In different countries' national dietary guidelines, red meats (beef, pork, and lamb) are often confined to a very small corner. Swedish officials, for example, advise the population to "eat less red and processed meat". Experts in Greece recommend consuming no more than four servings of red meat — not per week, but per month.
"Humans 100% rely on the microbes to digest this food."
Yet somehow, the matter is far from settled. Quibbles over the scientific evidence emerge on a regular basis — as in a recent BMJ article titled, "No need to cut red meat, say new guidelines." News headlines lately have declared that limiting red meat may be "bad advice," while carnivore diet enthusiasts boast about the weight loss and good health they've achieved on an all-meat diet. The wildly successful plant-based burgers? To them, a gimmick. The burger wars are on.
Nutrition science would seem the best place to look for answers on the health effects of specific foods. And on one hand, the science is rather clear: in large populations, people who eat more red meat tend to have more health problems, including cardiovascular disease, colorectal cancer, and other conditions. But this sort of correlational evidence fails to settle the matter once and for all; many who look closely at these studies cite methodological shortcomings and a low certainty of evidence.
Some scientists, meanwhile, are trying to cut through the noise by increasing their focus on the mechanisms: exactly how red meat is digested and the step-by-step of how this affects human health. And curiously, as these lines of evidence emerge, several of them center around gut microbes as active participants in red meat's ultimate effects on human health.
Dr. Stanley Hazen, researcher and medical director of preventive cardiology at Cleveland Clinic, was one of the first to zero in on gut microorganisms as possible contributors to the health effects of red meat. In looking for chemical compounds in the blood that could predict the future development of cardiovascular disease, his lab identified a molecule called trimethylamine-N-oxide (TMAO). Little by little, he and his colleagues began to gather both human and animal evidence that TMAO played a role in causing heart disease.
Naturally, they tried to figure out where the TMAO came from. Hazen says, "We found that animal products, and especially red meat, were a dietary source that, [along with] gut microbes, would generate this product that leads to heart disease development." They observed that the gut microbes were essential for making TMAO out of dietary compounds (like red meat) that contained its precursor, trimethylamine (TMA).
So in linking red meat to cardiovascular disease through TMAO, the surprising conclusion, says Hazen, was that, "Without a doubt, [the microbes] are the most important aspect of the whole pathway."
"I think it's just a matter of time [before] we will have therapeutic interventions that actually target our gut microbes, just like the way we take drugs that lower cholesterol levels."
Other researchers have taken an interest in different red-meat-associated health problems, like colorectal cancer and the inflammation that accompanies it. This was the mechanistic link tackled by the lab of professor Karsten Zengler of the UC San Diego Departments of Pediatrics and Bioengineering—and it also led straight back to the gut microbes.
Zengler and colleagues recently published a paper in Nature Microbiology that focused on the effects of a red meat carbohydrate (or sugar) called Neu5Gc.
He explains, "If you eat animal proteins in your diet… the bound sugars in your diet are cleaved off in your gut and they get recycled. Your own cells will not recognize between the foreign sugars and your own sugars, because they look almost identical." The unsuspecting human cells then take up these foreign sugars — spurring antibody production and creating inflammation.
Zengler showed, however, that gut bacteria use enzymes to cleave off the sugar during digestion, stopping the inflammation and rendering the sugar harmless. "There's no enzyme in the human body that can cleave this [sugar] off. Humans 100% rely on the microbes to digest this food," he says.
Both researchers are quick to caution that the health effects of diet are complex. Other work indicates, for example, that while intake of red meat can affect TMAO levels, so can intake of fish and seafood. But these new lines of evidence could help explain why some people, ironically, seem to be in perfect health despite eating a lot of red meat: their ideal frequency of meat consumption may depend on their existing community of gut microbes.
"It helps explain what accounts for inter-person variability," Hazen says.
These emerging mechanisms reinforce overall why it's prudent to limit red meat, just as the nutritional guidelines advised in the first place. But both Hazen and Zengler predict that interventions to buffer the effects of too many ribeyes may be just around the corner.
Zengler says, "Our idea is that you basically can help your own digestive system detoxify these inflammatory compounds in meat, if you continue eating red meat or you want to eat a high amount of red meat." A possibly strategy, he says, is to use specific pre- or probiotics to cultivate an inflammation-reducing gut microbial community.
Hazen foresees the emergence of drugs that act not on the human, but on the human's gut microorganisms. "I think it's just a matter of time [before] we will have therapeutic interventions that actually target our gut microbes, just like the way we take drugs that lower cholesterol levels."
He adds, "It's a matter of 'stay tuned', I think."
See a hot pizza sitting on a table. Count the missing pieces: three. They tasted delicious and yes, you've eaten enough—but you're still eyeing a fourth piece. Do you reach out and take it, or not?
"The difficulty comes in translating the animal data into the human situation."
Your behavior in that next moment is anything but simple: as far as scientists can tell, it comes down to a complex confluence of circumstances, genes, and personality characteristics. And the latest proposed addition to this list is the gut microbiome—the community of microorganisms, including bacteria, archaea, fungi, and viruses—that are full-time residents of your digestive tract.
It is entirely plausible that your gut microbiome might influence your behavior, scientists say: a well-known communication channel, called the gut-brain axis, runs both ways between your brain and your digestive tract. Gut bugs, which are close to the action, could amplify or dampen the messages, thereby shaping how you act. Messages about food-related behaviors could be particularly susceptible to interception by these microorganisms.
Perhaps it's convenient to imagine your resident microbes sitting greedily in your gut, crying for more pizza and tricking your brain into getting them what they want. The problem is, there's a distinct lack of scientific support for this actually happening in humans.
John Bienenstock, professor of pathology and molecular medicine at McMaster University (Canada), has worked on the gut microbiome-behavior connection for several decades. "There's a lot of evidence now in animals—particularly in mice," he says.
Indeed, his group and others have shown that, by eliminating or altering gut bugs, they can make mice exhibit different social behaviors or respond more coolly to stress; they can even make a shy mouse turn brave. But Bienenstock cautions: "The difficulty comes in translating the animal data into the human situation."
Animal behaviors are worlds apart from what we do on a daily basis—from brushing our teeth to navigating complex social situations.
Not that it's an easy task to figure out which aspects of animal research are relevant to people in everyday life. Animal behaviors are worlds apart from what we do on a daily basis—from brushing our teeth to navigating complex social situations.
Elaine Hsiao, assistant professor of integrative biology and physiology at UCLA, has also looked closely at the microbiome-gut-brain axis in mice and pondered how to translate the results into humans. She says, "Both the microbiome and behavior vary substantially [from person to person] and can be strongly influenced by environmental factors—which makes it difficult to run a well-controlled study on effects of the microbiome on human behavior."
She adds, "Human behaviors are very complex and the metrics used to quantify behavior are often not precise enough to derive clear interpretations." So the challenge is not only to figure out what people actually do, but also to give those actions numerical codes that allow them to be compared against other actions.
Hsiao and colleagues are nevertheless attempting to make connections: building on some animal research, their recent study found a three-way association in humans between molecules produced by their gut bacteria (that is, indole metabolites), the connectedness of different brain regions as measured through functional magnetic resonance imaging, and measures of behavior: questionnaires assessing food addiction and anxiety.
Meanwhile, other studies have found it may be possible to change a person's behavior through either probiotics or gut-localized antibiotics. Several probiotics even show promise for altering behavior in clinical conditions like depression. Yet how these phenomena occur is still unknown and, overall, scientists lack solid evidence on how bugs control behavior.
Bienenstock, however, is one of many continuing to investigate. He says, "Some of these observations are very striking. They're so striking that clearly something's up."
He says that after identifying a behavior-changing bug, or set of bugs, in mice: "The obvious next thing is: How [is it] occurring? Why is it occurring? What are the molecules involved?" Bienenstock favors the approach of nailing down a mechanism in animal models before starting to investigate its relevance to humans.
He explains, "[This preclinical work] should allow us to identify either target molecules or target pathways, which then can be translated."
Bienenstock also acknowledges the 'hype' that appears to surround this particular field of study. Despite the decidedly slow emergence of data linking the microbiome to human behavior, scientific reviews have appeared in brain-related scientific journals—for instance, Trends in Cognitive Sciences; CNS Drugs—with remarkable frequency. Not only this, but popular books and media articles have given the idea wings.
It might be compelling to blame our microbiomes for behaviors we don't prefer or can't explain—like reaching for another slice of pizza. But until the scientific observations yield stronger results, we still lack proof that we're doing what we do—or eating what we eat—exclusively at the behest of our resident microorganisms.
We all know the typical astronaut accessories—the EVA suit, the oxygen tanks, the radio assembly. But there's an invisible part of each space mission that's often overlooked: the trillions of microorganisms that hitch a ride.
Observing responses of pathogens in space could help scientists figure out how to outsmart them when they cause trouble on Earth.
Dr. Sarah Wallace is a NASA microbiologist who aims to keep microbes from causing problems for U.S. astronauts aboard the International Space Station. According to Wallace, research on microorganisms in space has more than cosmic importance. It can also reveal things about our health here on Earth:
1) Avoiding disease isn't all about maintaining a sterile environment.
NASA has a great track record of keeping the crew healthy on space missions. But surprisingly, it's not from having kept the space flight environment as sterile as possible.
Wallace says, "We [monitor] the environment but unless we find something that's medically significant, or [in] super high numbers, we're not going to do anything."
Not only is it impossible for astronauts to live in completely sterile quarters—crew members, after all, are microbe-shedding machines—but it may not even be desirable, given what we now know about the human microbiome. Scientists have found that the entire community of microorganisms (bacteria, archaea, fungi, and viruses) living in and on us likely have an active role in keeping us healthy. This means that down on the ground we need to let go of the germophobe idea that eradicating all microbes is always better for our health.
2) Disease-causing microbes change their behavior under different conditions.
Remember the recent E. coli O157:H7 outbreak linked to romaine lettuce? We're still grappling with a lot of pathogen problems here on Earth. One reason is that scientists are still learning which strategies these disease-causing microorganisms are capable of employing under different conditions.
Space missions are associated with a major shift in gut microbiome composition—as shown in NASA's twin study.
Wallace says experiments with Salmonella Typhimurium showed that the pathogen became more virulent in space. Yet curiously, the opposite seemed to happen to Staphylococcus aureus under space-flight-like conditions—it became more benign.
"The way these organisms have evolved, certain triggers [in the space flight environment] might be dictating how they're responding," Wallace says.
Observing these responses could help scientists figure out how to outsmart the pathogen when it causes trouble on Earth. "It's giving us some great insights into how we could target them differently in the future," she explains.
3) Major shifts in the gut microbiome could affect health in specific ways.
Scientists still have a lot to learn about which changes in an adult's gut microbiome actually cause a change in health status. In fact, microbiome-focused therapeutics companies are in hot pursuit of these connections.
Space missions are associated with a major shift in gut microbiome composition—as shown in NASA's twin study, which followed astronaut Scott Kelly during a year aboard the ISS while his identical twin brother Mark (a retired astronaut) stayed on the ground. Scott experienced simultaneous changes in telomere length and bone formation; were these related to the gut microbial differences?
Wallace says a soon-to-be-published study of nine additional astronauts could help answer this question. The research may reveal how closely gut microbiome shifts track health outcomes, and the reversibility of the changes.
She emphasizes the science from her lab isn't meant to help only the small minority of humans who will ever go to space: "That's always our goal—that our research is helping people on Earth."