Liqi Yangyin formula ameliorates CUMS-induced depression and comorbid constipation via ACE/FFAR2 modulation of the microbiota-gut-brain axis

Frontiers in Cellular and Infection Microbiology · 2025-11-07 · 3 citations

Background The gut-brain axis, involving bidirectional signaling between the gastrointestinal tract and the central nervous system. Clinical observations have shown that Liqi Yangyin (LQYY) can effectively relieve symptoms of depression accompanied by constipation. However, whether LQYY exerts its effects through gut-brain crosstalk remains to be elucidated. Methods A chronic unpredictable mild stress (CUMS) protocol was employed to establish a mouse model. H&E and Nissl staining were used to examine pathological changes in the prefrontal cortex (PFC) and colon. The ultrastructure of the intestinal barrier was observed via transmission electron microscopy, while the expression of the blood-brain barrier tight junction proteins was quantified by Western blotting (WB). ELISA quantified inflammatory factors and serotonin (5-HT) levels. Immunohistochemistry, immunofluorescence, and WB analyzed IBA-1 and Free fatty acid receptor 2 (FFAR2) expression levels. Gut microbiota composition was analyzed via 16S rDNA sequencing, and SCFAs levels were quantified using UHPLC-TSQ Altis Plus. Additionally, in vitro studies using BV-2 cells involved treatments with acetic acid (ACE) and an FFAR2 antagonist, after which the expression of relevant indicators was assessed. Results Our results demonstrated that LQYY significantly ameliorated CUMS-induced behavioral changes and improved intestinal motility. These effects were associated with the restoration of gut microbiota balance and an increase in ACE levels. LQYY increased FFAR2 expression, leading to reduced neuroinflammation and enhanced colonic 5-HT secretion. Furthermore, LQYY protected intestinal and blood-brain barrier integrity and improved neuronal morphology in the PFC. In vitro studies confirmed that ACE suppresses microglial inflammation through upregulating FFAR2 expression, an effect that was attenuated by the FFAR2 inhibitor GLPG0974. Conclusions These findings suggest that LQYY modulates the gut-brain axis through ACE/FFAR2, offering a promising therapeutic approach for depression and constipation.

Combination of electroacupuncture and Liqi Yangyin formula treatment alleviates cognitive impairment and constipation in D-gal-induced mice via modulation of the brain-gut axis

Brain Research Bulletin · 2025-07-02 · 4 citations

Mild cognitive impairment (MCI), a precursor to Alzheimer's disease, and constipation, a common gastrointestinal complaint in older adults, frequently co-occur and have been increasingly linked through the gut-brain axis. Emerging evidence suggests that disruptions in gut microbiota and intestinal function may contribute to cognitive decline. However, effective therapeutic strategies that simultaneously address both conditions remain limited. This study investigated the effects of electroacupuncture (EA) combined with the Liqi Yangyin (LQYY) formula on cognitive function and constipation in a D-galactose (D-gal)-induced mouse model of MCI. Forty-five C57BL/6 mice were randomized into five groups: control, D-gal model, EA, EA+LQYY, and donepezil groups. Behavioural tests, including the Y-maze and Morris water maze, were used to assess cognitive performance. Meanwhile, gastrointestinal (GI) transit rate, fecal water content, and histological analysis were conducted to evaluate constipation-related parameters. Intestinal barrier function was assessed via Occludin and ZO-1 protein expression, and levels of 5-hydroxytryptamine (5-HT) and amyloid-beta (Aβ42) were measured in the colon, serum, and hippocampus. Results showed that EA+LQYY significantly improved cognitive performance and alleviated constipation compared to the model group, with superior efficacy to EA alone or donepezil. Mechanistically, EA+LQYY restored intestinal barrier integrity (via upregulation of Occludin and ZO-1), increased 5-HT levels in the gut, serum, and hippocampus, and reduced Aβ42 deposition in the colon, serum, and hippocampus across tissues. These findings suggest that EA+LQYY modulates the gut-brain axis through multi-target mechanisms, offering a promising integrative therapy for MCI and associated constipation. Future studies should explore specific molecular pathways and long-term clinical efficacy to further validate its therapeutic potential.

Guideline concordant osimertinib and durvalumab in two US non-small cell lung cancer cohorts.

JCO Oncology Practice · 2025-10-01

37 Background: Adjuvant osimertinib (osi) and consolidative durvalumab (durva) in non-small cell lung cancer (NSCLC) improve patient (pt) survival; therefore, adherence to oncology guidelines for their use is of great interest. We sought to understand the rates and clinical factors associated with receipt of guideline-concordant care (GCC) across two clinical scenarios among pts with non-metastatic NSCLC. Methods: This study examined two cohorts from the US-based, EHR-derived, de-identified Flatiron Health Research Database. Included pts were age 18+, treated in a community oncology practice with or without access to the clinical decision support tool Flatiron Assist (FA), and had either surgically resected stage II–IIIA EGFR-mutant NSCLC diagnosed December 2020–April 2024 (Cohort A) or definitive chemoradiotherapy for unresectable stage III NSCLC diagnosed February 2018–April 2024 (Cohort B). We calculated the percentage of pts receiving osi (Cohort A) or durva (Cohort B) overall and by pt characteristics. Multivariable logistic regression was used to estimate the association between pt characteristics and receipt of GCC with adjusted odds ratios (aOR). Results: In Cohort A, 265/378 pts (70%) received adjuvant osi. In Cohort B, 6295/9307 pts (68%) received consolidative durva. After adjusting for pt factors, pts in Cohort A who received GCC were more likely to be Latinx vs. non-Latinx White, never- vs. ever-smokers, or diagnosed before 2022 vs. 2024 (Table). In Cohort B, pts who received GCC were more likely to be younger, female, non-Latinx White, ECOG 0, or diagnosed in 2024 vs. 2018. There was no significant difference in GCC by FA access in either cohort. Conclusions: Across two straightforward clinical scenarios in non-metastatic NSCLC, the pts most likely to receive GCC had vastly different characteristics highlighting the complex nuances affecting guideline adherence. Overall, 30% of pts did not receive GCC despite clear indications for osi and durva. Unmeasured comorbidities may explain some, but not all practice variation. Further research is needed to elucidate reasons for guideline non-concordance and inform strategies to aid clinicians in prescribing life-saving therapies. aOR of receiving concordant osi, (95% CI) aOR of receiving concordant durva, (95% CI) Age at diagnosis ≥80 vs. <50 2.72 (0.27, 21.5) 0.62 (0.41, 0.93) Male vs. female 0.74 (0.44, 1.26) 0.91 (0.83, 0.99) Latinx ethnicity vs. non-Latinx White 5.72 (1.18, 50.9) 0.85 (0.66, 1.12) Never-smoker vs. ever-smoker 2.69 (1.55, 4.8) 0.87 (0.70, 1.08) South vs. Northeast census region 0.65 (0.27, 1.48) 0.97 (0.84, 1.13) Highest area-level socioeconomic status vs. lowest 0.98 (0.39, 2.44) 1.16 (0.97, 1.41) Medicare vs. Commercial insurance 0.54 (0.24, 1.17) 1.04 (0.90, 1.21) No FA vs. FA access at site 0.82 (0.43, 1.52) 1.00 (0.87, 1.14) Diagnosis year 2024 vs. 2021/prior (osi) or 2018 (durva) 0.39 (0.16, 0.91) 1.39 (1.12, 1.72)

Electroacupuncture and Tongbian decoction ameliorate CUMS-induced depression and constipation in mice via TPH2/5-HT pathway of the gut-brain axis

Brain Research Bulletin · 2025-01-14 · 18 citations

Depression is commonly associated with gastrointestinal (GI) disorders, such as constipation, which can potentially intensify depressive symptoms. The interplay between these conditions is believed to be facilitated by the gut-brain axis, which suggests a complex bidirectional interaction. Current treatments, such as antidepressants and prokinetics, are often associated with side effects and high recurrence rates, highlighting the need for effective treatments targeting both depression and constipation. This study was designed to assess the therapeutic efficacy of electroacupuncture (EA) in conjunction with Tongbian decoction (TB) for the management of both depression and constipation, while also investigating the underlying mechanisms through the lens of the gut-brain axis. Chronic unpredictable mild stress (CUMS) was employed to induce a comorbidity model of depression and constipation in mice, followed by the administration of EA, EA + TB, and fluoxetine (FLX). The findings of the study demonstrated that the antidepressant effects of electroacupuncture (EA) in combination with Tongbian decoction (TB) were more pronounced than those of EA alone. The EA + TB treatment significantly ameliorated depression and anxiety-like behaviors, restored cognitive function, and enhanced gastrointestinal motility in chronic unpredictable mild stress (CUMS) mice. Furthermore, EA + TB reduced intestinal inflammation, restored neuronal morphology, increased the expression of tryptophan hydroxylase 2 (TPH2) in both the prefrontal cortex (PFC) and colon, elevated the serum levels of 5-hydroxytryptophan (5-HTP)—a molecule that acts as a gut-brain connector—and promoted the synthesis and production of serotonin (5-HT) in both the gastrointestinal tract and the brain. Contrastingly, FLX showed limited efficacy in improving constipation. In conclusion, EA + TB regulates the TPH2/5-HT pathway via the gut-brain axis, demonstrating synergistic regulation of the nervous and gastrointestinal systems, with favorable antidepressant and prokinetic effects. • EA + TB significantly alleviates depression, anxiety, cognitive impairment, and constipation in CUMS mice. • EA + TB demonstrates superior therapeutic effects compared to EA or FLX alone, particularly in alleviating constipation. • The treatment enhances gut-brain axis communication by modulating the TPH2/5-HT pathway. • EA + TB promotes serotonin synthesis and metabolism in both the gastrointestinal tract and brain. • Elevated serum 5-HTP levels highlight its role as a critical gut-brain connector and mediator.

Using Bomb Calorimetry to Investigate Intestinal Energy Harvest in Anorexia Nervosa: Preliminary Findings on Stool Calorie Loss

UNC Libraries · 2025-11-22

OBJECTIVE: Renourishment and weight restoration are critical first steps in anorexia nervosa (AN) treatment. The ability of the gastrointestinal tract to harvest and utilize energy from food is essential for successful weight restoration, but the functional capacity of the intestine after prolonged caloric restriction remains unknown. In an exploratory study, we quantified the stool energy content of individuals with AN before and after renourishment. METHOD: We used archived stool samples from a multisite cohort (NCT03119272) of 103 individuals with AN at admission and discharge from inpatient renourishment and 122 sex-matched non-eating disorder controls (non-ED). To determine whether bomb calorimetry may have utility in AN, we measured stool calorie loss as the number of kilocalories per gram of stool. Analyses included ANOVA, paired/unpaired t-tests, and Spearman rank correlations for associations between stool energy and clinical variables. RESULTS: Following 25.10 ± 19.73 days of renourishment, patients gained an average of 5.67 ± 4.27 kg. Raw stool energy at discharge (AN-DIS: 5.72 ± 0.86 kcal/g) was significantly higher than admission (AN-AD: 5.41 ± 0.86 kcal/g; p < 0.01). Weight and BMI at admission and discharge were negatively correlated with raw stool energy at discharge. DISCUSSION: Energy content in stool increases after inpatient refeeding, likely due to increased calorie consumption. Findings should be interpreted cautiously due to methodological limitations in this post hoc study design. Future studies should use a priori, gold-standard protocols to investigate stool calorie loss in AN, as prolonged restriction in AN may disrupt the gut and impede energy harvest. TRIAL REGISTRATION: clinicaltrials.gov: NCT03119272.

Decoding longitudinal microbiome trajectories: an interpretable machine learning approach for biomarker discovery and prediction

Briefings in Bioinformatics · 2025-07-01 · 1 citations

Information generated from longitudinally sampled microbial data has the potential to illuminate important aspects of development and progression for many human conditions and diseases. Identifying microbial biomarkers and their time-varying effects can not only advance our understanding of pathogenetic mechanisms, but also facilitate early diagnosis and guide optimal timing of interventions. However, longitudinal predictive modeling of highly noisy and dynamic microbial data (e.g. metagenomics) poses analytical challenges.To overcome these challenges, we introduce a robust and interpretable machine-learning-based longitudinal microbiome analysis framework, LP-Micro, that encompasses (i) longitudinal microbial feature screening via a polynomial group lasso, (ii) disease outcome prediction implemented via machine learning methods (e.g. XGBoost, deep neural networks), and (iii) interpretable association testing between time points, microbial features, and disease outcomes via permutation feature importance. We demonstrate in simulations that LP-Micro can not only identify incident disease-related microbiome taxa, but also offers improved prediction accuracy compared with existing approaches. Applications of LP-Micro in two longitudinal microbiome studies with clinical outcomes of childhood dental disease and weight loss following bariatric surgery yield consistently high prediction accuracy. Moreover, LP-Micro highlights critical time points and associated microbial changes: oral microbial changes, including Streptococcus mutans, are most informative for predicting childhood dental disease at around 39 months of age, while gut microbial changes shortly after bariatric surgery strongly predict future weight loss. These findings are both informative and aligned with clinical expectations. The tool LP-Micro can be seen at https://github.com/IV012/LPMicro.

Naringenin targets and inhibits Monoamine Oxidase A/B to bidirectionally regulate intestinal motility.

Chemico-Biological Interactions · 2025-09-12 · 1 citations

BACKGROUND: Monoamine oxidase (MAO), the principal enzymatic regulator of monoamine neurotransmitter catabolism, plays a critical role in modulating intestinal motility dynamics. In colonic tissues, MAO-A is predominantly expressed during monoamine degradation, whereas MAO-B exhibits a relatively lower expression level. This differential expression of MAO subtypes endows naringenin (NAR), a flavonoid compound that can competitively bind to the active sites of both MAO-A and MAO-B, with distinct dose-response thresholds for inhibiting these two enzyme isoforms. Consequently, this study aims to systematically elucidate the molecular mechanisms underlying NAR's regulation of intestinal motility through its selective inhibition of the two MAO subtypes, and to comprehensively analyze the associated dose-effect relationships. Ultimately, the research seeks to provide a theoretical basis for its dose optimization and the mitigation of toxicity and side effects. METHODS: In this study, we constructed a slow-transmission constipation model in male C57BL/6 mice induced by loperamide (LOP), and systematically investigated the effects of NAR at different concentrations on intestinal motility, MAO activity and neurotransmitter metabolism. RESULTS: This research showed that NAR at a dose of 25-300 mg/kg selectively targeted intestinal MAO-A, suppressing enzymatic activity and reducing 5-hydroxytryptamine (5-HT) catabolism. This accumulation of 5-HT enhanced intestinal motility. However, when the NAR concentration is ≥ 150 mg/kg, it can additionally cause MAO-B inhibition, which resulted in significant blockage of dopamine metabolism and caused an abnormal increase in dopamine content. Ultimately, it inhibited colonic peristalsis through the activation of the dopamine signaling pathway. CONCLUSION: The results confirmed that NAR can regulate the activities of MAO-A/B in a threshold-dependent manner to achieve bidirectional regulation of intestinal motility.

MSR24 Leveraging Machine Learning to Assess the Association of Rash and Survival in Patients With Advanced NSCLC

Value in Health · 2025-07-01 · 2 citations

Total flavone of <i>Abelmoschus manihot</i> regulates autophagy through the AMPK/mTOR signaling pathway to treat intestinal fibrosis in Crohn's disease

Journal of Gastroenterology and Hepatology · 2024-05-27 · 10 citations

BACKGROUND AND AIM: Drug therapy is the treatment of choice for Crohn's disease because it effectively controls or prevents intestinal inflammation. The purpose was to research the molecular mechanism of the total flavones of Abelmoschus manihot (TFA) on intestinal fibrosis in Crohn's disease. METHODS: A 2,4,6-Trinitrobenzenesulfonic acid (TNBS)-induced colitis model and IGF-1-treated intestinal fibroblasts were established. Then, TFA, 3-MA, and compound C were used treatments. Hematoxylin and eosin, Masson, and Picrosirius red staining were performed to observe the colon tissue. Immunohistochemical staining was used to detect α-SMA expression. Flow cytometry, CCK8, wound healing, and Transwell assays were conducted to determine apoptosis, proliferation, invasion, and migration. Col1a1 and Col3a1 levels were detected using quantitative polymerase chain reaction. Proteins related to autophagy and apoptosis were detected using western blotting. RESULTS: TFA treated intestinal fibrosis in chronic Crohn's disease. Colon length was the shortest in the ethanol + TNBS group, and TFA treatment significantly improved the situation. Intestinal fibrosis and the percentage of collagen area decreased after TFA treatment. TFA reduced fibrosis by enhancing autophagy stimulation, whereas an autophagy inhibitor reversed the TFA effect. TFA also inhibited migration, proliferation, and collagen synthesis in intestinal fibroblasts. Moreover, it enhanced autophagy and apoptosis of intestinal fibroblasts. TFA upregulated p-AMPK expression and decreases p-mTOR levels. Compound C partially rescued the effect of TFA, indicating that TFA affected intestinal fibroblasts via the AMPK/mTOR pathway in vitro and in vivo. TFA also downregulated Col1a1 and Col3a1 expression. CONCLUSION: TFA regulates autophagy through AMPK/mTOR signaling pathway to treat intestinal fibrosis, which may provide a new therapy for Crohn's disease treatment.

Intestinal Energy Harvest Mediates Gut Microbiota-Associated Weight Loss Following Bariatric Surgery

Obesity Surgery · 2024-08-28 · 5 citations