Abstract

The number of microorganisms that reside on and inside our human bodies is a staggering figure – some estimates propose that there are up to ten times as many bacterial cells as human cells on the average person. These communities of microorganisms, called the microbiome, are found on our skin, in our mouth, and predominantly in our gut. Most of these microorganisms are beneficial and critical to human health – they help train our immune system, fight off pathogens (i.e., disease microbes), help us digest food, make vitamins, control weight, and even impact our mental condition. Recent research indicates that there is a strong gut microbiome-brain connection, suggesting that even neurological disorders might be somehow tied to microbiome dysfunction.

Scientists at ORNL and elsewhere are using advanced measurement approaches to examine and more fully understand how microbiomes function in healthy vs. diseased conditions, and whether microbiomes cause or respond to diseased conditions (often termed “microbial dysbiosis). My research group at ORNL has helped pioneer the field of “metaproteomics,” which is focused on using advanced mass spectrometry to measure the suite of microbial proteins in a variety of human microbiome systems. The research goal here is to try to understand how the proteins expressed by the microbial genes vary as a function of health vs. disease systems, such as inflammatory bowel disease. This information is starting to reveal unprecedented details about how human microbiomes establish at infancy, how robust they are with respect to aging or environmental changes, and how they differ in disease conditions.

Many of these microbiome characterization measurements are conducted on fecal samples, which can be up to 50% microbial composition by weight. By measuring both human and microbial proteins in these samples, it is possible to obtain information about the symbiotic system (i.e., delicate balance between the human host and associated microbiome). For example, we have examined how human microbiomes establish in premature human infants and how abnormal development can lead to necrotizing enterocolitis, a condition that is usually fatal to a newborn infant. Additionally, we have examined human gut microbiomes in healthy individuals and compared them with those of persons who have inflammatory bowel diseases, specifically Crohn’s Disease. The goal of this research is to better understand the driver and details of this common disease to help enable scientists to develop or identify safer and more effective treatment options.

In this presentation, I will describe some of the driving science questions in human microbiome research and then highlight technology advances that we and others have used to address these issues. This entire field is exploding and yielding a barrage of information that has previously been unknown. It is pretty clear that our personal microbiome information will be important to our physicians in the near future and that such information will be used in the personalized treatment of a variety of conditions.

Biographical Sketch

Dr. Robert Hettich is a corporate fellow and leader of the Bioanalytical Mass Spectrometry Group of the Biosciences Division at Oak Ridge National Laboratory; he is also a joint faculty member in the Microbiology Department at the University of Tennessee. He is recognized as a founder of the field of metaproteomics and a pioneer in the development and demonstration of advanced biological mass spectrometry technologies. Hettich’s work has focused on research to characterize a variety of complex biological mixtures, including detection and examination of higher-order structures for both microbial and human proteins.

His research in metaproteomics spans from environmental microbiology (i.e., microbial communities in soil and groundwater ecosystems) to bioenergy (engineering of microbial solubilization of cellulosic biomass to generate biofuels and bioproducts) and finally to the human microbiome (characterizing the microbial connections between human health and disease). His stature as a leader in metaproteomics has placed him at the forefront of several international research initiatives. 

Before joining the ORNL research staff in 1986, Hettich received a doctorate in analytical chemistry from Purdue University. He is a joint faculty member with the University of Tennessee’s microbiology department and a faculty member of the Bredesen Center for Interdisciplinary Research, where he was named outstanding faculty member in 2023. He has authored/co-authored over 330 publications. Hettich has mentored more than 40 postdoctoral and graduate students (including 31 Ph.D. students who graduated as of 2024). He teaches analytical technology and advanced biological mass spectrometry classes. He is an associate editor for Microbiome and Frontiers in Microbiology, as well as a member of the editorial advisory board of Mass Spectrometry Reviews.