Blair River was described as “a big guy with a big heart.” The 575-pound former high school wrestler from Mesa, Ariz., became such a fixture at the Heart Attack Grill that he was recruited to be the restaurant’s official spokesperson. His satirical ads made him a minor celebrity in central Arizona. He died in 2011 at age 29 — not because of his heart but from complications of influenza.
It was not entirely surprising: Many reports have observed that heavier patients appear more likely to come down with infections during a hospital stay, acquire weaker protection from vaccinations and, as with River, suffer more complications from the flu.
Weight alone may not be the entire explanation. A tantalizing line of evidence suggests that unhealthful foods — fatty, salty, sugary, processed foods — may disrupt the body’s defenses in a way that promotes inflammation, infection, autoimmune diseases and even illnesses like cancer.
While the interplay between diet and immunity is complex — and still largely uncharted — many researchers believe some foods perturb gut microbiota, the body’s inner bacterial community that may be as important to proper health as any major organ (SN: 6/18/11, p. 26).
Among their long list of tasks, gut bacteria may help train the immune system to distinguish between human and microbe so that it can confront what’s bad, tolerate what’s not, and recruit a diverse army of cellular foot soldiers to stop invading germs. Writing in Nutrition Journal in June 2014, one scientist likened gut microbiota to a sparring partner, providing a regular workout that strengthens the contender for a true opponent.
To function at their best, though, gut microbes, like most living things, need to be well fed. And many of the species responsible for immune equilibrium don’t seem to care for junk food. In a study reported in Nature Communications in April, African-American volunteers who shifted from an American diet to high-fiber, low-fat African cuisine experienced a drop in inflammation in just two weeks.
“It’s becoming clear that the typical American diet can damage the immune system,” says Ian Myles, a physician and researcher at the National Institute of Allergy and Infectious Diseases in Bethesda, Md. After a lethal infection, most of the blame is understandably leveled against the microbe responsible, Myles says. “It’s harder to make the connection that it may have had something to do with what you’ve been eating the past 30 years.”
A slow boil
In a series of experiments over the last decade, scientists have made the case that a poor diet and an out-of-balance intestinal ecosystem can unleash a persistent, low-level immune activation. This is not to be mistaken with the good kind of inflammation, which occurs when bacteria, viruses or anything else foreign slips into the bloodstream. Immune cells rally to surround and eliminate the threat. It’s a healthy response necessary for survival.
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But this life-saving reaction turns sour when the immune system gets stuck on a slow, endless burn. In an ironic twist of biology, one of the consequences of an immune system that never takes a rest is that it may be asleep when it’s really needed. Like an annoying car alarm that everyone hears but no one responds to, chronic activation might desensitize the system to actual danger.
There is also evidence that certain kinds of fats and refined sugar, consumed in excess, may compromise the inner lining of the intestine, allowing microscopic leaks that trigger unrelenting immune activation. Also, adipose tissue, or body fat, is so capable of hormone production that it is often referred to as an endocrine organ by itself, able to kindle a low-grade inflammation that stresses tissues and promotes disease.
Taken together, Myles says, the combination of unhealthy diet and obesity explain in part the rise in autoimmune conditions such as celiac disease, type 1 diabetes and other illnesses that occur when the body turns on itself. (For instance, a 2012 report found that the prevalence of inflammatory bowel disease is rising, and rates are highest in Westernized parts of the world.) The connection also suggests avenues for management. One study reported that probiotic foods might help increase insulin sensitivity among diabetics. That’s not to say that diet is completely at fault. Why auto-immune diseases occur is a mystery — and theories abound — but a large body of evidence gives some culpability to changes in gut bacteria.
Until recently, bacteria in the intestine were largely unexplored because they are difficult to grow in a laboratory. Thanks to advances in molecular tools that work outside a petri dish, researchers are getting a better handle on a partnership that serves both host and microbes. While about 1,000 species of bacteria are thought to live in the intestine, only a portion are dominant players. As with ecosystems throughout nature, diversity rules, and an abundance of species signals a healthy environment.
In general, beneficial bacteria appear to prefer certain foods — such as fiber and the complex carbohydrates found in vegetables and whole grains — and dislike others, such as refined sugar and (according to some experiments) saturated fat. Essentially, it’s possible to satisfy your own sweet tooth while starving a lot of your microscopic friends.
A landmark experiment in 2009 found that among mice carrying the same microbes found in humans, a high-fat, high-sugar diet caused certain bacterial populations to drop and others to rise. As a result, the microbial community was “dramatically altered over a time scale of hours,” researchers from Washington University School of Medicine in St. Louis and the University of Colorado Boulder reported in Science Translational Medicine.
In a follow-up study with human volunteers published last year in Nature, a team from Harvard and the University of California, San Francisco found similarly abrupt responses (SN Online: 12/11/13). A day after volunteers started a diet dominated by animal products, bacterial diversity in their intestines dropped, which coincided with a bloom in Bilophila wadsworthia, a normally minor occupant that has been associated with inflammatory bowel disease.
“There aren’t too many microbes that like to live in the presence of certain types of fat. It’s too difficult for them to use as a food source,” says Vanessa Leone, a nutrition scientist at the University of Chicago. “So you’re selecting for micro-organisms that can live in that environment.” In 2012, Leone’s team reported in Nature that a diet high in saturated fat also increases the production of one type of bile. The digestive fluid made by the liver favors some microbes while killing off others. (And as in other experiments, a major beneficiary appears to be B. wadsworthia.)
Break on through
Epithelial cells and mucus that line the intestine protect the rest of the body from pathogens. But a diet heavy in sugars and fats can disrupt the delicate balance of friendly and harmful bacteria and make the gut lining more porous. When bacteria slip through the lining, they set off alarm bells called toll-like receptors. The TLRs signal immune cells, including T cells and macrophages, to produce inflammatory cytokines. The cytokines can weaken the tight junctions between epithelial cells, setting off an inflammatory cycle that might lead to bowel diseases.
Credit: Andrei Ivanov/VCU, adapted by T. Shipley and M. Telfer
In experiments in mice published in PLOS ONE and the British Journal of Nutrition in 2013, Gibson and her colleagues reported that diets high in omega-6 fatty acids disrupted gut microbiota. The researchers also saw the kinds of increased inflammatory responses that lead to colitis, a condition resulting from inflammation in the colon.
The mechanisms in the intestine that trigger inflammation are still not fully understood. But toll-like receptors, molecules that sit on certain immune cells, appear to be important players. Once activated, toll-like receptors are capable of setting off alarms. Some respond to the presence of lipopolysaccharides, molecules that are part of the membranes of some bacteria.
Normally, bacteria in the gut hardly come in contact with the rest of the body, because the mucus and epithelial cells lining the intestine keep them in the gut. But diets high in sugar and fat and low in fiber may cause the intestine to become porous. Writing last year in Cell Metabolism, researchers from Stanford University pointed out that the calories contained in refined sugars — which constitute an ever-growing part of the American diet — aren’t a good food source for the gut’s microbiota. In response, evidence suggests, some of the bacteria will eat the mucus lining of the intestine, which may cause the lining to deteriorate.
Eventually, some gut organisms slip through and encounter toll-like receptors on immune cells, setting off an immune reaction. Some experiments also suggest that saturated fat itself may stimulate toll-like receptors.
It’s still too early to draw firm conclusions, however. Researchers in South Carolina and Iowa tested the ability of three different diets to activate the toll-like receptors TLR2 and TLR4 on macrophages, key immune cells. All three diets had the same amount of fat, but varied in the proportion of saturated fat: 6 percent, 12 percent or 24 percent. (The diet with 12 percent saturated fat mimicked typical American eating patterns.)
Based on previous studies, the scientists expected the diet with the highest saturated fat to produce the most inflammation. To their surprise, the highest inflammation, and greatest body fat accumulation, occurred with the 12-percent saturated fat diet, the team reported in the Journal of Lipid Research in 2013. Since all the diets had the same proportion of total fat, the authors speculate that the combination of different types of fat is responsible for the overall effect.
Salt of the girth
Fat isn’t the only thing on the drive-through menu. The average American gets more than twice as much salt as recommended, a problem largely driven by heavy consumption of processed and prepackaged foods. In a study published last year in Pediatrics, adolescents who ate the most salt were more likely than others to be obese and have signs of inflammation.
Such results are not conclusive; salty foods could also have a high sugar and fat content. But many studies are not reassuring. A multinational research team fed each of six volunteers four diets that differed only in the amount of salt: 12 grams per day, 9 grams, 6 grams, then 12 again. Immune activation spiked on the high-salt diet. More important, in a trend suggesting cause and effect, levels of most immune cytokines gradually fell as salt intake diminished. “These findings raise the possibility that high salt intake might trigger tissue inflammation and autoimmune disease in humans,” the scientists wrote last year in Translational Research.
Other studies have raised similar concerns. In 2013, researchers demonstrated that excess salt in the diets of mice could increase activity of certain T cells that have a role in autoimmunity. There’s more to learn, cautions immunologist Markus Kleinewietfeld of Yale University and TU Dresden in Germany, lead author of the study, published in Nature. “Salt seems to be, in general, a proinflammatory signal for the immune system, but the physiology is not well understood,” he says.
There may be situations where the presence of salt is beneficial. He points to a study published this spring in Cell Metabolism suggesting that sodium storage in the skin may help protect against infection from a parasite that causes leishmaniasis.
The implications for T cells may be especially important because of their complex role not just in fighting germs, but also in autoimmunity and cancer. T cells may either suppress or promote cancer depending on the circumstances, and their proper balance may rest in part on the health of the gut microbiota.
Don’t pass the salt
Healthy volunteers (yellow dots) ate diets with varying levels of salt for about 50 days each. At high salt intake, monocytes, white blood cells that play a role in inflammation, increased. At lower salt levels, the opposite happened. (Black bars are mean values.)
Credit: B. Yi et al/Translational Research 2015, adapted by M. Telfer
Studies find that the ebb and flow of these cells depends highly on gut bacteria. Germ-free mice — raised in sterile environments with squeaky-clean intestines — are depleted of Th17 cells. But when the mice’s insides are populated with certain bacteria, Th17 cells reappear. Furthermore, a study published in Nature Medicine in 2009 reported that when mice predisposed to colon cancer were exposed to bacteria that promote Th17 growth, tumor cells grew more aggressively. In short, gut bacteria in the intestine appear to serve as a thermostat for Th17 and T-reg cells.
The good news is that just as a bad diet might promote inflammation, foods that promote healthy microbiota appear to restore order. Microbes that get the food they crave not only maintain normal bacterial ratios, but also produce beneficial fermentation products such as butyrate. (In several studies, butyrate is emerging as a natural compound that tamps down inflammation.)
Other food components also appear to be anti-inflammatory, including omega-3 fatty acids, which are common in fish and nuts. And in one experiment, published in PLOS ONE in 2013, Yale’s Kleinewietfeld and collaborators used bacteria found in yogurt to reverse the inflammation from a fast food–like diet in mice. The treatment seemed to protect against some of the weight gain such food encourages. Other work by some of the same researchers also raises the possibility that disease risk from microbiota can cross generations (see sidebar below).
In any case, it is clear that diet can affect gut microbiota, says cancer biologist Susan Erdman of MIT, senior author of the 2013 study in PLOS ONE. “And those changes seem to influence the immune system,” she says. “We need a diet that supports the microbes that become an important part of who we are.” In other words, choose foods that keep gut bacteria healthy, and odds are, they’ll return the favor.
Offspring can inherit the effects of parents’ lousy food choices
The impact of a Western diet on risk for obesity and cancer can persist for generations, and gut microbes may be responsible, a study published in April suggests. If supported by more research, the findings mean that inherited risk for some diseases is about more than genetics and may be reversible.
In a series of experiments, researchers fed pregnant female mice a high-fat, low-fiber diet representative of typical fast-food fare, while a comparison group ate regular chow. The offspring of the mice on the unhealthy diet were more prone to obesity and cancer — even when the offspring ate normally. The increased risk persisted to the next generation, which also showed signs of premature aging.
The researchers, from MIT and Aristotle University of Thessaloniki in Greece, then zeroed in on the microbiota. Simply transferring intestinal bacteria of mice eating the unhealthy diet to mice eating normal chow that later got pregnant was enough to raise the cancer risk of their pups.
The reverse was true as well: Cancer risk dropped among mice whose mothers ate the fast-food diet but received doses of beneficial bacteria.
“Targeting microbes may be a highly effective population-based approach to lower risk for cancer,” the researchers wrote in Cancer Research. — Laura Beil
This article appeared in the May 30, 2015, issue of Science News under the headline, “Food Fight: Our gut microbes are no fans of junk food.”
Editor’s note: This article was updated on June 2, 2015, to correct that bile is a digestive fluid, not an enzyme.