Our group addresses fundamental questions about the symbiosis between microbiome and human host. We take an evolutionary and genetic approach to identify microbiota with key roles in the host-microbiome relationship, which we then interrogate for their molecular underpinnings in animal and in-vitro models.
We have identified a specific suite of microbes that are responsive to differences in human host genotype. Using a large population of genotyped and phenotyped human twin pairs (>3,000 samples, >1,000 twin pairs with ~60:40 dizygotic/monozygotic), we identified bacteria and archaea whose variation in abundance across the population was partially attributable to host genotype. We then used these heritable microbes as quantitative traits in genome-wide associations to identify human genes linked to the variation in the abundances of heritable microbiota. This approach revealed heritable microbiota, whose relationship with the host we now study in mechanistic detail by building intentional communities in vitro and in vivo. The microbiota-host interactions that we currently focus on include (i) the Christensenellaceae-Methanogen consortium and its relationship to host adiposity; (ii) the Bifidobacteria relationship to host lactase-persistence genotype and lactose intolerance phenotype; and (iii) the impact of Bacteroidetes-derived sphingolipids on host sphingolipid metabolism. In addition to these three main projects outlined below, we continue to explore other exciting areas of host-microbiome interactions.
1. Heritability of Christensenellaceae and Methanogens and their role in metabolism
A gut microbial consortium that impacts adiposity - Our search in twins for specific gut microbes responsive to host genotype identified the bacterial family Christensenellaceae as the most highly heritable taxon. Its high heritability has since been confirmed in three independent populations, including one in Korea. This family forms the hub of a co-occurrence network that includes methanogenic Archaea, namely Methanobrevibacter smithii. We noted that this consortium was enriched in lean versus obese subjects. Indeed, the Christensenellaceae-methanogen consortium is consistently associated with a healthy metabolic status in the host across populations. Using gnotobiotics, we have demonstrated that the introduction of Christensenella minuta, into an obese-microbiome protects against its obesogenic effects in germfree mice. Project Leader Jill Waters is leading the effort to dissect the molecular underpinnings of this effect and to better understand the host phenotype.
Genomics of archaeal heritability - Our heritable-microbe screen also revealed methanogenic Archaea. The methanogens of the human gut are thought to influence fermentation dynamics by uptake of H2 and CO2, and also possibly trimethylamine production through the use of methyl groups. Project Leader Nick Youngblut is leading efforts to characterize the genomic basis for heritability in the human gut methanogens and is taking a comparative phylogenetic approach to letter understand the mammalian-archaeal relationship.
2. Bifidobacteria and microbially-acquired lactose tolerance
The strongest signal that emerged from our GWAS is an association between the LCT gene and the abundance of Bifidobacteria in the human gut. This link has since been corroborated in multiple populations of European descent. The LCT genotype is predictive of lactase persistence; individuals genetically lactase-nonpersistent harbor higher levels of gut Bifidobacteria, suggesting a role for these bacteria in lactose degradation. Lactase persistence evolved independently in several places (Europe, North Africa, Eastern Siberia) but its impact on the microbiome outside of Europe and North America is unknown. What is known is that lactase-persistance does not map well onto lactose tolerance, which is microbially mediated. We are investigating how the relationship between host genotype, microbiome and phenotype differs around the world.
3. Bacterial sphingolipids in human lipid homeostasis
We are investigating the contribution of sphingolipid production by the Bacteroidetes in the human gut as a fundamental service in human-microbiome interactions. The phylum Bacteroidetes is highly prevalent as members of the gut microbiome across animal species. In humans, representative general may differ between populations, but the phylum comprises 40-50% of the microbiome, on average. The Bacteroidetes stand out as one of only two known phyla (of >100) that have the capacity to produce sphingolipids. The source of sphingolipids for the human host is the diet and a small but important contribution from de novo production. Since humans carry sphingolipid-producin bacteria in their guts, we are investigating the importance of this endogenous source in human sphingolipid homeostasis in various body sites.