Beyond the Gut: Charting the Human Microbiome

WRITTEN BY ALEJANDRO DAUGUET & DANIEL JOHN  |  ILLUSTRATED BY YICHEN WANG  |  UNDER THE SCOPE VOL. 11

The incredibly diverse human microbiome plays a vital role across its host’s many organ environments, carrying enormous implications for treating diseases and preserving humankind’s well-being.

A MICROBIAL MEDLEY
Although room is scarce, many species within the human microbiome live in relative harmony—the fruit and insects represent the sheer diversity of microbial species within these tiny niches.
PHOTO BY BRIDGET SPENCER

The human body is composed of tens of trillions of cells, with almost as many cells as all of the stars in the Milky Way. Operating together as a wonder of evolution, the body’s organ systems work constantly to maintain a living balance. So, what would it mean for the human body to harbor more microbial life than bodily cells themselves?

Meet the human microbiota, the miniscule zoo inside each one of us, inhabiting a vast landscape of surfaces across the human body. The microbiota, collectively known as the microbiome, reflects this diversity, together sporting over three million unique protein-coding genes.

This adaptability of microbes to the unique niches of the human body allows them to forge a symbiotic relationship with their hosts. The benefits are many, ranging from keeping their locale in homeostasis by ensuring metabolic balance, to synthesizing valuable compounds such as vitamins, to contributing to a more robust immune system. Conversely, without the help of these microbes, symptoms of disease begin to emerge. Microbiota changes have been associated with weight fluctuations, states of mood, and even the growth of cancer.

What makes the microbiome so uniquely fascinating? Since the beginning of time, humans have gravitated toward “big picture” interpretations that explain every nuance of the natural world, even when these were a stretch. Galen, the father of ancient medicine and Hippocrates’s most prominent student, believed the body to be composed of four fluids that could explain all human function. We now know, of course, the errors of Galenic theory, but besides DNA, the language of all living organisms, very few discoveries with all-encompassing ramifications have surfaced.

Although the field is extremely novel, the microbiome already unveils an expanded view of human life. Its origin in each person is brewed in the habits of their predecessors and molded by the qualities of that person’s diet, stress levels, and related ailments. The microbiome’s presence across the diverse environments of any one human body is difficult to fully describe, a biochemically intricate display with many nuanced effects on its human host and mysterious behaviors yet to be deciphered. As the microbiome’s full story becomes clearer, there remains little doubt as to how integral it has been in the evolution and wellbeing of humanity, a realization that would tickle even the likes of Galen and Plato.

CHASING CANCER’S TRACKS

The ancient Greeks may have found their idol in Dr. Rob Knight. An expert in microscopic organisms, he is the Director of the Center for Microbiome Innovation at UC San Diego. His development of the computational tool Unifrac, allowing measurements of differences among microbial genomes, has propelled a career in microbiota and inspired auxiliary projects among his cohort of graduate students. Greg Poore, an MD/PhD candidate in close collaboration with Dr. Knight, elaborated on his own research.

Previous papers had shown the ways in which bacteria were often associated with a variety of cancer cells and metastases. Using the Microbe Genome Atlas, which is a vast catalogue of microbial DNA sequences, Knight and Poore applied machine learning methods to diagnose cancer types solely by identifying the types of microbial DNA found in blood samples from cancer patients.

Decades of literature showed that patients suffering from certain bacteremias, or bacterial infections of the blood, were later diagnosed with colon cancer—even asymptomatically. “We wanted to see if we could selectively diagnose colon cancer versus other types,” said Poore. “The results were phenomenal.” He used the Atlas’s reserve of 2000 whole genome sequences from blood across twenty cancer types to produce correlation curves between microbial DNA and colon cancer characteristics. The area readings for these curves were 0.98 or 0.99. For reference, the maximum possible value for a correlation coefficient that has perfect overlap is 1. To further test the validity of their analyses, blood plasma samples from patients at the UCSD Moores Cancer Center were compared, both between cancer types and between patients with and without cancer. These are the most controversial sample types, as they were conventionally thought to be sterile and devoid of microbial DNA. In terms of these validity studies, the best results were seen with lung and prostate cancer. Supported by extensive data analyses and validation studies, their data indicated an ability to locate and diagnose many kinds of cancer across the body in their initial stages (Stage 1 or 2). In other words, malignancies could be identified early on, all thanks to the presence of specific microbial genomic residues serving as beacons for the presence of cancer prior to the onset of conventionally detected symptoms.

MICROSCOPIC, MERCURIAL MESSENGERS

At UC San Diego’s School of Medicine, the Weg Ongkeko Lab explores another facet of the microbiome’s connection to pathology. Harrison Li, a recipient of the Churchill Scholarship and recent UC San Diego graduate, studied the microbiome in a host of diseases and organs in order to understand its greater implications in fomenting states of disease. For example, the analysis of microbes present in patients’ joints yielded results that potentially implicated certain microbes’ role in the development of arthritis. An abundance of recent papers have similarly found microbes contributing to tumor formation in numerous ways. Their metabolic interactions with healthy tissue cells promote normal cell growth, but this may spin out of control, disrupting cell cycle controls that can then domino into tumor development. To worsen matters, microbes can also damage cell DNA, jumpstarting the route to cancer. Moreover, microbes may stimulate the growth factors that nurture tumor cells, while hindering the immune system’s ability to detect these abnormalities early on.

Given the many unknowns of the physiological jungle within us, therapeutic applications of the microbiome appear unlimited. Cancerous cells could be screened for biomarkers that indicate the presence or activity of microbial species, especially those that work synergistically with the disease. The microbiome could also be manipulated using probiotics, i.e. healthy bacterial species. Probiotics might thus be used to alleviate disease conditions. Alternatively, they might serve as a drug delivery tool through genetic engineering, capable of transporting a treatment to a microscopic bodily point of interest. “If you were able to take a probiotic supplement,” claimed Li, “there would be no need for poisonous chemicals.” Further research is taking place to make Li’s vision of therapeutic probiotics a reality.

MOBILE + MICROBES = MALICIOUS?
Microbes’ ability to use metastasized cells as vehicles is only part of the microbe-body relationship, a connection that is just starting to be understood and utilized.
RUMBLE IN THE JUNGLE

The microbiota’s ubiquitous role in the jungle of human organ systems relies just as much on the bacterial populations’ interactions with one another as it does on these populations’ interactions with the human body. Dr. Karsten Zengler’s lab in the Pediatrics and Engineering Departments at UCSD focuses on the microbiomes of community systems, which encompass ecosystems, animals, and the people that interact with them. Dr. Cristal Zuniga, a former postdoctoral researcher in the lab, studied the metabolic workings of bacteria on human skin, a “savannah”-like environment where conditions are not as dark and damp as some of these microbes would prefer.

The helpful Staphylococcus epidermidis bacteria and the infectious S. aureus bacteria are two related species in perpetual competition for resources. The “goodness” of each is relative to the bodily region they inhabit; S. epidermidis has a commensal relationship with its human skin environment, where it benefits by obtaining nutrients while the human host is unaffected. It outcompetes the more virulent S. aureus on human skin, thus maintaining healthy nutrient cycling across this surface. However, S. epidermidis may also become an opportunistic pathogen, hitching a ride on a host’s medical devices or implants and turning infectious or “bad” once it enters the body. Zuniga’s work centered on designing community models, computer simulations that incorporated all elements of the bacteria’s surroundings in order to predict their interactions with the body—and tentatively, each other.

COLON CARTOGRAPHY
The moniker ‘gut bacteria’ evokes the most common image of the microbiome—within the large intestine. Probing this wilderness may offer clues to the nature of microbial denizens in other organ systems.

“There is very little known about modeling microbe interactions,” Zuniga said. “The skin is a very interesting organ. On the surface, you have a lot of exposure to oxygen, but you can go deep enough that it is almost anaerobic [doesn’t rely on oxygen].” Using computational systems, community skin models can predict how specific mixtures of oxygen-associated metabolites, or molecules produced as a result of reactions sparked by oxygen, may contribute to skin health. In fact, the varied bacterial populations themselves were associated with these molecular findings.

Such modeling, called constraint-based modeling, said Zuniga, “changes constraints … and gives you results that contextualize things. We look at the problems in a very mathematical way.” S. epidermidis’s helpful qualities on the harshly exposed skin surface shifts to harmful, parasitic goals in the host’s bountiful insides, as access to resources increases. Therefore, we see that a bacterial species’ utility to the host can vary widely. It was observed that S. aureus could consume almost any metabolite, even in deep layers of the skin where there is little oxygen. Overall, while S. epidermidis changes its relationship to the host based on its location, S. aureus acts as a pathogen in both environments. Indeed, both bodily geography and responsiveness to resource ratios are central to this microbial tug-of-war. Ultimately, such models have the potential to serve as powerful predictors of the species’ contribution to other localized infections, such as pneumonia.

FOR THE FUTURE

The cutting edge of microbiome research today is especially sharp. Venturing beyond the bacteria of the gut, current efforts sample the composition, behavior, and effects of bacterial communities throughout the body, which together rival the Amazon rainforest in sheer biological wealth. In the blood, microbial genomic elements serve as red flags for the more insidious threat of early cancer, while on the skin and in the lungs, the open ground promotes a wild arena for microbial competition. The frontier of microbiome research is advancing on an almost monthly basis, spurred forward by gene-editing technologies such as CRISPR, which allows for microbial manipulation. Likewise, the medical field is beginning to realize the gargantuan therapeutic potential of the human microbiota, with personalized treatments forging a possible revolution in the battle against infectious disease. As the scientific community expands its sights, the microbial ecosphere of our bodies may well become the next frontier in healthcare.

WRITTEN BY ALEJANDRO DAUGUET & DANIEL JOHN

Alejandro Dauguet is a fourth year student majoring in Neurobiology. Daniel John is a first year student majoring in Bioengineering: Biotechnology.

FROM UNDER THE SCOPE VOL. 11

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