Host Factors May 25th, 2023 Overview • How can we study host factors? • Examples • Twin studies • GWAS • Large population - based cohort studies 2 Genetics or Environment? Hall, A. B.; Tolonen , A. C.; Xavier, R. J. Human Genetic Variation and the Gut Microbiome in Disease. Nat Rev Genet 2017 , 18 (11), 690 – 699. https://doi.org/10.1038/nrg.2017.63 3 Genetics or Environment? • Much of the impact is hypothesized to be through immune function • E.g. Rausch P et al 2011, Rehman A et al 2011, Frank et al 2011. • However, several early studies conducted on human twins found no associations with host genetics, possibly because they were underpowered • E.g. Turnbaugh et al 2009, Yatsunenko et al 2012 • Most studies of beta diversity find far greater impacts of environment relative to host genetics Levy M et al. Metagenomic cross - talk: the regulatory interplay between immunogenomics and the microbiome. Genome Med. 2015 Nov 20;7:120. PMC4654884. How do we study host factors? • Twins • GWAS • Large population - based cohort studies 8 GWAS (Genome wide association studies) • Identify genomic variants that are associated with a risk for disease or particular trait • Manhattan plot • Each dot is a variant • Red line or significant at p<5 x 10 - 8 9 Overview • 416 twin pairs in the UK • Most twin pairs share very similar birth modes and environments • 171 monozygotic (MZ) twin pairs (“identical twins”; share nearly 100% of genes) • 245 dizygotic (DZ) twin pairs (“non - identical or fraternal twins”; share ~50% of genes) • 16S rRNA sequencing Goodrich, J. K.; Waters, J. L.; Poole, A. C.; Sutter, J. L.; Koren , O.; Blekhman , R.; Beaumont, M.; Van Treuren , W.; Knight, R.; Bell, J. T.; Spector, T. D.; Clark, A. G.; Ley, R. E. Human Genetics Shape the Gut Microbiome. Cell 2014 , 159 (4), 789 – 799. https://doi.org/10.1016/j.cell.2014.09.053 10 1. Do heritable traits (genetics) impact the human gut microbiome independent of environment? 2. Which specific taxa within the gut microbiome are “heritable”, and to what extent? • Heritable = their presence in adulthood is dependent on heritable human genetic traits 3. How do heritable microbes relate to host BMI (body - mass index)? Objectives: 11 • Fecal microbiome more similar within twin pairs • MZ (identical) more similar than DZ (fraternal) 12 • Fecal microbiome more similar within twin pairs • MZ (identical) more similar than DZ (fraternal) 16 • More correlation between relative abundance in MZ (identical) twin pairs than DZ (fraternal) 17 Christensenella • Genus of non - spore - forming, anaerobic, non - motile bacteria within the family Christensenellaceae • C. minuta in the gut has been associated with reduction in body weight and obesity in mice and humans. • Commercial interest is running ahead of the science. 18 Previous study of twins from US and Malawi • More correlation in abundances of Christensenellaceae of MZ compared to DZ twins 19 • Took donor stool and added Christensenella minuta and put in germ free mice • Saw that Christensenella led to weight loss and increased muscle 20