YTHDF1 Attenuates TBI-Induced Brain-Gut Axis Dysfunction in Mice

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Abstract
The brain-gut axis (BGA) is a significant bidirectional communication pathway between the brain and gut. Traumatic brain injury (TBI) induced neurotoxicity and neuroinflammation can affect gut functions through BGA. N6-methyladenosine (m6A), as the most popular posttranscriptional modification of eukaryotic mRNA, has recently been identified as playing important roles in both the brain and gut. However, whether m6A RNA methylation modification is involved in TBI-induced BGA dysfunction is not clear. Here, we showed that YTHDF1 knockout reduced histopathological lesions and decreased the levels of apoptosis, inflammation, and oedema proteins in brain and gut tissues in mice after TBI. We also found that YTHDF1 knockout improved fungal mycobiome abundance and probiotic (particularly Akkermansia) colonization in mice at 3 days post-CCI. Then, we identified the differentially expressed genes (DEGs) in the cortex between YTHDF1-knockout and WT mice. These genes were primarily enriched in the regulation of neurotransmitter-related neuronal signalling pathways, inflammatory signalling pathways, and apoptotic signalling pathways. This study reveals that the ITGA6-mediated cell adhesion molecule signalling pathway may be the key feature of m6A regulation in TBI-induced BGA dysfunction. Our results suggest that YTHDF1 knockout could attenuate TBI-induced BGA dysfunction.
Funding Information
  • National Natural Science Foundation of China (82271406, 81771332, 82172820, 82070541, 22ZR1451200, PWZxq2022-10, PWYgy 2021-07, PWR12018-07, 202040125, LJS-201901A)
  • Natural Science Foundation of Shanghai Municipality (82271406, 81771332, 82172820, 82070541, 22ZR1451200, PWZxq2022-10, PWYgy 2021-07, PWR12018-07, 202040125, LJS-201901A)
  • Key Disciplines Group Construction Project of Shanghai Pudong New Area Health Commission (82271406, 81771332, 82172820, 82070541, 22ZR1451200, PWZxq2022-10, PWYgy 2021-07, PWR12018-07, 202040125, LJS-201901A)
  • Medical Discipline Construction Project of Pudong Health Committee of Shanghai (82271406, 81771332, 82172820, 82070541, 22ZR1451200, PWZxq2022-10, PWYgy 2021-07, PWR12018-07, 202040125, LJS-201901A)
  • Outstanding Leaders Training Program of Pudong Health Bureau of Shanghai (82271406, 81771332, 82172820, 82070541, 22ZR1451200, PWZxq2022-10, PWYgy 2021-07, PWR12018-07, 202040125, LJS-201901A)
  • Special Project of Clinical Research of Health Industry of Shanghai Municipal Health Commission (82271406, 81771332, 82172820, 82070541, 22ZR1451200, PWZxq2022-10, PWYgy 2021-07, PWR12018-07, 202040125, LJS-201901A)
  • Li Jieshou Intestinal Barrier Research Foundation (82271406, 81771332, 82172820, 82070541, 22ZR1451200, PWZxq2022-10, PWYgy 2021-07, PWR12018-07, 202040125, LJS-201901A)
  • No. 43 Investigator of the China-Japan Sasagawa Medical Scholarship (82271406, 81771332, 82172820, 82070541, 22ZR1451200, PWZxq2022-10, PWYgy 2021-07, PWR12018-07, 202040125, LJS-201901A)

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