Mitochondrion-Mediated Metabolism and Microbiome Biodiversity Influence Autism-alike Behaviors - Abstract
Background: The BTBR T+Itpr3tf/J (BTBR) strain has autism spectrum disorder (ASD)-like behaviors, which has been associated with mitochondrial dysfunction. Therefore, a new mouse strain was developed. The BTBR-mtB6 strain has the nuclear genome of BTBR but mitochondria from C57BL/6J (B6) mice,hich have normal behaviors and immunity. The BTBR-mtB6 strain had more normal behavios and immunity. Therefore, the mechanisnisms associated with the improvements were investigated.
Aim: Since replacement of mitochondria in BTBR mice improved behavior and some immune differences, the associated mechanisms were researched.
Methods: Since mitochondria functions affect gut microbiota and metabolomics, the bacteria in fecal samples and metabolites in the blood and organs including the brain were investigated. Microbiome sequences were retrieved from Illumina BaseSpace. Genetic and molecular changes incuding metabolomics were assayed.
Results: The fecal microbiomes of BTBR, B6 and BTBR-mtB6 mice were different from each other. The serum and brain cholesterol levels were intermediate between males of the BTBR and B6 strain. The liver PPAR? level also was intermediate between the BTBR and B6 strain which may relate to the BTBR-mtB6 intermediate amount of lipid in the liver. The BTBR-mtB6 mice also had an intermediate number of T cells in the white adipose tissue compared to the BTBR and B6 mice. Complex IV of the ETC in the liver was slightly lower in the BTBR-mtB6 mice than B6 mice. The BTBR-mtB6 strain lost production of IgG to brain antigen that is observed in BTBR mice.
Conclusion: The mitochondrial shift is shown to affect fecal microbiota, mitochondrion-dependent metabolism affecting lipid accumulation, the levels of cholesterol in the brain and serum, and brain expression of myelin basic protein (MBP) and 2’,3’-cyclic nucleotide 3’-phosphodiesterase (CNPase), which improves myelination in BTBR-mtB6 brains. The metabolite and microbiome differences likely relate to mitochondrial/nuclear differences affecting metabolism, immunity, and behavior.