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Background: Emerging evidence suggests that the gut microbiota plays an important role in the pathological progression of Alzheimer's disease (AD). Photobiomodulation (PBM) therapy is believed to have a positive regulatory effect on the imbalance of certain body functions, including in ammation, immunity, wound healing, nerve repair, and pain. Previous studies have found that the intestinal ora of patients with AD is in an unbalanced state. Therefore, we have proposed the use of gut ora-targeted PBM (gf-targeted PBM) as a method to improve AD in an Aß-induced AD mouse model. Methods: PBM was performed on the abdomen of the mice at the wavelengths of 630 nm, 730 nm, and 850 nm at 100 J/cm 2 for 8 weeks. Morris water maze test, immuno uorescence and proteomic of hippocampus, and intestinal ora detection of fecal were used to evaluate the treatment effects of gftargeted PBM on AD rats.Results: PBM at all three wavelengths (especially 630 nm and 730 nm) signi cantly improved learning retention as measured by the Morris water maze. In addition, we found reduced amyloidosis and tau phosphorylation in the hippocampus by immuno uorescence in AD mice. By using a quantitative proteomic analysis of the hippocampus, we found that gf-targeted PBM signi cantly altered the expression levels of 509 proteins (the same differentially expressed proteins in all three wavelengths of PBM), which involved the pathways of hormone synthesis, phagocytosis, and metabolism. The 16s rRNA gene sequencing of fecal contents showed that PBM signi cantly altered the diversity and abundance of intestinal ora. Speci cally, PBM treatment reversed the typical increase of Helicobacter and uncultured Bacteroidales and the decrease of Rikenella seen in AD mice.Conclusions: Our data indicate that gf-targeted PBM regulates the diversity of intestinal ora, which may improve damage caused by AD. Gf-targeted PBM has the potential to be a noninvasive micro ora regulation method for AD patients.

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