Our digestive tract contains trillions of bacteria encompassing thousands of different species that collectively make up the gut microbiome. In fact, the number of bacterial cells that have colonized our bodies outnumbers the human cells that make up our bodies by a factor of ten to one, and the majority of those bacteria reside in our gut! These little passengers aren’t just along for the ride, and you could say that we’ve entered into a mutually beneficial contract with them; they enjoy a place to call home and a constant supply of food, while we benefit from their ability to break down our food into vital nutrients.
It turns out, however, that the gut microbiome plays an even larger role than helping us digest our food, and many of our body’s biological functions – from our metabolic processes to our immune system – are exquisitely sensitive to changes in the composition of the bacteria that reside in our gut. Disruption of this delicate balance has been implicated in a host of health conditions such as diabetes, obesity and autoimmune diseases like inflammatory bowel disorder and multiple sclerosis. I will return to the link between the gut microbiome and MS in a moment.
The microbial ecosystem in our guts is shaped by the various exposures that we come across in life, such as the food we eat, the air we breathe, any infections we’ve acquired or drugs we’ve taken, along with a host of other environmental factors. These environmental exposures interact with our body’s own physiological processes, such as metabolism and stress, to further alter the balance of our microbial communities. There’s even evidence to suggest that our genes have a hand in influencing the composition and abundance of the gut microbiome, and that these “heritable” strains of bacteria are associated with health and disease. What this means is that each individual’s gut microbiome is unique, acting as a microbial “fingerprint” that carries the potential in the future to help predict risk of various diseases or offer new therapeutic targets.
Mapping out our gut microbiomes is no trivial task. To realize such a complex endeavour, the Human Microbiome Project (a play on the Human Genome Project from several decades ago) was launched in 2008 by the US National Institutes of Health (NIH) with the aim of cataloguing the diverse species of microbes residing in a sample of healthy individuals. Such a catalogue, in turn, can serve as a reference point for comparing how different disease states can alter the composition of the gut microbiome and suggest new avenues for therapy.
While studying bacteria traditionally has involved “culturing” bacterial colonies on plates of growth medium, modern approaches have shifted to advanced, high-throughput sequencing techniques that are faster, more accurate, and provide a great deal more information. Today, gut microbiome researchers rely on DNA sequencing approaches and complex computational tools to catalogue the genes comprising our complex gut microbial communities. Researchers first purify DNA from samples that are teeming with microbes (to sample the gut microbiome, researchers rely on stool samples), sequence the genetic information using one of several techniques, and compare this sequencing data using complex algorithms to existing databases. One technique, called 16S rDNA sequence analysis, allows researchers to determine which bacterial species are present in the sample (i.e. “who’s there?”), while a second approach called metagenomics analysis determines the function(s) of the microbes, or answer the question “what can they do?” At the end of the day, these powerful approaches are not only able to capture the biological diversity of the gut microbiome, but also their functional interactions with the host’s physiology, leading to valuable insights for health and disease.
Gut microbiome: The link to multiple sclerosis
Earlier, I mentioned that imbalances in the composition of the microbial communities in our guts have been linked to various diseases, including MS. The connection between the gut microbiome and MS is rooted in the interactions between microbes in the gut and the immune system.
Since the gastro-intestinal system is a major point of entry for many foreign substances into the body, including potential pathogens, the immune system employs a complex surveillance system that monitors the composition of the gut microbiome in order to distinguish the “good” bacteria from the “bad” ones. Our gut microbes, in turn, secrete certain compounds – such as cytokines and chemokines – that can regulate the activity of certain immune cells that are implicated in autoimmune disorders like MS. For example, the bacterial species Bacteroides fragilis has been shown to promote uncontrolled activity of T helper-1 cells – which are normally involved in host defense against infection but can lead to attacks on our own tissues in autoimmune disease – through the release of certain molecules. In addition, segmented filamentous bacteria activate another type of immune cell called T helper-17 cell which also contributes to the MS disease process.
To date, the bulk of the research examining the link between the gut microbiome and MS has taken place in animal models. Interestingly, one of the first studies to look at this question came to a sobering conclusion: the gut microbiome is essential for the development of MS-like disease in mice. The Nature paper, published by Kerstein Berer (Max Planck Institute of Neurobiology, Germany) and colleagues, described an experiment where mice that were experimentally induced to develop an MS-like disease were bred under two different conditions: a sterile, germ-free environment or a conventional, pathogen-free (but not sterile) environment. They found that mice raised in the sterile environment did not harbour microbes in their guts and, importantly, did not develop the MS-like disease. On the other hand, most non-sterile mice did go on to develop the disease. When sterile mice were recolonized with the gut microbiomes transplanted from the non-sterile ones, they rapidly went on to develop the MS-like disease. These observations followed in the wake of an earlier study from a group in Dartmouth Medical School (Hanover, NH), who treated mice induced to develop MS-like disease with a cocktail of various antibiotics. They found that antibiotics appeared to protect against development of MS-like disease, presumably through a reduction in proinflammatory cytokines.
At first glance, this broad-brush approach would seem to suggest that the microbes inhabiting our gut are detrimental and can increase the risk of developing MS, but it’s not necessarily quite so simple. On the contrary, more recent research has put the spotlight on certain gut bacterial strains as playing a potentially beneficial and even therapeutic role for combating autoimmunity. A study by Shahram Lavasani and colleagues (Lund University, Sweden) found that a probiotic mixture of three Lactobacillus strains suppressed the progression of MS-like disease and reversed both clinical signs of the disease and inflammatory lesions. Of course, these findings showing a gut microbiome-driven therapeutic strategy in an animal model, while exciting, are still in their infancy and a great deal more work needs to be done to draw conclusions about the therapeutic potential of using probiotic substances in humans.
More recently, researchers have begun to investigate the role of the gut microbiome in humans in order to ask the question “is there something about the gut microbiome in people living with MS that’s unique compared to people without MS?” Dr. Sushrut Jangi, who works in the laboratory of Dr. Howard Weiner (Brigham and Women’s Hospital, Boston MA), has been determined to answer just that question. Dr. Jangi and colleagues collected stool samples from a cohort of people living with relapsing remitting MS as well as healthy controls and subjected the samples to high-throughput sequencing to determine the functional composition of the gut microbiome. They found that the proinflammatory bacterium Methanobrevibacteriaceae was found in a higher proportion in the gut of people living with MS, whereas the Butyricimonas bacteria, which produce a compound that generally suppresses the immune system, was found to be relatively lower compared to healthy individuals.
With a great deal of research attention now turned towards determining how and why MS can develop in children and adolescents, the inquiry into the role of the gut microbiome in MS has followed suit. Since the gut microbiome is thought to play a pivotal role in how the immune system develops during childhood, it only stands to reason that researchers will seize on this “critical window” of immune development to ask whether the gut microbiome differs in youth living with MS compared to their healthy counterparts and, if so, whether this difference is a cause or consequence of the disease. Just today, we announced the launch of a new study called “From bugs to brains: the gut microbiome in paediatric multiple sclerosis” that is asking that exact question. The study, led by Dr. Helen Tremlett (University of British Columbia) and funded by the Multiple Sclerosis Scientific Research Foundation, is being carried out in collaboration with Dr. Brenda Banwell’s pediatric MS study as part of the Canadian Pediatric Demyelinating Disease Network at pediatric MS centres across Canada and The Children’s Hospital of Philadelphia. Although the study is just starting to get underway, the MS community will be keeping an eager eye on this pivotal study in the coming years, since the results will reveal important information about the triggers and drivers of MS for people of all ages. Read our news update for more information about this exciting collaboration.
Any thoughts or questions about the gut microbiome? Leave them here.
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