Abstract Body: Purpose: The present study seeks to examine sex and strain dependent effects on gut microbiome diversity and abundance and, in turn, potential effects on AAAs.

Methods: To investigate strain- and sex-related differences in the gut microbiome in AAAs, 8–12-week-old male/female C57BL/6J and C3H (+/-TLR4) mice underwent AAA induction via peri-adventitial aortic application of elastase (n=10-19/group). At day 14, AAA size was assessed using video micrometry with fecal, blood, and aortic sample collection. Fecal samples were analyzed via whole genome microbiome sequencing and blood was analyzed via metabolomics. Male/female C57BL/6J and C3H(+/-TLR4) mice were treated with a cocktail of oral antibiotics to suppress the endogenous gut microbiome for two weeks prior to and during AAA induction followed by harvest after 14 days (n=20-25/group). Male C57BL/6J and C3H mice were treated with a cocktail of oral antibiotics followed by cross-strain fecal transplantation via oral gavage for 16 weeks prior to AAA induction and harvest(n=5-8/group)

Results: AAAs in male C57BL/6J (135.4±9.6%) and C3H (-TLR4: 35.57±10.89%, p=0.0001; +TLR4: 31.32±10.81%, p=0.0001) mice was larger than female C57BL/6J AAAs (56.73±17.57%) or C3H females (-TLR4: 20.72±7.25%, p=0.0001; +TLR4: 21.32±6.83%, p=0.0001). Relative abundance and diversity of taxa in C57BL/6J and C3H was different in male vs female mice before AAA induction. After AAAs, C57BL/6J male mice exhibited decreased taxa diversity and increased pro-inflammatory taxa in comparison to male C3H and female mice of both strains. Metabolomics analysis in male C57BL/6J vs C3H mice demonstrated changes in long chain acyl-carnitine and TCA cycle (succinate, fumarate and malate) in blood after AAAs. Suppression endogenous gut microbiome with antibiotics attenuated AAA in male C57BL/6J (WT: 130.3±7.4% vs. ABX: 88.1 ±11.6%, p =.0031) while C57BL/6 female (p=0.0985), C3H male (p =0.0581), and C3H female (p=0.0001) demonstrated increased trends or significant increases in AAAs with antibiotics. Sequential microbiome sequencing confirmed depletion of gut microbiome with antibiotic treatment. Oral Fecal transplantation decreased AAAs in male C57BL/6 mice with C3H fecal transplantation (p=0.001). Microbiome sequencing confirmed oral fecal transfer across mouse strains.

Conclusion: Our studies suggest sex and host genetics can impact of the gut microbiome on AAAs and further emphasize the importance of sex in AAA disease.