Jeffrey I. Gordon
2021 Balzan Prize for Microbiome in Health and Disease
We are never alone. Propelled by the revolution in genomics, it is becoming increasing apparent that we are very complex mixtures of human and microbial cellular and genetic parts that, normally, operate together in a mutually beneficial fashion. Our microbial partners include members of all three domains of life on Earth (Bacteria, Archaea, and Eukarya) and their viruses. They colonize various parts of our bodies (mouth, airways, skin, gastrointestinal tract, vagina) beginning at birth. The gut is home to our largest microbial community – tens of trillions of organisms whose genomes collectively contain ~100 fold more genes than our human genome and provide us with functional capabilities we have not had to evolve on our own. This expanding view of ‘self’ raises basic questions about the mechanisms by which our microbial communities (microbiota) and their genes (microbiomes) assemble and maintain themselves, how they adapt to changing conditions, and what functions they perform. The first in-depth and illuminating results in this respect were reported in the mid-1990s by Jeffrey Gordon at Washington University in St. Louis, Missouri, where he trained and went through his entire cursus honorum from Assistant Professor of Medicine and Biological Chemistry to his present position as Distinguished University Professor and Director of an interdisciplinary Center for Genome Sciences and Systems Biology. His lab began by focusing its attention on intestinal development; namely, how does the ‘epithelium’ lining the intestine establish and maintain its different functions along the length of the gut? His studies of genetically engineered mice led him to propose that the ‘positional identity’ of these cells was shaped in important ways by environmental cues. Jeffrey Gordon turned to the microbiota to search for these positional ‘instructions.’ In 1996, he reported that colonizing mice initially reared under sterile (‘germ-free’) conditions with a single prominent human gut bacterial species – Bacteroides thetaiotaomicron(Bt) – activated a developmental program of expanding intestinal epithelial production of complex cell-surface sugars (polysaccharides), but only if Bt had functional genes for utilizing these polysaccharides as nutrients. This finding emphasized the importance of nutrient-sharing relationships in establishing and maintaining host-microbial symbioses in the intestine. He then demonstrated that it was feasible to colonize germ-free animals with defined communities of increasing complexity and diversity, composed of cultured and genome-sequenced members of the human gut microbiota. With this fantastic result, for the first time scientists could use these ‘gnotobiotic’ animals, whose microbial citizenship could be systematically manipulated, to address fundamental questions about how members of the human gut microbiota cooperate, compete, and succeed in influencing the physiology of their host in different nutrient, metabolic and genetic environments. A new field of research was born – one with immense potential for basic biology and for biomedicine, and the father of this field is clearly Jeffrey Gordon. In subsequent years, he and his group reported a series of breakthrough findings linking the human microbiome to two global health problems – obesity and childhood undernutrition. His finding that transplanting intestinal microbiota from genetically-obese mice, or obese humans, into germ-free mice transmitted increased adiposity and altered metabolic phenotypes compared to lean donor microbiota opened the door to the concept that microbial communities, not just single organisms, can determine health status. His findings dramatically altered ‘germ-theory’. His results were used by the NIH (US National Institutes of Health) as a justification for why human microbiome projects were needed and timely. Undernutrition is the leading cause of death worldwide in children under five years of age and not explained by food security alone. Moreover, current treatments remain inadequate. In birth cohort studies conducted in several low- and middle-income countries, he and his team identified ‘age-discriminatory’ bacterial strains whose changing pattern of representation in the developing microbiota collectively define a program of normal gut community assembly in healthy infants and children. He found that this program is largely completed by the end of the second postnatal year but is perturbed in children with moderate and severe acute malnutrition – leaving them with immature microbiota. Moreover, their microbiota ‘immaturity’ is not repaired with current therapies. By transplanting microbiota from healthy or undernourished children into germ-free mice, they identified bacterial strains that promote growth. These strains, a number of which are under-represented in immature microbiota, became his therapeutic targets. To develop culturally-acceptable, affordable and scalable treatments, he tested different combinations of Bangladeshi complementary foods (i.e., those given as children are being weaned) in gnotobiotic mice and gnotobiotic piglets colonized with gut communities from undernourished Bangladeshi children. The results yielded microbiota-directed complementary food (MDCF) prototypes that increased the fitness and beneficial activities of his targeted bacterial strains. Translating these results to humans, one of their lead MDCFs produced significantly greater rates of weight gain in Bangladeshi children with moderate acute malnutrition compared to an existing ready-to-use therapeutic food; this response to MDCF was linked to microbiota repair and alterations in key regulators of multiple aspects of healthy growth.In conclusion, Professor Gordon has played a pioneering role in our understanding of the essential role of the gut microbiome in human health and disease. His groundbreaking scientific discoveries have opened the door to new therapeutic approaches for many devastating human illnesses. His efforts to obtain deeper knowledge of the interrelationships between the foods we consume and our gut microbial communities promise to fundamentally change our understanding of how food ingredients are linked to human health and how to combat the pressing global challenge of poor nutrition. The microbiome field he founded has experienced explosive growth worldwide in universities, pharma, and biotech, and his lab has yielded a diaspora of its next generation of leaders.