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Recently, a large number of experimenters have found that the pathogenesis of Parkinson’s disease may be related to the gut microbiome and proposed the microbiome–gut–brain axis. Studies have shown that Toll-like receptors, especially Toll-like receptor 2 (TLR2) and Toll-like receptor 4 (TLR4), are key mediators of gut homeostasis. In addition to their established role in innate immunity throughout the body, research is increasingly showing that the Toll-like receptor 2 and Toll-like receptor 4 signaling pathways shape the development and function of the gut and enteric nervous system. Notably, Toll-like receptor 2 and Toll-like receptor 4 are dysregulated in Parkinson’s disease patients and may therefore be identified as the core of early gut dysfunction in Parkinson’s disease. To better understand the contribution of Toll-like receptor 2 and Toll-like receptor 4 dysfunction in the gut to early α-synuclein aggregation, we discussed the structural function of Toll-like receptor 2 and Toll-like receptor 4 and signal transduction of Toll-like receptor 2 and Toll-like receptor 4 in Parkinson’s disease by reviewing clinical, animal models, and in vitro studies. We also present a conceptual model of the pathogenesis of Parkinson’s disease, in which microbial dysbiosis alters the gut barrier as well as the Toll-like receptor 2 and Toll-like receptor 4 signaling pathways, ultimately leading to a positive feedback loop for chronic gut dysfunction, promoting α-synuclein aggregation in the gut and vagus nerve.

Abstract Background Sheep genomes undergo numerous genes losses, gains and mutation that generates genome variability among breeds of the same species after long time natural and artificial selection. However, the microevolution of native sheep in northwest China remains elusive. Our aim was to compare the genomes and relevant reproductive traits of four sheep breeds from different climatic environments, to unveil the selection challenges that this species cope with, and the microevolutionary differences in sheep genomes. Here, we resequenced the genomes of 4 representative sheep breeds in northwest China, including Kazakh sheep and Duolang sheep of native breeds, and Hu sheep and Suffolk sheep of exotic breeds with different reproductive characteristics. Results We found that these four breeds had a similar expansion experience from ~ 10,000 to 1,000,000 years ago. In the past 10,000 years, the selection intensity of the four breeds was inconsistent, resulting in differences in reproductive traits. We explored the sheep variome and selection signatures by F ST and θπ. The genomic regions containing genes associated with different reproductive traits that may be potential targets for breeding and selection were detected. Furthermore, non-synonymous mutations in a set of plausible candidate genes and significant differences in their allele frequency distributions across breeds with different reproductive characteristics were found. We identified PAK1, CYP19A1 and PER1 as a likely causal gene for seasonal reproduction in native sheep through qPCR, Western blot and ELISA analyses. Also, the haplotype frequencies of 3 tested gene regions related to reproduction were significantly different among four sheep breeds. Conclusions Our results provide insights into the microevolution of native sheep and valuable genomic information for identifying genes associated with important reproductive traits in sheep.