Diving deep into the nexus of human health: Tiny gut bacteria with huge impacts

The human gastrointestinal (GI) tract is teeming with trillions of microorganisms. These microbes are too small to be seen by us, but they constitute a vital organ of the body that shapes our health. According to scientists, if we can find ways to restore gut health and achieve “eubiosis”, a state in which the human gut microbiota and the host enjoy a healthy, symbiotic relationship, then there may be hope for those suffering from neurodegenerative, metabolic, and immune and inflammatory diseases, as well as many types of cancer. Microbes are not always foes to humans; they can often be our friends.

In this issue, PAIR chats with Prof. Eugene B. CHANG, microbiome expert on the gut microbiota-host interplay and on harnessing the power of the gut microbiome for health solutions. Prof. Chang is the Martin Boyer Distinguished Professor of Medicine and Director of Microbiome Medicine Program at the University of Chicago (UChicago). He is also a Senior Fellow at PAIR, working closely with the Research Institute for Future Food (RiFood) to extend the frontiers of microbiome research on the GI tract.

Why is the human gut microbiome so important to our health?

It is now well accepted that the trillions of microbes that live within us provide beneficial and vital functions that we cannot live without. Our biology, genetics and immunity have evolved to attract and harbour these organisms, particularly in the gastrointestinal (GI) tract.

This does not occur randomly, but rather is determined by co-evolution and co-speciation. In humans, microbiomes—defined as communities of microbes and the ecosystems in which they live—can be found in many parts of the body, including the skin, lungs and GI tract, the latter being the largest based on sheer numbers of cells and genetic content. Moreover, regional gut microbiomes provide functions that are vital for health such as protection against pathogens, nutrient digestion, immune development and maintenance, and regulation of host metabolism. When a host-microbe mismatch occurs, say, due to diet, antibiotics or faecal microbiota transplant, this disturbs the gut microbial ecosystem, resulting in a state called “dysbiosis” that can compromise host health and promote disease. Thus, the microbiomes of the GI tract are nurtured and maintained through resources (e.g., diet) and conditions (e.g., sanctuary from immune responses) that the host provides.

How do these tiny microbes in our GI tracts affect other parts of our bodies?

In the human body, if one organ goes wrong, the others are impacted. The gut-brain axis is a good example of this. Gut microbes produce bioactive molecules, which normally enter the bloodstream, pass through the liver and get detoxified. However, in the case of a disease called hepatic encephalopathy, which occurs when these molecules bypass the liver and are not detoxified, patients develop disorientation as well as motor and cognitive problems. When we put patients on antibiotics that affect the gut bacteria, these issues are cleared up within 24 hours. This is a solid demonstration of the functions of the gut microbiome. It has implications for Parkinson’s disease, since dysbiosis is often observed in the guts of these patients. Thus, the gut microbiome affects both our central and peripheral nervous systems.

Metabolism is another example. We know that there are people who can eat a lot and do not gain weight, whereas others are continuously dieting and fail to lose weight. We explain this by differences in their metabolism, although the scientific basis for these observations remains unclear. We believe that differences in the membership and function of an individual’s gut microbiome play an important role in regulating host metabolism. In a controlled animal experiment, mice that are fed a high-fat, low-fibre “western-style” diet will become obese. In contrast, germ-free (GF) mice that lack any microbes on the same genetic background, when fed the same diet, do not become obese. The restoration of a gut microbiome in GF mice, however, now renders them susceptible to the development of diet-induced obesity. These studies show that diet-induced changes in the gut microbiota play an important role in changing the host metabolism.

If scientists could identify the underlying mechanism, they would open up many possibilities for the management of numerous metabolic diseases including obesity, type 2 diabetes, metabolic syndromes and fatty liver diseases. This is particularly important in modern industrialised societies where diet-induced metabolic diseases lead to higher morbidity and mortality.

You work closely with the Research Institute for Future Food (RiFood) and serve as a member of the Institute’s International Advisory Committee. Can you share with us more about these collaborations?

Defining the state of health of the gut microbiome is a challenging and unsolved problem. Without this ability, it is difficult to determine the efficacy and impact of emerging microbiome-based interventions.

My team at UChicago has successfully developed technologies which enable us to quantitatively measure the functional profiles of the human gut microbiome. We are very interested in partnering with RiFood in applying our technologies to provide objective evidence for the efficacy of RiFood-led innovations. In this regard, RiFood has been forward-thinking in creating initiatives and programs to develop medical and functional foods that not only promote health in general, but also mitigate and treat diseases that have a microbial basis.

Aquaponic-related systems are another area  of interest to us. During my stay here in Hong Kong, I was invited by the RiFood team to visit an indoor aquaponic system. It is an amazing automated monitoring system where many types of plants can be grown vertically in tight quarters in the absence of soil. This system provides a research opportunity for us to work with RiFood to determine how monitoring and optimising the microbiomes of the system can yield bigger and more nutritious plant-based foods. There are different microbiomes throughout the system. In one section, live fish provide fertiliser materials that are converted to nutrients by microbes, which in turn are used by the plants. This system is therefore designed to create a symbiotic and mutualistic ecology. If we are able to apply UChicago-developed tools to study the system’s microbiomes, it should be possible to enhance and increase the nutritional value and production of sustainable, effective foods. We hope that UChicago and RiFood will have the opportunity to collaborate with the aquaponics company to further this technology.

Collaboration, be it across disciplines or across organisations, is important in developing impactful research solutions. How can we ensure that collaborative efforts are effective and successful?

Mutual trust and respect come first. One thing about PolyU that attracts me is that the University has outstanding scientists who are forward thinking in terms of meeting present and future societal needs. Scientific rigor, e.g., ensuring data reproducibility and sharing common goals, is important for building a trusting, successful partnership in which the two parties are equal partners. This is like going on a road trip where you and your friend choose to take different paths to reach the same destination. By doing so, each learns from the other to find the most efficient path for the future.

Complementary expertise is another key to success. RiFood is interested in functional food for sustained health. I am a physician-scientist, and I firmly believe that disease prevention is more cost-effective and yields better outcomes than treatments. So, if we can identify the foods that maintain health and reduce risk for disease, then food becomes medicine.

My vision for the future is that these functional foods can be used as if they are prescribed treatment in precision medicine. We can build an inventory of food-derived compounds that have specific indications. There will be no more guessing as to how to get the most out of foods.

In health-related research and engineering projects at PAIR, PolyU researchers leverage the University’s strengths and resources in allied health, and solicit medical and clinical inputs from external parties. What are your views on the expertise needs in health research?

Starting new medical schools and building university hospitals are big-ticket items that take a long time and require a long-term commitment. There also has to be clear medical need. That being said, I also think that having a medical school and hospital as part of or affiliated with PolyU is essential for medical research and therapeutic discovery. At UChicago, we are very fortunate to be in an environment where basic science and the pursuit of discovery are integrated into clinical practice. Our research is supported by a team of technicians based in hospital clinics that enroll subjects for clinical studies, collect samples, and perform follow-ups. This has enabled a seamless transition from basic science to clinical practice.

Because there are no animal models that faithfully reproduce the human condition, all therapeutic interventions ultimately need to have demonstrated efficacy and safety in humans. Clinical expertise is really essential for proving the efficacy of any new therapeutics developed. Having the appropriate medical facilities and personnel in university research is very useful.

Health research solutions take years to pass all phases of clinical trials before they reach the general public. How can we retain health researchers and encourage them to make continuous efforts on this long journey?

Ensuring funding and sustained revenue is one of the biggest challenges. It is not very sustainable for researchers to fully depend on governmental funding and philanthropic donations. Research grants enable researchers to establish proof-of-concept and gain mechanistic and conceptual insights. However, if they are to take their innovations to the next level, then they need to consider commercialisation of their research. At UChicago, we have programs that help researchers gain business knowledge, determine if their innovations have a market niche, and facilitate connections to potential business partners.

My foray into entrepreneurship has been a huge learning experience. I started by recognising that business and medicine are very different. Entrepreneurship is something that we as academics must think about. It is the only way that we can bring innovation and discovery to the clinical arena. In the medical industry, investors are willing to take the risk to promote innovation because the anticipated pay-out can be very large.

Therefore, building networks with the industry is important in scientific ventures. The industry helps in developing the value proposition of the research discoveries, while scientists can focus on the development of an idea, technology, or treatment that addresses unmet needs in health care. If researchers establish successful ventures, they can enjoy sustaining revenue to continue their research and product development and translate them into practical applications.

Academics are under growing expectations to conduct research work and deliver commercialisable research products. Can you provide some advice to scholars on ways to balance the business and academic components?

It is hard. This is because trying to establish a spin-off company from research and moving the company along require time and effort that become a second job. Falling short of this commitment usually leads to failure of the company. None of these business operations are on autopilot.

While taking the entrepreneurial path was not something I envisioned, I now believe it is an essential part of academic research. Yes – I am working twice as hard now, but I am beginning to see how our discoveries will benefit human health and well-being.

Can you provide any advice to young researchers aspiring to become successful scientist-entrepreneurs?

An open mind and willingness to learn new things, work hard, and take on calculated risk are important for success. Because I only realised this late in my career, I missed many opportunities. My advice to young researchers is to start thinking about entrepreneurship now, particularly if opportunities arise.