Total abdominal irradiation exposure impairs cognitive function involving miR-34a-5p/BDNF axis

Abstract

Radiotherapy is often employed to treat abdominal and pelvic malignancies, but is frequently accompanied by diverse acute and chronic local injuries. It was previously unknown whether abdominal and pelvic radiotherapy impairs distant cognitive dysfunction. In the present study, we demonstrated that total abdominal irradiation (TAI) exposure caused cognitive deficits in mouse models. Mechanically, microarray assay analysis revealed that TAI elevated the expression level of miR-34a-5p in small intestine tissues and peripheral blood (PD), which targeted the 3′UTR of Brain-derived neurotrophic factor (Bdnf) mRNA in hippocampus to mediate cognitive dysfunction. Tail intravenous injection of miR-34a-5p antagomir immediately after TAI exposure rescued TAI-mediated cognitive impairment via blocking the up-regulation of miR-34a-5p in PD, resulting in restoring the Bdnf expression in the hippocampus. More importantly, high throughput sequencing validated that the gut bacterial composition of mice was shifted after TAI exposure, which was retained by miR-34a-5p antagomir injection. Thus, 27(7):916-932our findings provide new insights into pathogenic mechanism underlying abdominal and pelvic radiotherapy-mediated distant cognitive impairment.

Gut microbiota, cognitive frailty and dementia in older individuals: a systematic review

“…The results, summarized in Table 2, highlight the role of gut microbiota in regulating neuroinflammation, cerebral amyloid deposition and clearance, hippocampal synthesis of mediators or receptors involved in neurotransmission 50–54. Bacterial metabolites and circulating miRNAs have been hypothesized as playing a pivotal role in this gut–brain crosstalk 52,53. Interestingly, antibiotic-induced dysbiosis may not necessarily imply unfavorable consequences on brain pathology.…”

Interactions between the MicroRNAs and Microbiota in Cancer Development: Roles and Therapeutic Opportunities

“…A management of the microbiota and its effects on miRNAs could also have important results in preventing damage from radiotherapy. One group of researchers has demonstrated that radiation can influence the structure of gut microbiota and miRNAs expression [82,83], while faecal microbiota transplantation from healthy subjects may present a therapeutic option for radiation-provoked toxicity [84]. Moreover, high-throughput sequencing of microbial 16S rRNA and host miRNA demonstrated that simvastatin or high-fat diet block radiation-altered enteric bacterial taxonomic structure and protect miRNA expression profile [85].…”

The roles of the gut microbiota–miRNA interaction in the host pathophysiology

“…It can up-regulate miR-34a-5p expression and change bacterial composition, mediating cognitive dysfunction by targeting Bdnf, which has been reported to participate in many neurodegenerative disorders (Zuccato and Cattaneo 2009 ). Interestingly, the inhibition of miR-34a-5p by an antagomir could alleviate TAI-mediated cognitive impairment and restore the composition of the gut microbiota (Cui et al 2017 ). Therefore, it is reasonable to speculate that the gut microbiota is associated with cognitive impairment, which can be regulated by miR-34a-5p.…”