Animal Modeling for Hologenome: New inbred and conplastic rat exercise models for uncovering crosstalk between nuclear DNA, mitochondrial DNA, and gut microbiota

The hologenome is an ensemble of nuclear DNA (nDNA), mitochondrial DNA (mtDNA), and the microbiome that forms a unit of genetic selection that can propagate from one generation to the next. There is increasing evidence for inherited mitochondria‐gut microbiota involvement in cardiovascular and metabolic diseases. Here, we expand on the selectively‐bred Low Capacity Runner/High Capacity Runner (LCR/HCR) rat exercise model system into a genetically defined rat model framework for studying holobionts in controlled laboratory settings. Methods At Generation 23 of selection, we identified extreme representatives of female and male LCR and HCR rats and conducted a series of brother‐sister mating to produce inbred strains‐ LCR/Tol and HCR/Tol. We also developed two conplastic strains, one with nDNA from HCR and mtDNA from LCR, and the other with nDNA from LCR and mtDNA from HCR ‐LCR.HCR mt /Tol and HCR.LCR mt /Tol. mtDNA from LCR/Tol and HCR/Tol strains were compared with publicly available mtDNA from common inbred strains. Rats were phenotyped for cardiovascular risks, which included treadmill exercise capacity, VO 2 max, echocardiography, and blood pressure (BP) telemetry. Fecal microbial communities were profiled using 16S rRNA sequencing and metatranscriptomics. Results As expected, HCR/Tol had significantly higher exercise capacity compared to LCR/Tol but little effect by mismatched mtDNA suggesting that the nDNA is dominant for regulating aerobic exercise capacity. VO 2 max measurement confirmed high exercise capacity in HCR/Tol and low in LCR/Tol. LCR mtDNA was identical to mtDNA from Wistar Kyoto inbred strain, while HCR mtDNA was identical to mtDNA from Fischer 344 × Brown Norway F1‐hybrid strain. Consistent with reports from selected LCR HCR rats, LCR/Tol showed significantly increased mean arterial pressure (MAP), systolic BP (SBP), and diastolic BP (DBP) compared to the HCR/Tol. Transfer of mtDNA from HCR to LCR nDNA background decreased MAP, SBP, DBP, and preserved diastolic cardiac function. In contrast, there was no difference in BP or cardiac parameters between HCR/Tol and HCR.LCR mt /Tol. Microbiome analysis indicated that host genomes co‐inhabit with differential commensal microbiota. Metatranscriptomics showed HCR/Tol had enhanced function in carbohydrate and amino acid metabolism, microbial metabolites production, and stress management. Conclusion We successfully generated and systematically characterized genotypes and phenotypes of inbred and conplastic LCR/Tol and HCR/Tol animal models for holobiont studies. The inbred and conplastic strains retained key features of LCR HCR selectively bred models ‐‐ some influenced by nDNA‐mtDNA interaction. These models provide for a new pre‐clinical method to explore gut microbiota as therapeutic targets for complex diseases such as hypertension. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .