Accumulating evidence suggests the critical role of the gut–brain axis (GBA) in Parkinson’s disease (PD) pathology and treatment. Recently, stem cell transplantation in transgenic PD mice further implicated the GBA’s contribution to the therapeutic effects of transplanted stem cells. In particular, intravenous transplantation of human umbilical-cord-blood-derived stem/progenitor cells and plasma reduced motor deficits, improved nigral dopaminergic neuronal survival, and dampened α-synuclein and inflammatory-relevant microbiota and cytokines in both the gut and brain of mouse and rat PD models. That the gut robustly responded to intravenously transplanted stem cells and prompted us to examine in the present study whether direct cell implantation into the gut of transgenic PD mice would enhance the therapeutic effects of stem cells. Contrary to our hypothesis, results revealed that intragut transplantation of stem cells exacerbated motor and gut motility deficits that corresponded with the aggravated expression of inflammatory microbiota, cytokines, and α-synuclein in both the gut and brain of transgenic PD mice. These results suggest that, while the GBA stands as a major source of inflammation in PD, targeting the gut directly for stem cell transplantation may not improve, but may even worsen, functional outcomes, likely due to the invasive approach exacerbating the already inflamed gut. The minimally invasive intravenous transplantation, which likely avoided worsening the inflammatory response of the gut, appears to be a more optimal cell delivery route to ameliorate PD symptoms.