Xanomeline-trospium reverses phencyclidine-induced cognitive deficits through modulation of the gut microbiota-brain axis in mice

Abstract

Cognitive impairment in schizophrenia remains largely unaddressed by dopamine-based antipsychotics. Xanomeline–trospium (KarXT; Cobenfy^®), a combination of the muscarinic M1/M4 receptor agonist xanomeline and the peripherally restricted antagonist trospium, effectively reduces psychosis but is associated with gastrointestinal adverse effects. Here, we tested whether KarXT reverses phencyclidine (PCP)–induced cognitive deficits through microbiota-associated mechanisms in adult male mice. Mice received saline or PCP (10 mg/kg/day, s.c.) on days 1–5 and 8–12, followed by vehicle or KarXT [xanomeline 2 mg/kg/day + trospium 1 mg/kg/day, intragastric] on days 15–28. Recognition memory was evaluated using the novel object recognition test (NORT), and lung and intestinal microbiota (small intestine, cecum, and colon) were profiled by 16S rRNA sequencing. KarXT significantly rescued PCP-induced recognition-memory deficits without exacerbating PCP-related reductions in weight gain or fecal output. Microbiome analyses revealed region-specific dysbiosis after PCP exposure, most pronounced in the small intestine and cecum. Several taxa elevated by PCP—including Bacteroides fragilis, Veillonella ratti, Megamonas funiformis, Cupriavidus numazuensis, and Acetanaerobacterium elongatum—were normalized following KarXT treatment. Notably, restoration of multiple pulmonary, cecal, and colonic taxa correlated positively with the NORT recognition index. These findings demonstrate that KarXT reverses PCP-induced cognitive dysfunction while modulating microbial composition in a region-specific manner. Elucidating these relationships may help optimize cognitive efficacy and reduce gastrointestinal adverse effects of muscarinic therapies for schizophrenia.