We are Not as Alone as We Think

We are not as alone as we think—microbially speaking.

In the past few years, scientists have made enormous strides in the field of microbiome research. In our body, bacterial genes outnumber human genes by a factor of one hundred. Before we are born, certain bacteria have already begun to colonize our body—in the gut, the mouth, the genitals, and the skin, to name a few places—establishing intimate relationships that remain with us until the day we die. Our so-called microbiota performs essential functions such as nutrient digestion, immune development, and even neuronal function.

Research on the microbiome, the collective genes of the organisms comprising the microbiota, has blossomed in recent years, and the advances made have not gone unnoticed. We can now have our microbiomes sequenced, and novel treatments options have been successfully deployed in severe, otherwise untreatable cases of bacteria-associated diarrhea. Not only is our microbiota essential, but it is also readily mutable. Changes in our dietary habits, lifestyles, cultural environments, and health can drastically affect our microbiome’s composition. These perturbations to our microbiota can have lasting effects on our health: studies have proposed tentative links between microbial composition of the gut and metabolism, fetal health, and even neurodevelopmental disorders such as autism. But how much do we really understand about these bugs that call us home—and more importantly, do we know enough to start taking medical action?

Dr. Dennis Kasper, a researcher in the Microbiology & Immunobiology Department at Harvard Medical School, studies the microbe-host relationship and is particularly interested in “opportunistic pathogens” of the gut—that is, species that normally live in the gut without causing any harm to their human hosts, but in the event of specific disturbances, can cause infection and disease. Central to his research is the concept of dysbiosis—a state of microbial imbalance in the body, in which the composition of the gut microbiota is altered. Dysbiosis has been linked to conditions such as colitis, obesity, and cancer.

HippoReads Science Correspondent Katherine Wu spoke with Dr. Kasper about what we currently know about the microbiome and its many implications in medicine.

KW: How did you get interested in this sort of research?

DK: My original training and interest was in chemistry, and I’ve had a longstanding interest in carbohydrates. I was by no stretch of the imagination a mucosal immunologist, and still am not, but I’ve learned a lot about it. Still, [my background in chemistry] has allowed my lab to define molecules in the gut that have immune implications. It’s the desire to, and willingness to, move into peripheral, related fields that allowed us to move our projects forward.

When I first joined the faculty here in 1985, we knew the least about anaerobic bacteria—a class of bacteria that grow in the absence of oxygen. But I was interested in how bacteria were involved in infection. In the years since, my lab has discovered a number of polysaccharides produced by anaerobes that affect the immune system and colonization of the gut. So far, there have been two molecules in the gut microbiota that have been clearly implicated in mediating the immune response overall, and our lab discovered both of them.

KW: Tell me more about these microbially-derived molecules, and how they interact with the immune system.

DK: About 12 years ago, I became interested in interactions between bacteria in the gut and the immune system. My lab has focused on how specific molecules from bacteria influence the development of the immune system, using a reductionist approach.

Bacteroides fragilis is a common organism in the human gut, but it’s also a species that is often isolated when there is fecal contamination of a sterile site. We discovered a few years ago that, unlike most bacteria, which only make one or two types of capsules, B. fragilis can make eight different polysaccharides (named polysaccharides A, B, C, D, E, F, G, and H; A is the most abundant and the most important), but has ways of preferentially expressing one type over another.

Polysaccharides are important because they cover the surface of the bacteria, and that’s the first thing the immune system sees. We found polysaccharide A really interesting because it activates a type of immune cell called a regulatory T cell. It makes these cells produce a signaling molecule called IL-10 that decreases inflammation. So polysaccharide A might be something which could be used to interrupt or prevent disease progression.

The other molecule is found in most Gram-negative anaerobes. Gram-negative bacteria have an outer membrane which contains lipid molecules called sphingolipids. Sphingolipids affect a unique class of T cells called NKT cells. NKT cells are normally recruited to sites of inflammation, particularly at mucosal surfaces, and have been shown to be important in asthma and ulcerative colitis, the most common type of inflammatory bowel disease. So, the fewer NKT cells one has, the less susceptible they are to inflammation.

It turns out that gut bacteria affect how many NKT cells there can be in an animal. We have found in germ-free mice [mice that are born in sterile conditions, and thus live without gut bacteria] that the sphingolipids they see early on in development affect how many NKT cells they have in their adult life. If germ-free mice are exposed to bacteria, or even just one class of sphingolipids, early in development, then they have fewer NKT cells in adulthood. However, if this exposure does not occur, then there is an overabundance of NKT cells in adulthood, and the mice are now susceptible to inflammation. All of this is due to a sphingolipid made by B. fragilis called BF17.

This has interesting implications for human disease, since we don’t know when to target diseases like colitis in humans. We aren’t sure if it should be in the first year or two of life. People in my lab looking to see how different bacterial species in germ-free mice affect the development of the immune system. This is done in collaboration with Diane Mathis and Christopher Benoit.

KW: What are some limitations in studying the gut microbiome?

DK: It’s complicated. When we use mice to study inflammation, we know we are studying diseases that mice don’t get. When you focus on a specific cell type and a specific target, you may cause a similar disease in mice, but it may not be the same as what is happening in humans. That’s a big gap. I don’t think there’s anything wrong with mouse models, and we’ve developed an amazing understanding because of them, but I do think there’s a significant leap from mouse to human. Maybe the predictability of animal models to human therapeutics is not as wide in vaccines as in immunie-mediated disease. Still, it’s not ideal—you’d prefer to do preclinical work in a species that’s closer.

KW: Is there potential for manipulating the microbiome in medicine?

DK: For certain diseases. The one for which it’s most clear is Clostridium difficile colitis, which usually happens after antibiotic treatment, which gets rid of a lot of the normal flora in the gut. This allows the overgrowth of particular microbes. This colitis has been treated with antibiotics, but it’s not always successful. So-called fecal transplantations have a very significant impact on the outcome of that disease in these cases that can’t be treated with antibiotics.

I’m not as sure about [manipulating the microbiome] in relation to immune-mediated disease. I tend to favor the idea that just giving microbes to an animal when they have an established microbiome does not do much… the microbiota is very robust and it bounces back quickly, to its original state, and you would not establish a permanent change. There are minor changes, but it’s not easily controlled. If you have one very strong organism that you administer every day, maybe you can stimulate it in a certain way, but I don’t think our science is there yet, to know what that microbe would be.

One important thing to remember is, you have hundreds of species in the gut—you can’t think for a second that there’s a microbe that does something that is unique. This system evolved with great functional redundancy because it’s so important; what that means is there are a lot of different species doing the same thing to make sure that even if one is lost, the system will still work. So, giving one anti-inflammatory organism isn’t really going to have an impact… whereas giving one drug might, once we find the right molecule.

KW: Given that there are a lot of redundancies in the species composition of the gut microbiome, and no one’s microbiome is exactly like someone else’s, how much does a person’s microbiome really say about their health status?

DK: Now? I don’t think it’s proven. There are a lot of companies that think they’re going to make money off of sequencing the gut microbiome and telling people what it means, but I don’t think there’s evidence to back this up. I think people see an opportunity to make some money and are seizing on that. And there will be people who will buy into it [personalized sequencing]. I don’t know what they would do with the information. Even with things where we know there’s an association, like BRCA [a gene that has been linked to breast cancer], once you have that information about yourself or your family members, there are big decisions about what you’re going to do about it. You have to be careful of what you learn.

KW: Are people over-exaggerating the importance of the microbiome in autism, obesity, or pregnancy? How can we approach the research findings more cautiously?

DK: It’s very hard to mediate these kinds of things. Someone writes a paper on autism and the microbiome, and it’s a well-done study, it’s in mice, it’s in a high-level journal, there’s nothing wrong with the science—the specific findings are hard to communicate. It’s very exciting for the newspapers to pick up stories like that, and it gets put into the press. Scientists have gotten better about adding cautionary notes when these things are published, like, “We won’t know definitely for at least another five years.” But still, rather than point out the downsides of the study, scientists also like to see their work publicized and see their name in the New York Times. They want to make something out of it. I don’t know what can be done to prevent that.

On the other hand, it’s been proven that diarrhea is caused by C. difficile. There are some interesting stories with certain diseases—multiple sclerosis, for example. I don’t know if the microbiome is critical in modulating the clinical symptoms. But you have to consider if the animal models we are using are good models. Even if they are, it’s still a leap to humans. And it’s hard not to believe that the microbiota is important in inflammatory bowel disease. It’s right there, and we know a lot of the immune response is directed against bowel microbes.

Other things are less clear. Arthritis, for example—is the disease causing change, or a change in the microbiota causing disease? It’s a chicken and egg situation. But it’s certainly a possibility. Also, I’m not quite as sure about the involvement of the microbiome in obesity. In that case, I think the science seems a little further away to make a clear association.

KW: What should the general public understand about their own microbiomes? Should we be more conscious of our health in the context of the gut microbiome?

DK: There are a couple things that are clear, like the relationship of the microbiome to the immune system. There’s a complex community of organisms in the intestine that directs the immune system on how to respond to infection. It may be that diet could alter the composition of the microbiome, but whether diet affects the immune system is a complex question that we can’t say anything definitively about right now.

Another thing that is probably real is the hygiene hypothesis. As people have used more antibiotics over the past century to combat infectious disease, people have stopped dying of infections, but we have seen an increased prevalence of autoimmune disease and chronic disorders—probably because antibiotics are disturbing our microbiota. The changes in the microbiome is a very plausible explanation in this case, and an increase in these immune-mediated diseases may be penance for getting past the burden of infectious diseases.

All in all, though, there’s not a lot we understand fully, so we have to be cautious. Ten thousand species can colonize the microbiome; each of us has several hundred of those species, and they’re not always the same. Think about what it means to try to understand that: we don’t even know what most of these organisms are. It’s a huge challenge. I think science is up to it—it could be that in 10 years we will know about it. But right now, we’re still in a pretty early learning stage.

KW: If that’s the case, where is microbiome research headed?

DK: I personally believe that there is a lot more to be learned from studying individual organism effects, or unique combinations of organism effects rather than whole microbiome effects. But you can learn by mixing certain species and learning how it affects, at least in my case, the immune system, and develop some paradigms. So far, I have yet to be convinced that any complex set of bioinformatics has given us any insight into disease.

Studying the relationship between nervous system and the microbiome is new—there is a clear gut-brain axis that exists. Our largest immune organ is the gut. We have a lot of immune cells there, and those cells are capable of going elsewhere in the body and affecting other diseased areas and other health areas. But I personally don’t have any real insight into how you study things at that level, at least until you have some understanding about the gut microbes and other organisms that live in the gut, like viruses. These viruses undoubtedly have effects on the microbes—some of them are phage, some are enteric viruses that can affect the immune system. It’s all very complicated.

KW: The microbiome has become a particularly trendy topic lately. Is this encouraging for research? How can we better communicate about the microbiome to a more general audience?

DK: It’s one thing to communicate about this research with other scientists, but it’s more difficult for scientists to communicate with a more general population. The lay public is not educated in the areas you need to be. They just don’t speak the same language, because it’s so unique.

We don’t get people interested at an early age, and we’re not teaching it effectively. We need to prioritize getting people interested in biology, and getting people to have enough of an education in science, and then translating what scientists have to say to the majority of people to understand. Scientists are not really trained in talking to the lay public either. It really requires a whole different level of exchange. There are those in our community who are brilliant at communicating with the public, and then there are those in our community who are brilliant, but cannot communicate with the public.

The more scientists communicate with the public, the better. It’s important for more people to understand the complexity of disease and the issues that science faces in figuring things out. That’s a big step, and I’m all for it.

Further reading

• Michael Pollan. Some of My Best Friends are Germs. NY Times.
• Ilseung Cho and Martin J. Blaser. The Human Microbiome: at the interface of health and disease. Nature Reviews: Genetics.
• Moises Velasquez-Manoff. Among Trillions of Microbes in the Gut, a Few Are Special. Scientific American.
• Christine Gorman. Explore the Human Microbiome. Scientific American.

Image Credit: Milosz1 from Flickr