Alexander, M. | bioRxiv Science

bioRxiv2019

Perturbation of the human gut microbiome by a non-antibiotic drug contributes to the resolution of autoimmune disease

The trillions of microorganisms (microbiota) found within the human gut play a critical role in shaping the immune system, yet these complex microbial communities are also highly sensitive to numerous environmental factors. While much of the focus to date has been on dietary intake, emerging data has begun to suggest that the use of pharmaceutical drugs, even those that are not considered to be antibiotics, can alter the human gut microbiota with unknown consequences for treatment outcomes. Here, we use a combination of in vitro, in vivo, and ex vivo methods to demonstrate that the first-line therapy for rheumatoid arthritis (RA), methotrexate (MTX), has off-target effects on the human gut microbiota, resulting in a significant growth advantage for drug-resistant Firmicutes over the Bacteroidetes, which tend to be more sensitive. Longitudinal analyses of the gut microbiotas of RA patients revealed that MTX-induced shifts in bacterial relative abundance are associated with improved drug response and transplant experiments in gnotobiotic mice show that these shifts lead to reduced inflammation. Together, these results suggest that the mechanism-of-action of non-antibiotic drugs may be due in part to off-target effects on the gut microbiota, while providing a critical first step towards explaining long-standing differences in drug response between patients.

microbiology↗

bioRxiv2019

LD scores are associated with differences in allele frequencies between populations but LD score regression can still distinguish confounding from polygenicity

The LD score regression method tests whether there is an association between the LD score and allele frequency differences between cases and controls. It makes the assumption that there is no association between LD score and allele frequency differences between populations and hence that any observed association is due to a polygenic effect rather than population stratification. This assumption has not previously been tested. In comparisons between HapMap populations we observe that there is indeed an association between the LD score and allele frequency differences. However this effect is small and when we carry out simulations of large case-control samples the effect becomes negligible. We conclude that if the intercept is small then any increase in mean chi-squared does indeed reflect a polygenic effect rather than population stratification.

genetics↗