Gut check

Local scientists explore the microscopic worlds within the human gut




Josie Luciano

When I was in the third grade, my class took a field trip to the Ruth Lilly Health Center in Indianapolis. As the lights dimmed in the amphitheater, a spotlight directed our gaze towards TAM—the Transparent Anatomical Manikin best known as the skin-less, winged model on the cover of Nirvana’s 1993 album In Utero.

Even as 8-year-olds, we knew TAM was beautiful. Her organs blinked on and off while a disembodied voice narrated the story of her parts. We giggled when her breasts flickered and gawked at her endless intestines. But TAM was missing the 100 trillion microbes that reside in what scientists sometimes call the “forgotten organ”—the human microbiome. This is the teeming community of bacteria, fungi and viruses that silently make their home in our guts.

Last week, I saw TAM on sale for $1,900 on a museum listserv, and thought I would write her a primer on her missing part.

Dear TAM, grab a sandwich. This is going to take about 12 minutes to read.

Small wonders

The fact that we’re crawling with microbes is not breaking news. Humans have been aware of bacteria since the late 17th century when Dutch basketmaker and amateur scientist Antony Van Leeuwenhoek discovered tiny “animalcules” swimming in circles under his microscope.

Over the years, microbiology grew up alongside natural selection and germ theory. By the 1870s, the initial wonder and amazement surrounding microbes had been replaced by a shock-and-awe campaign aimed at destroying all disease-causing pathogens.

Today, germ theory still maintains a strong foothold in hospitals (a necessary thing), sterilized playgrounds (an unnecessary thing), and at every CVS checkout counter across the country that sells antibacterial hand soap (a thing that was banned by the FDA last month).

But just as CVS is preparing to stop stocking their shelves with these products, they’re also restocking the Greek yogurt and probiotic supply. Things are changing, and it definitely seems like the narrative around microbes is too. “Germs” are now “bacteria,” and “bacteria” is now a “good guy.”

Sort of.

As in any other ecosystem, good guys are only good when they’re in the right place at the right time, and the same goes for the bad ones. Whatever part of our forgotten organ they live in—stomach, small intestine, large intestine—every part has a different state of “normal” that changes over time.

For humans, our long-term relationship with microbes begins on Day One. During birth, babies travel from the sterile womb to a world that is decidedly not. On the way out, they pick up their first residents and spend the next few years nurturing them.

It’s a subject that David Mills, a professor and biochemist at the University of California, Davis, has been studying for the past 20 years.

“It’s all about how the baby gets inoculated,” Mills explained to me in his lab. “When a baby is born, especially vaginally, there’s a whole bunch of microbes in the vagina that get into the mouth of the baby. This is going to get gross—but as the baby comes out, its face is typically facing mom’s rectum. And I think nature intended it that way … a baby starts out in life literally with an inoculum from mom.”

He went on to explain that babies born via C-section are colonized differently, mostly picking up skin microbes during delivery. Research suggests that although the longer term impacts on eventual gut flora are still up for debate, there is often a delay in prominent members of the formative gut microbiome.

What isn’t as questionable is the impact of breast milk on development. If you were going to design a health food specifically formulated to shape the human gut, it would look exactly like breast milk. Besides providing essential nutrients and fatty acids, breast milk antibodies also inhibit the growth of certain microbes while prebiotic fiber—indigestible to babies—is broken down in the colon by a different set of beneficial microbes.

University of California, Davis professor David Mills thinks bifidobacteria longum infantis co-evolved with human milk.

Photo/Josie Luciano

One subspecies in particular, Bifidobacteria longum infantis, can “vacuum it all up,” according to Mills. “It has every kind of glycosyl hydrolase cutting enzyme necessary to cleave any human milk oligosaccharides that can be thrown at it. And it has all the transport systems for pulling stuff into the cells, so we think it co-evolved with human milk. It’s literally a partner to mom’s milk.”

After 300 million years of mammalian evolution, breast milk is a strong example of symbionts that benefit each other over the long run. But we shouldn’t be fooled into projecting any intended generosity on their part.

Roommates, not lovers

“The bacteria are not there for us,” explained Shavawn Forester, a dietician and nutrition professor at the University of Nevada, Reno. “They’re in it for themselves. We just happen to be their environment. … They work together because they’re in balance, whatever that balance might be, even if that balance is a little bit more of one than the other.”

Forester’s take on symbiosis may run counter to the commonly held belief that symbiosis implies mutual intent, but intention is never part of the equation. Even when two organisms “help” each other, their cooperation is only based on a shaky alliance of function and individual benefit. If something surrounding the environmental conditions of that relationship changes, so does the relationship itself.

Take E. coli for example. Though we often think of Escherichia coli bacteria as the pathogen responsible for incidents like the infamous Jack-in-the-Box outbreak of 1993 or the two to three beef/sprouts/salad-related headlines that we have come to expect every year, there are plenty of nonpathogenic strains that are usual residents in our gut.

These strains provide the important function of producing Vitamin K and B-complex vitamins as well as taking up important real estate that could otherwise become a home to more harmful microorganisms. However, if E. coli crosses a perforated intestinal barrier, it can cause problems such as urinary tract infections in its new conditions.

Given the thousand or so species of microbes that live in our inner ecosystems, there is a whole lot of potential for interaction. So much, in fact, that we’re just beginning to map the basic patterns that play out in our guts every day.

“What we’re learning is that we change the microbiome when we change diet,” said Forester. “We can see differences in people who eat a mostly meat-based diet compared to a plant-based diet. We can see differences in younger people versus older people, people who exercise versus people who don’t exercise.”

Vegetarians might have a greater concentration of Prevotella than in omnivores, a genus-level bacteria that helps break down carbohydrates. But all that means is that vegetarians feed microbes more carbohydrates and therefore colonize a niche of bacteria that breaks down carbs. Their numbers are also determined in part by having less competition with fat- and protein-eating bacteria.

Although there are correlations between certain phyla-level bacteria for conditions such as obesity and heart disease, specific genus species for particular diseases like food poisoning and yeast overgrowth, as well a general association between diversity and health—it can be frustrating to know there isn’t a definitive list of microbes that make up a healthy gut.

Unless there’s a pathogenic species present, DNA sequencing provides a snapshot for a moment in time and a stage of succession.

Forester put it broadly, “There are differences, and those differences contribute to health. And I would say for the most part that’s kind of what we know for sure.”

She still subscribes to the same diet that she always has for her patients—a 50-60 percent plant-based diet, and although Forester advises eating lots of vegetables with prebiotic fiber for our microorganisms to eat, she stops short of recommending probiotic supplements, calling into question the use of air-dropping a dozen species into a gut that already has hundreds of established communities.

Others echo this sentiment. Jack Gilbert, the microbial ecologist behind projects such as the Earth Microbiome Project and the Hospital Microbiome Project cites the success of targeted probiotic use for certain conditions like diarrhea and food allergies, but decries many of the claims that the unregulated probiotic industry is known for.

“It’s hard, isn’t it?” Gilbert said in a recent phone interview. “The vast majority of the spurious claims are around the improvement of ’wellness’ in your gut. Because that’s the only claim. … There’s no evidence that consistent consumption of a probiotic yogurt or of a probiotic pill will have any substantial influence on maintaining health.”

This is probably true for a majority of the population for the majority of the probiotics out there—but don’t worry, TAM, there’s still promise. A recent study by microbiologist Jens Walter of the University of Alberta demonstrated that when volunteers were given a strain of Bifidobacterium longum, a common gut bacteria belonging to the same species as Mills’ B. longum infantis, almost a third of the participants retained the bacteria in their gut for as long as six months, demonstrating that it is possible to establish a residence of probiotics far more permanent than the typical three-day flush.

Mills in his lab at UC Davis.

Photo/Josie Luciano

The key to making them stick? There needs to be a niche available for the bacteria to fill. So, those who were best able to integrate the new species were also those who already had less B. longum as well as fewer bacteria that performed similar functions. Just like any species in any ecosystem.

Number 2

Even if you have missed every microbiome headline that has graced science and news magazines alike for the past few years, you might have still managed to hear about fecal microbial transplants (FMTs). And they are exactly what they sound like.

While scientists step through all the hoops to perform exploratory mouse experiments and double-blind, peer-reviewed studies on things like milk, probiotics, and gut-brain axis studies, there has been a different kind of demand for one particularly nasty pathogen called Clostridium difficile, or C. diff, as it’s commonly known.

Though C. diff is a naturally occurring bacteria in a small percentage of the population, it doesn’t affect the majority of people who carry it. Those who do become infected often have compromised immune systems from recent antibiotic use that paves the way for C. diff to out-compete a gut that’s depleted of its regular flora.

Overnight, those afflicted with a severe infection can experience chronic bouts of diarrhea, abdominal cramping, vomiting, colitis, and even kidney failure. It’s a terrible disease and patients will do anything to find relief.

Due to the persistent and crippling nature of the disease, it had been common for C. diff patients to go the DIY route, well before official human trials were underway. A mix of a friend or family member’s stool sample, a blender, and an enema bag is just about all you need. When word spread that it actually worked, a still bustling internet community sprung up around the procedure. In 2013, the first randomized human trial took place and produced a staggering 94 percent success rate, an unheard of number for medical studies. The next year, FMTs were classified as an Investigational New Drug by the FDA for cases of C. diff.

But until FMTs are formally approved for other inflammatory bowel diseases like Crohn’s, people continue to administer them on their own. Many thousands of people have been helped by FMTs, but it is not all smooth sailing for patients. Since FMTs move entire microbial ecosystems from one person to another—an interaction that the medical community still knows very little about on a species-to-species basis—there are bound to be unintended consequences.

In a FMT performed last year, the concept behind a mouse trial was unwittingly replicated in humans when a 32-year old woman experienced significant weight gain (41 pounds) in the two months following the procedure after receiving a stool sample from her daughter who, although obese, had no other health problems that came up during screening. Although the patient’s C. diff symptoms have disappeared, she has been unable to lose the weight, according to the clinician’s report.

Looking ahead to the future of FMTs, weight gain is probably one of the lighter consequences of undergoing a procedure that is not well understood. But since they seem like the magic ticket to a population that would do just about anything to get rid of their pain, it goes without saying that clinical doctors and scientists have a responsibility to point out the potential dangers of transplants and the holes that exist in screening.

This doesn’t always happen, though, which is the reason that one microbiologist, Jonathan Eisen, has taken to the Twitterverse to haze doctors and fellow scientists for hyping what science hasn’t yet proven.

Over the past few years, Eisen has given out several “Overselling the Microbiome” awards to doctors who recommend FMTs for neurological disorders, an unproven treatment.

Although it is too soon to make the assertion that FMTs should be used to treat disorders like schizophrenia, depression or Alzheimer’s, the concept of the gut-brain axis is sound.

Basically, it describes the two-way communication that happens between the body’s two brains—the enteric nervous system (located in the gut and gut flora) and the central nervous system. This can happen a few different ways. Like when the GI tract send signals up to the brain through the vagus nerve. Or when the gut bacteria secrete neurotransmitters such as GABA and tryptophan. Or blood-borne chemicals. Or hormones. In many cases, the enteric nervous system does not even need to communicate with the central nervous system to elicit reflexes.

All of this has earned the gut its “second brain” nickname and has inspired research ranging from how microbiome formation affects neurotransmitters to the way the gut regulates appetite and the effect that probiotics and gut flora have on stress.

This last study was recently presented at Sierra Nevada College in a talk by UC Davis physiologist Melanie Gareau, titled “Gut Feeling: How Intestinal Microbes Modulate Mood and Behavior.” It was delivered to a packed house.

During the talk, Gareau presented mouse trials showing that negative manipulation of the gut microbiota could lead to permeability and therefore changes in mood and behavior. They also found that adding beneficial bacteria mitigated this response. No one in the audience missed the implications of this result—the possibility that probiotics might just work after all.

The rest of the evening was spent with Gareau graciously fielding personal health questions, a gesture that—in the midst of her special research presentation—captured the tricky state of microbiome research in general—just a few facts and a gut full of questions.