A combination of genetic factors and dietary tryptophan shapes gut microbial dysbiosis in a lupus-prone mouse model

Abstract

Abstract Gut microbial dysbiosis, impaired intestinal barrier and altered tryptophan metabolism have been reported in lupus patients. Dietary tryptophan modulated disease activity and modified the composition of microbiota in triple congenic (TC), B6.Sle1.Sle2.Sle3, lupus-prone mice. However, whether this modification is facilitated by tryptophan acting directly on the microbiota, or indirectly through lupus genetic susceptibility remains unknown. To address this question, we transplanted fecal samples from TC and B6 control mice into germ-free or antibiotic-treated B6 mice that were fed with high or low tryptophan. Tryptophan enriched different species of bacteria from transferred TC and B6 microbiota. A bloom of Ruminococcus gnavus, a bacterium associated with human lupus nephritis, only emerged in the recipients of TC microbiota fed with high tryptophan. Further, recipient mice showed distinct fecal metabolite profiles based on dietary tryptophan and the TC or B6 origin of the microbiota. Interestingly, both genetics and tryptophan impaired gut barrier integrity in recipient mice. These results suggest that the dysbiotic lupus microbiota is shaped by a combination of dietary tryptophan and genetic background, the latter most likely through autoimmune inflammation. In particular, the exclusive expansion of the pathobiont Ruminococcus gnavus by high tryptophan from the microbiota of lupus-prone mouse demonstrate that the interplay of genetic and environmental factors can influence the pathogenesis of lupus through modifying gut microbiota and gut permeability. This work was supported by a grant from the NIH R01 AI43313 to Laurence Morel.