The Triple Helix @ UChicago

Winter 2015

"The Microbial World Inside of Us" by Jeremy Chang

 

The human gastrointestinal tract, the largest microbiome of the body, is a red-hot field in science today. The topic has garnered so much attention that even the mainstream news discusses the field’s latest findings. What makes this dark (and potentially smelly) environment so appealing to scientists?

The gut microbiome is novel because unlike the brain, which has already developed partially at birth, the gut microbiome begins as a sterile environment and develops into a dense network of bacteria. This microbial world plays a vital role for nutrient processing, immune function, and the homeostasis of the gastrointestinal system.[1] The sheer complexity of the interactions between the gut microbiome and human body has historically made studying the microbiome difficult. With the development of advanced sequencing technology, however, scientists are piecing together the puzzle within every human.

Colonization and Early Exposure

Colonization of the intestinal tract begins immediately after a baby is born. The growth is so fast that the microbial population reaches that of an adult’s in only a few days.[2] The tremendous microbial bloom is characterized by its fair share of chaos as different families of bacteria compete for dominance. The variability of bacterial profiles for young babies demonstrate the frenetic pace of the ecosystem’s development.[3] Yet, despite the appearance of disorder, there is a method to the madness. 

Evolution has fine-tuned the symbiotic relationship between gut microbes and the host—a process called coevolution. A baby’s intestinal tract does not represent “open season” for all types of bacteria. In the colon, for example, only five bacterial subtypes exist, which is an extremely low number given the diversity of bacteria.[4] This means that only microbes that are highly specialized can inhabit the ordinarily hostile environment of the gut. 

A single gene can make all the difference when a bacterium attempts to colonize the gut. The intestinal lining contains innate colonization resistance mechanisms that prevent any run-of-the-mill microbe from attaching itself to the lining, so specialized genes on the bacterium’s part are necessary. Genes that appear to be prominent during the colonization process are those that allow the organisms to utilize the local resources of the intestinal environment. When these genes function properly, the bacterium can overcome the host’s resistance mechanisms.[5] 

Despite the high turnover rate of the dominant bacterial type early in development, the individual’s gut microbiome stabilizes by three years of age. It is believed that this occurs because existing bacteria in the microbiome act as alternative forms of colonization resistance, actively excluding other microbe types from the ecosystem. This would indicate that early exposure to microbes for a baby is essential for a healthy gut. Even the mode of delivery can affect the baby’s microbiome for up to seven years.[6] Babies who are born through a Cesarean section (C-section) have reduced exposure to maternal microbes, which may lead to increased numbers of infections and allergenic disorders.[7] Other factors such as hygiene, use of antibiotics, and infant feeding practices (breast milk versus formula) undeniably play a role in the development of the gut ecosystem.[8]

Diet and Disease

Unsurprisingly, diet influences the long-term profiles of an individual’s gut microbiome immensely, and it is also strongly linked to the pathogenesis of numerous diseases. Scientists have been hard at work revealing the role of gut bacteria as an intermediary that connects A to B. 

One study attempted to correlate diet, the gut microbiome, and disease by comparing individuals of radically different diets. The study focused on native Africans who had high-fiber diets and urban African Americans who had high fat diets. The bacterial subtype Prevotella dominated the microbiomes of the native Africans and Bacteriodes dominated the microbiomes of the African Americans. The preponderance of Bacteriodes enterotype for the African Americans was associated with higher secondary bile acids.[9] Given the fact that African Americans have significantly higher rates of colorectal cancer compared to native Africans, the study highlighted a correlation that implicated the microbiome’s potential involvement in disease. 

The possible role of gut bacteria in sickness has also been elucidated through mouse models.[10] This experiment began with mice who had a nonfunctioning IL-10 gene, which traditionally codes for anti-inflammatory proteins. The mice were then fed a diet of saturated milk fat. The absence of a bile acid due to the genetic defects of the mice led to the presence of organic sulfur in the gut. There was a subsequent bloom of B. wadsworthia, which uses the organic sulfur sources to produce hydrogen sulfide (H2S).[11] High H2S concentrations induce inflammatory responses, alter gene expression, and prevent DNA repair, contributing to numerous illnesses.[12] When humans were placed on a fatty diet based on animal product, a similar result occurred—there was an increase in the B. wadsworthia bacterium.[13] These findings provide strong evidence that abnormal gut microbiomes can translate into long-term, harmful effects for hosts. 

The world in the last half century has trended towards a Westernized high fat diet, and it shows. In the same time span, there has been a dramatic increase in inflammatory bowel disease, diabetes, obesity, and cardiovascular disease. For most of these afflictions, there is some association with altered gut microbiota structure whether it be low microbial diversity, the growth of harmful bacteria, or even suboptimal bacterial ratios in the microbiome. Hopefully, our research in the gut microbiome will lead to proactive methods of maintaining healthy gut bacteria. By helping them, we are helping ourselves. 

What’s Next?

With our current knowledge, a comprehensive understanding of the gut microbiome remains elusive. Similar to many things, but especially for the gut ecosystem, we know less than we would like to know. By understanding the ecosystem more clearly, we gain a better appreciation of our intimate relationship with the microbial world that has followed us since our births. On the practical side, we will also be more prepared to treat and prevent diseases that are rising at alarming levels around the globe. This field definitely deserves our attention, and do not be surprised to find yourself reading more articles about our unseen companions. 

References

[1] Sang Sun Yoon, Eun-Kyoung Kim, and Won-Jae Lee, “Functional genomic and metagenomic approaches to understanding gut microbiota–animal mutualism,” Cell Regulation, 24 (2015): 38-46, accessed February 24, 2015, doi:10.1016/j.mib.2015.01.007. 
[2] Yatsunenko, T.a, Rey, F.E.a, Manary, M.J.bc, Trehan, I.bd, Dominguez-Bello, M.G.e, Contreras, M.f, Magris, M.g, Hidalgo, G.g, Baldassano, R.N.h, Anokhin, A.P.i, Heath, A.C.i, Warner, B.b, Reeder, J.j, Kuczynski, J.j, Caporaso, J.G.k, Lozupone, C.A.j, Lauber, C.j, Clemente, J.C.j, Knights, D.j, Knight, R.jl, Gordon, J.I., “Human gut microbiome viewed across age and geography,” Nature, 486 (2012): 222-227, accessed February 24, 2015, doi: 10.1038/nature11053. 
[3] Chana Palmer, Elisabeth M Bik, Daniel B DiGiulio, David A Relman, Patrick O Brown, “Development of the Human Infant Intestinal Microbiota,” PLOS Biology, (2007): accessed February 24, 2015, doi: 10.1371/journal.pbio.0050177. 
[4] Paul B. Eckburg, Elisabeth M. Bik, Charles N. Bernstein, Elizabeth Purdom, Les Dethlefsen, Michael Sargent, Steven R. Gill, Karen E. Nelson, David A. Relman, “Diversity of the Human Intestinal Microbial Flora,” Science, 308 (2005): 1635-1638, accessed February 24, 2015, doi: 10.1126/science.1110591. 
[5] S.M. Lee, G.P. Donaldson, Z. Mikulski, S. Boyajian, K. Ley, S.K. Mazmanian, “Bacterial colonization factors control specificity and stability of the gut microbiota” Nature, 501 (2013): 426–429, accessed February 24, 2015, doi10.1038/nature12447. 
[6] S Salminen, G R Gibson, A L McCartney, E Isolauri, “Influence of mode of delivery on gut microbiota composition in seven year old children,” Gut, 53 (2004): 1388-1389, accessed February 24, 2015, doi: 10.1136/gut.2004.041640. 
[7] Peter Bager, Jacob Simonsen, Steen Ethelberg, and Morten Frisch, “Cesarean Delivery and Risk of Intestinal Bacterial Infection,” The Journal of Infectious Diseases, 201, (2009): 898-902, accessed February 24, 2015, doi: 10.1086/650998. 
[8] Joël Doré, and Hervé Blottière, “The influence of diet on the gut microbiota and its consequences for health,” Food Biotechnology • Plant Biotechnology, 32 (2015): 195-9, accessed February 24, 2015, doi: 10.1016/j.copbio.2015.01.002. 
[9] Junhai Ou, Franck Carbonero, Erwin G Zoetendal, James P DeLany, Mei Wang, Keith Newton, H Rex Gaskins, and Stephen JD O'Keefe, “Diet, microbiota, and microbial metabolites in colon cancer risk in rural Africans and African Americans,” American Journal of Clinical Nutrition, 98 (2013): 111-20, accessed February 24, 2015, doi: 10.3945/ajcn.112.056689. 
[10] Vanessa A Leone, Candace M Cham, and Eugene B Chang, “Diet, gut microbes, and genetics in immune function: can we leverage our current knowledge to achieve better outcomes in inflammatory bowel diseases?,” Autoimmunity * Allergy and hypersensitivity, 31 (2014):16-23, accessed February 24, 2015, doi:10.1016/j.coi.2014.08.004. 
[11] S.D. Devkota, Y. Wang, M.W. Musch, V.L. Leone, H. Fehlner-Peach, A. Nadimpalli, D.A. Antonopoulos, B. Jabri, E.B. Chang. “Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in Il10−/− mice,” Nature, 487 (2012): 104–108, accessed February 24, 2015, doi:10.1038/nature11225. 
[12] M.S. Attene-Ramos, G.M. Nava, M.G. Muellner, E.D. Wagner, M.J. Plewa, H.R. Gaskins, “DNA damage and toxicogenomic analyses of hydrogen sulfide in human intestinal epithelial FHs 74 Int cells,” Environ Mol Mutagen, 51 (2010): 304–314, accessed Feburary 24, 2015, doi: 10.1002/em.20546. 
[13] L.A. David, C.F. Maurice, R.N. Carmody, D.B. Gootenberg, J.E. Button, B.E. Wolfe, A.V. Ling, A.S. Devlin, Y. Varma, M.A. Fischbach, “Diet rapidly and reproducibly alters the human gut microbiome,” Nature, 505 (2014): 559–563, accessed February 24, 2015, 10.1038/nature12820.

 
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