Chronic stress impairs cognition through gut–brain axis dysregulation and metabolic imbalance. This study applied untargeted fecal metabolomics to investigate the cognitive and metabolic effects of Bacopa monnieri (L.) Wettst (Brahmi), mixed Thai berry, and their combined extracts in rats exposed to chronic unpredictable mild stress. Cognitive performance was evaluated using the novel object recognition test. Fecal metabolites were profiled using LC-ESI-QTOF-MS, followed by data preprocessing and multivariate statistical analysis. Orthogonal partial least squares regression was applied to identify metabolites associated with the recognition index, and pathway enrichment analysis was subsequently performed to interpret biological relevance. All interventions were associated with improved recognition performance and treatment-related metabolic modulation. Biosynthesis of unsaturated fatty acids was consistently enriched across treatment groups, indicating a shared involvement of lipid remodeling. Treatment-specific responses were also observed: Brahmi was associated with linoleic and alpha-linolenic acid metabolism; mixed Thai berry extract demonstrated dose-dependent modulation of lipid metabolism, with low-dose supplementation additionally yielding amino-acid-derived metabolites; and bile acid-related signaling was uniquely detected in the low-dose combined extract group. These findings demonstrate that fecal metabolomics can capture distinct metabolic signatures associated with herbal extract-induced cognitive improvement and highlight lipid remodeling as a shared metabolic feature across interventions under chronic stress.

Background/Objectives: Chronic stress contributes to anxiety disorders and cognitive impairment, while effective multi-target therapeutic strategies remain limited. This study investigated the effects of a standardized extract prepared from the aerial parts of Bacopa monnieri (L.) Wettst. (Brahmi) extract and an anthocyanin-rich mixed Thai berry extract, administered individually and in combination, in a chronic unpredictable mild stress (CUMS) rat model. Methods: Extracts derived from Morus alba L. (mulberry), Antidesma ghaesembilla Gaertn. (mamao), and Syzygium nervosum DC. (ma-kiang) were characterized for anthocyanin and phenolic contents, antioxidant activities, and cyanidin-3-O-glucoside levels using HPLC. Male Sprague Dawley rats were subjected to a 14-day CUMS protocol and treated with Brahmi extract, mixed Thai berry extract, or their combinations. Behavioral assessments included the open-field test, elevated plus maze, and novel object recognition test. Histopathological evaluation of the prefrontal cortex and hippocampus was also performed. Results: Brahmi extract and mixed Thai berry extract attenuated selected anxiety-related behaviors and improved recognition memory-related parameters in CUMS-exposed rats. The low-dose berry extract produced the most consistent behavioral improvements, whereas combination-treated groups showed greater histological preservation. Histopathological analysis revealed reduced neuronal degeneration and improved tissue organization in the prefrontal cortex and hippocampus of treated animals. Conclusions: These findings support the potential therapeutic relevance of Bacopa monnieri and anthocyanin-rich Thai berry extracts under chronic stress conditions, with differential effects observed between individual and combination treatments.