Parkinson's disease (PD) is the second most common neurodegenerative disease, but none of the current treatments for PD can halt the progress of the disease due to the limited understanding of the pathogenesis. In PD development, the communication between the brain and the gastrointestinal system influenced by gut microbiota is known as microbiota–gut–brain axis. However, the explicit mechanisms of microbiota dysbiosis in PD development have not been well elucidated yet. FLZ, a novel squamosamide derivative, has been proved to be effective in many PD models and is undergoing the phase I clinical trial to treat PD in China. Moreover, our previous pharmacokinetic study revealed that gut microbiota could regulate the absorption of FLZ in vivo . The aims of our study were to assess the protective effects of FLZ treatment on PD and to further explore the underlying microbiota-related mechanisms of PD by using FLZ as a tool. In the current study, chronic oral administration of rotenone was utilized to induce a mouse model to mimic the pathological process of PD. Here we revealed that FLZ treatment alleviated gastrointestinal dysfunctions, motor symptoms, and dopaminergic neuron death in rotenone-challenged mice. 16S rRNA sequencing found that PD-related microbiota alterations induced by rotenone were reversed by FLZ treatment. Remarkably, FLZ administration attenuated intestinal inflammation and gut barrier destruction, which subsequently inhibited systemic inflammation. Eventually, FLZ treatment restored blood–brain barrier structure and suppressed neuroinflammation by inhibiting the activation of astrocytes and microglia in the substantia nigra (SN). Further mechanistic research demonstrated that FLZ treatment suppressed the TLR4/MyD88/NF- κ B pathway both in the SN and colon. Collectively, FLZ treatment ameliorates microbiota dysbiosis to protect the PD model via inhibiting TLR4 pathway, which contributes to one of the underlying mechanisms beneath its neuroprotective effects. Our research also supports the importance of microbiota–gut–brain axis in PD pathogenesis, suggesting its potential role as a novel therapeutic target for PD treatment.

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Endophytes live asymptomatically within many cool‐season grasses for at least a portion of their life cycle. Although the leaf endophyte effects on the growth and stress resistance of host grasses have been relatively well studied, less attention has been focused on how this relationship may impact soil microbial communities, especially arbuscular mycorrhizal fungi (AMF). We defined endophyte‐infected and endophyte‐free Leymus chinensis as the host grass and neighbouring Stipa krylovii, which was not infected by endophytes, as the non‐host grass. Our objective was to examine the effect of endophyte infection on the colonization rate and composition of AMF communities in both the rhizosphere and bulk soils of their host (L. chinensis) and a neighbouring non‐host (S. krylovii) by a consecutive 2‐year survey. We described AMF communities using high‐throughput DNA sequencing, quantified the proportion of root length colonized by AMF using microscopy, and estimated AMF biomass using a lipid biomarker. Structural equation modelling (SEM) was applied to disentangle the direct and indirect effects (mediated by multiple environmental factors) of an endophyte on AMF. We found that endophyte infection significantly increased colonization rates and rhizosphere soil biomass of AMF but had no significant effect on the bulk soil around the host grass. The endophyte increased the diversity of the rhizosphere soil AMF community by decreasing the abundance of the dominant species Glomus while increasing the abundance of some unidentified AMF. SEM showed that the endophyte effects on AMF biomass in rhizosphere soil were primarily mediated by soil total carbon, total nitrogen and pH. With respect to the non‐host grass, the endophyte infection of host grass did not change the colonization rates or AMF biomass in either the rhizosphere or bulk soil but did cause a shift in the rhizosphere soil AMF community composition, resulting in a decrease in the relative abundance of Septoglomus and an increase in the relative abundance of some unidentified AMF. Highlights Effects of endophyte infection on AMF communities in both the rhizosphere and bulk soils were studied. Endophyte effect was studied not only on the host but also on the non‐host grass. Endophyte infection significantly increased colonization rates and rhizosphere soil biomass of AMF. Endophyte effect on AMF biomass in rhizosphere soil was primarily mediated by soil physicochemical properties.