The Triple Helix @ UChicago

Fall 2015

"The Next Frontier" by Stephanie Williams

 

In what feels like science-fiction fantasy, researchers have found that swapping intestinal bacteria between two individuals can cause the recipient to take on the donor’s personality. Microbiologist Premsyl Bercik and gastroenterologist Stephen Collins investigated this phenomenon by colonizing the intestines of one strain of germ-free mice with bacteria from another strain. They found that recipient animals took on the donor’s personality: mice turned from outgoing, friendly creatures to timid and reserved ones (Bercik, 2011). In a similar experiment, Irish researchers removed all intestinal microbes from mice, and found that the animals suddenly lost their ability to recognize other mice (Schmidt, 2015). 

These are only two of the many recent experiments that highlight the remarkable role that the microbiome plays in human health. A densely populated ecosystem, the microbiota that inhabit our gut harbor more than 3.3 million genes, exceeding the human genome by two orders of magnitude. A portion of these genes are conserved across individuals, and are primarily responsible for basic nutrition: harvesting nutrients and energy, fermenting mannose, fructose, cellulose and sucrose into short chain fatty acids, and biosynthesizing vitamins. The rest of the genes, which vary from individual to individual, provide an immense repository of signaling information that can distinguish individuals from each other within a population. These unique genes are largely uncharted territory, but there is speculation that medical researchers could tailor prescriptions to the different kinds of aberrant genes in the microbiome, increasing the effectiveness of medication on a person-by-person basis. This lies, along with other personalized medicine endeavors, far in the future. 

Together, the three million microbiome genes code for roughly 160 species of bacteria that populate the intestine. These species coexist in a highly dynamic environment and are affected by a range of factors: ethnicity, geography, circadian rhythms, gene polymorphisms, epigenetics, ENS, diet, innate and adaptive immunity, bile acids, and host metabolites, among others (Wu, 2015). Despite the variability in species and in the factors affecting their activities, there is evidence suggesting that, like distinct blood types, there exist three distinct gut population types—Bacteroides, Prevotella and Ruminococcus—which are named after their most populous genus. Each population is equipped to carry out certain metabolic tasks given certain raw material. Bacteriodes efficiently metabolize carbohydrates, Prevotella break down gut mucus, and Ruminococcus efficiently absorb sugars (Jones, 2011). Each has associated benefits and drawbacks; having one dominant type predisposes an individuals for other a set of health issues; individuals with bacteriods as the dominant type may struggle with obesity, individuals with dominant prevotella may experience gut pain, and individuals with dominant Ruminococcus may experience natural weight gain (Jones, 2011). Knowing which genus dominates the gut ecosystem can inform doctors who are creating treatment plans for individuals facing metabolic-related obesity disorders. The importance of microbiota is hard to overstate. The organisms play a major role in the host’s mental health, immune system, metabolism, homeostasis, and the transformation of small bioactive molecules that act as drug-like regulators. Disrupting the homeostasis between the microbiota and the host (“dysbiosis”) has a more important role than host genetics do in the development of certain diseases, such as Irritable Bowel Disease, obesity, and type 2 diabetes. “We don't want to oversell it, but everywhere we look there is some connection,” says Michael Dority, program administrator for the Host Microbiome Initiative. 

Autism is one disease that has long been associated with intestinal dysbiosis; Individuals with autism spectrum disorder often report experiencing intestinal problems. To investigate the link to the microbiome, researchers took a metabolomics survey of affected individuals, and discovered one particular microbial metabolite, 4-ethylphenylsulfate (4EPS) (Garber, 2015). When the researchers Fed 4EPS to normal mice, they developed anxiety-like behaviors that resembled those of autistic mice. Currently, the mechanism that the metabolite uses to effect the changes is being investigated. This is one of many promising examples of potential alternative therapies for systemic disorders. 

Other biota research has focused keenly on the effect of diet on the metabolic activities of microbiota. Certain diets can prevent bacteria from carrying out their metabolic tasks. Dietary-fiber deficient diets, for example, lead to “a reduction in short-chain fatty acid production,” says microbiologist Justin Sonnenburg, “the modern, relatively fiber-deficient Western diet is out of balance with the gut microbial community, and it's this simmering state of inflammation that the Western immune system exists in that's really the cause of all the diseases that we've been talking about.” This is particularly important given the recent finding of the three different micobiota populations. 

Small molecule drugs that can target certain genes in microbiome and bacterial species’ metabolites are currently being pursued as therapies for previously untreatable chronic diseases. Many traditional therapies are ineffective, and treat symptoms rather than the root of chronic disease. The human microbiome is a “massive untapped source of novel drug targets,” commented Tadataka Yamada, medical and scientific officer, ““we're talking about roughly several million microbial targets.” The human genome, in contrast, has traditionally provided only 20,000 drug targets (Garber, 2015). As a part of their normal functioning, microbiota naturally produce thousands of drug-like compounds. The problem is, as Sonnenburg said, “We don't [know] what their chemical structures are and...we don't know what pathways and receptors they're binding to in our biology.” Simulating the body’s natural function of producing small drug-like compounds, and hijacking its own machinery for doing so is a promising idea for treating diseases linked to or affected by signaling pathways with their origins in the enteric nervous system (ENS). Elucidating these structures and pathways will be the next steps in microbiology research, and will likely be used as a blueprint for the creation of new drugs. 

As for the current “probiotic” and “prebiotic” treatments, which are supposed to promote “good” bacteria, it is best to remain cautious of their claims. Most probiotics and prebiotics do not account for the three major microbiota populations, and they exert system wide effects—they alter the entire microbial community. Stan Hazen, the chair of cellular and molecular medicine at the Cleveland Clinic Lerner Research Institute, says that the new approach may be more reliable than probiotics and prebiotics. “[They are] a huge black box. That's why I actually think that the drugs approach is a more scientifically predictable and tractable approach.” 

Though a great deal of the microbiome’s signaling and content lays still untouched by researchers, there is remarkable potential in what has already been discovered. Future research will likely provide novel drugs that can alleviate previously incurable aspects of chronic disorders, and will help catalyze the movement towards personalized medicine. 

References

[1] Bercik, P., et al. (2011). The intestinal microbiota effect central levels of brain-derived neurotropic factor and behavior in mice. Gastroenterology, 141 (2), 599-609. doi: 10.1053/j.gastro.2011.04.052
[2] Carabotti, M., Scirocco, A., Maselli, M. A., & Severi, C. (2015). The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems. Annals of Gastroenterology : Quarterly Publication of the Hellenic Society of Gastroenterology, 28(2), 203–209. 
[3] Garber, K. (2015). Drugging the Gut Microbiome. Nature Biotechnology 33, 228–231. 
[4] Jones, N. (2011). Gut study divides people into three types. Nature. doi:10.1038/news.2011.249
[5] Qin, J. et al. (2010). A human gut microbial gene catalogue established by metagenomic sequencing. Nature, 464, 59–65. 
[6] Reardon, S. (2014). Gut Brain Link Grabs Neuroscientists. Nature, 515, 175-177. 
[7] Shmidt, C. (2015). Mental health: Thinking from the Gut. Nature, 518, S12-S15. doi:10.1038/518S13a
[8] Young, E. (2012). Gut Instincts: The Secrets of your Second Brain. New Scientist, 2895, 38-42, doi:10.1016/S0262-4079(12)63204-7
[9] Wu, H., et al. (2015). Linking Microbiota to Human Diseases: A Systems Biology Perspective. Trends in Endocrinology & Metabolism, 26, 12, 758 – 770.

 
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