by maternal inflammation. IL-17a reduces neural activity in S1DZ, which makes the mice temporarily more interested in interacting with other mice.
If the researchers inhibited IL-17a or knocked out the receptors for IL-17a, this symptom reversal did not occur. They also showed that simply raising the mice's body temperature did not have any effect on behavior, offering further evidence that IL-17a is necessary for the reversal of symptoms.
"This suggests that the immune system uses molecules like IL-17a to directly talk to the brain, and it actually can work almost like a neuromodulator to bring about these behavioral changes," Choi says. "Our study provides another example as to how the brain can be modulated by the immune system."
"What's remarkable about this paper is that it shows that this effect on behavior is not necessarily a result of fever but the result of cytokines being made," says Dan Littman, a professor of immunology at New York University, who was not involved in the study. "There's a growing body of evidence that the central nervous system, in mammals at least, has evolved to be dependent to some degree on cytokine signaling at various times during development or postnatally."
The researchers then performed the same experiments in three additional mouse models of neurological disorders. These mice lack a gene linked to autism and similar disorders — either Shank3, Cntnap2, or Fmr1. These mice all show deficits in social behavior similar to those of mice exposed to inflammation in the womb, even though the origin of their symptoms is different.
Injecting those mice with LPS did produce inflammation, but it did not have any effect on their behavior. The reason for that, the researchers found, is that in these mice, inflammation did not stimulate IL-17a production. However, if the researchers injected IL-17a into these mice, their behavioral symptoms did improve.
This suggests that mice who are exposed to inflammation during gestation end up with their immune systems somehow primed to more readily produce IL-17a during subsequent infections. Choi and Huh have previously shown that the presence of certain bacteria in the gut can also prime IL-17a responses. They are now investigating whether the same gut-residing bacteria contribute to the LPS-induced reversal of social behavior symptoms that they found in the new Nature study.
"It was amazing to discover that the same immune molecule, IL-17a, could have dramatically opposite effects depending on context: Promoting autism-like behaviors when it acts on the developing fetal brain and ameliorating autism-like behaviors when it modulates neural activity in the adult mouse brain. This is the degree of complexity we are trying to make sense of," Huh says.
Choi's lab is also exploring whether any immune molecules other than IL-17a may affect the brain and behavior.
"What's fascinating about this communication is the immune system directly sends its messengers to the brain, where they work as if they're brain molecules, to change how the circuits work and how the behaviors are shaped," Choi says.
The research was funded by the Jeongho Kim Neurodevelopmental Research Fund, Perry Ha, the Hock E. Tan and K. Lisa Yang Center for Autism Research, the Simons Center for the Social Brain, the Simons Foundation Autism Research Initiative, the Champions of the Brain Weedon Fellowship, and a National Science Foundation Graduate Research Fellowship.
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A new study finds that dogs fed fresh human-grade food don't need to eat—or do their business—as much.
- Most dogs eat a diet that's primarily kibble.
- When fed a fresh-food diet, however, they don't need to consume as much.
- Dogs on fresh-food diets have healthier gut biomes.
Four diets were tested<img type="lazy-image" data-runner-src="https://assets.rebelmouse.io/eyJhbGciOiJIUzI1NiIsInR5cCI6IkpXVCJ9.eyJpbWFnZSI6Imh0dHBzOi8vYXNzZXRzLnJibC5tcy8yNTU5ODI1MS9vcmlnaW4uanBnIiwiZXhwaXJlc19hdCI6MTY1NjY0NjIxMn0._w0k-qFOC86AqmtPHJBK_i-9F5oVyVYsYtUrdvfUxWQ/img.jpg?width=980" id="1b1e4" class="rm-shortcode" data-rm-shortcode-id="87937436a81c700a8ab3b1d763354843" data-rm-shortcode-name="rebelmouse-image" data-width="1440" data-height="960" />
Credit: AntonioDiaz/Adobe Stock<p>The researchers tested refrigerated and fresh human-grade foods against kibble, the food most dogs live on. The <a href="https://frontierpets.com.au/blogs/news/how-kibble-or-dry-dog-food-is-made" target="_blank">ingredients</a> of kibble are mashed into a dough and then extruded, forced through a die of some kind into the desired shape — think a <a href="https://en.wikipedia.org/wiki/Food_extrusion" target="_blank">pasta maker</a>. The resulting pellets are sprayed with additional flavor and color.</p><p>For four weeks, researchers fed 12 beagles one of four diets:</p><ol><li>a extruded diet — Blue Buffalo Chicken and Brown Rice Recipe</li><li>a fresh refrigerated diet — Freshpet Roasted Meals Tender Chicken Recipe</li><li>a fresh diet — JustFoodforDogs Beef & Russet Potato Recipe</li><li>another fresh diet — JustFoodforDogs Chicken & White Rice Recipe.</li></ol><p>The two fresh diets contained minimally processed beef, chicken, broccoli, rice, carrots, and various food chunks in a canine casserole of sorts. </p><p>(One can't help but think how hard it would be to get finicky cats to test new diets. As if.)</p><p>Senior author <a href="https://ansc.illinois.edu/directory/ksswanso" target="_blank" rel="noopener noreferrer">Kelly S. Swanson</a> of U of I's Department of Animal Sciences and the Division of Nutritional Sciences, was a bit surprised at how much better dogs did on people food than even refrigerated dog chow. "Based on past research we've conducted I'm not surprised with the results when feeding human-grade compared to an extruded dry diet," he <a href="https://aces.illinois.edu/news/feed-fido-fresh-human-grade-dog-food-scoop-less-poop" target="_blank">says</a>, adding, "However, I did not expect to see how well the human-grade fresh food performed, even compared to a fresh commercial processed brand."</p>
Tracking the effect of each diet<img type="lazy-image" data-runner-src="https://assets.rebelmouse.io/eyJhbGciOiJIUzI1NiIsInR5cCI6IkpXVCJ9.eyJpbWFnZSI6Imh0dHBzOi8vYXNzZXRzLnJibC5tcy8yNTU5ODI1OC9vcmlnaW4uanBnIiwiZXhwaXJlc19hdCI6MTY3NjY1NTgyOX0.AdyMb8OEcjCD6iWYnXjToDmcnjfTSn-0-dfG96SIpUA/img.jpg?width=980" id="da892" class="rm-shortcode" data-rm-shortcode-id="880d952420679aeccd1eaf32b5339810" data-rm-shortcode-name="rebelmouse-image" data-width="1440" data-height="960" />
Credit: Patryk Kosmider/Adobe Stock<p>The researchers tracked the dogs' weights and analyzed the microbiota in their fecal matter.</p><p>It turned out that the dogs on kibble had to eat more to maintain their body weight. This resulted in their producing 1.5 to 2.9 times the amount of poop produced by dogs on the fresh diets.</p><p>Says Swanson, "This is consistent with a 2019 National Institute of Health study in humans that found people eating a fresh whole food diet consumed on average 500 less calories per day, and reported being more satisfied, than people eating a more processed diet."</p><p>Maybe even more interesting was the effect of fresh food on the gut biome. Though there remains much we don't yet know about microbiota, it was nonetheless the case that the microbial communities found in fresh-food poo was different.</p><p>"Because a healthy gut means a healthy mutt," says Swanson, "fecal microbial and metabolite profiles are important readouts of diet assessment. As we have shown in <a href="https://academic.oup.com/jas/article/92/9/3781/4702209#110855647" target="_blank">previous studies</a>, the fecal microbial communities of healthy dogs fed fresh diets were different than those fed kibble. These unique microbial profiles were likely due to differences in diet processing, ingredient source, and the concentration and type of dietary fibers, proteins, and fats that are known to influence what is digested by the dog and what reaches the colon for fermentation."</p>
How did kibble take over canine diets?<p>Historically, dogs ate scraps left over by humans. It has only been <a href="https://www.thefarmersdog.com/digest/the-history-of-commercial-pet-food-a-great-american-marketing-story/" target="_blank">since 1870</a>, with the arrival of the luxe Spratt's Meat Fibrine Dog Cakes—made from "the dried unsalted gelatinous parts of Prairie Beef", mmm—that commercial dog food began to take hold. Dog bone-shaped biscuits first appeared in 1907. Ken-L Ration dates from 1922. Kibble was first extruded in 1956. Pet food had become a great way to turn <a href="https://www.dogfoodadvisor.com/choosing-dog-food/animal-by-products/" target="_blank">human-food waste</a> into profit.</p><p>Commercial dog food became the norm for most household canines only after a massive marketing campaign led by a group of dog-food industry lobbyists called the Pet Food Institute in 1964. Over time, for most households, dog food was what dogs ate — what else? Human food? These days more than half of U.S. dogs are <a href="https://www.nytimes.com/2014/08/03/magazine/who-made-that-dog-biscuit.html" target="_blank">overweight or obese</a>, and certainly their diet is a factor.<span></span></p><p>We're not so special among animals after all. If something's healthy for us to eat—we're <em>not</em> looking at you, chocolate—maybe we should remember to share with our canine compatriots. Not from the table, though.</p>
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Eating veggies is good for you. Now we can stop debating how much we should eat.
- A massive new study confirms that five servings of fruit and veggies a day can lower the risk of death.
- The maximum benefit is found at two servings of fruit and three of veggies—anything more offers no extra benefit according to the researchers.
- Not all fruits and veggies are equal. Leafy greens are better for you than starchy corn and potatoes.