[Effects of Jianpi Jiedu optimized formula on chemotherapy-related toxicities and gut microbiota in patients with colorectal carcinoma: A prospective controlled study].
Patients with colorectal carcinoma (CRC) frequently experience adverse effects during chemotherapy, including gastrointestinal reactions, weight loss, and myelosuppression, which may compromise treatment continuity and functional status. Gut microbiota dysbiosis has been associated with CRC progression, chemotherapy-related adverse effects, and treatment response. This study aims to evaluate the clinical efficacy and safety of Jianpi Jiedu optimized formula (JPJDYHF) as an adjunct to chemotherapy in patients with stage Ⅲ-Ⅳ CRC and to investigate its effects on gut microbiota composition.
A total of 121 patients with primary stage III-IV CRC were prospectively enrolled and allocated, according to patient preference, to a combination group (JPJDYHF plus chemotherapy) or a control group (chemotherapy alone). The control group received first-line chemotherapy regimens recommended by the Chinese Society of Clinical Oncology (CSCO) guidelines, whereas the combination group additionally received JPJDYHF Formula No.1 and Formula No.2 orally in a stage-specific manner. After exclusion of dropouts, 113 patients who completed 6 chemotherapy cycles were included in propensity score matching (PSM) based on 9 baseline variables, including age, sex, TNM stage, and chemotherapy regimen. Using 1꞉1 nearest-neighbor matching with a caliper of 0.25, 60 patients were selected for statistical analysis, with 30 patients in each group. The ability to proceed with chemotherapy from the first to the second cycle was recorded. At the end of each chemotherapy cycle, the objective response rate (ORR), disease control rate (DCR), Karnofsky Performance Status (KPS) score, traditional Chinese medicine (TCM) syndrome score, and chemotherapy-related adverse effects, including gastrointestinal reactions, weight loss, and myelosuppression, were assessed. Serum carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), and liver and renal function indices were measured before and after chemotherapy. After completion of six chemotherapy cycles, fecal samples were collected and total DNA was extracted. High-throughput sequencing targeting the V3-V4 region of the 16S ribosomal RNA (16S rRNA) gene was performed. Alpha and beta diversity were evaluated, and differentially abundant taxa were identified using linear discriminant analysis effect size (LEfSe). Functional profiles were predicted using Phylogenetic Investigation of Communities by Reconstruction of Unobserved States 2 (PICRUSt2) and the Clusters of Orthologous Groups (COG) database.
After PSM, baseline characteristics were well balanced between the two groups. In terms of clinical efficacy, the combination group showed better chemotherapy continuation than the control group and had higher ORR (46.67% vs 16.67%) and DCR (90.00% vs 73.33%) (both P<0.05). The overall response rate for TCM syndromes was 73.3% in the combination group, significantly higher than 30.0% in the control group (P<0.05). At cycles 3 and 6, KPS scores were higher in the combination group than in the control group (both P<0.05). Regarding safety and adverse effects, by the end of cycle 6, the combination group showed less severe gastrointestinal reactions, less weight loss, and less myelosuppression than the control group (all P<0.05), whereas changes in liver and renal function indices did not differ significantly between the groups (all P>0.05). For serum biomarkers, CEA levels were lower and the reduction rate was greater in the combination group at the end of cycles 5 and 6 (all P<0.05), whereas no significant between-group differences were observed in CA19-9 levels or reduction rates (all P>0.05). Gut microbiota analysis showed no significant difference in alpha diversity between the 2 groups (P>0.05), whereas beta diversity showed significant separation (P<0.05). LEfSe analysis indicated decreased relative abundances of Bacteroidota, Fusobacteriota, and Campylobacterota in the combination group. At the genus level, the relative abundances of Bacteroides, Parabacteroides, and cancer-associated genus Fusobacterium were reduced, whereas the relative abundances of the short-chain fatty acid-producing genera Blautia and Ruminococcaceae-UCG-014 were increased (all P<0.05). COG-based functional prediction showed downregulation of pathways related to lipid transport and metabolism and cell wall/membrane/envelope biogenesis, together with activation of signal transduction functions, in the gut microbiota of the combination group.
In patients with stage III-IV CRC, adjunctive JPJDYHF may improve chemotherapy tolerance and short-term objective response, reduce myelosuppression and gastrointestinal adverse effects, promote reductions in serum CEA levels, and improve overall functional status. These effects may be related to remodeling of the gut microbial ecosystem, including reduced abundance of drug resistance-associated taxa such as Fusobacterium and enrichment of short-chain fatty acid-producing bacteria, thereby modulating lipid metabolism and signal transduction pathways. Future studies integrating multi-omics approaches with large multicenter cohorts are warranted to further clarify the specific molecular targets through which gut microbiota-derived metabolites regulate host immunity and enhance chemotherapy efficacy.
A total of 121 patients with primary stage III-IV CRC were prospectively enrolled and allocated, according to patient preference, to a combination group (JPJDYHF plus chemotherapy) or a control group (chemotherapy alone). The control group received first-line chemotherapy regimens recommended by the Chinese Society of Clinical Oncology (CSCO) guidelines, whereas the combination group additionally received JPJDYHF Formula No.1 and Formula No.2 orally in a stage-specific manner. After exclusion of dropouts, 113 patients who completed 6 chemotherapy cycles were included in propensity score matching (PSM) based on 9 baseline variables, including age, sex, TNM stage, and chemotherapy regimen. Using 1꞉1 nearest-neighbor matching with a caliper of 0.25, 60 patients were selected for statistical analysis, with 30 patients in each group. The ability to proceed with chemotherapy from the first to the second cycle was recorded. At the end of each chemotherapy cycle, the objective response rate (ORR), disease control rate (DCR), Karnofsky Performance Status (KPS) score, traditional Chinese medicine (TCM) syndrome score, and chemotherapy-related adverse effects, including gastrointestinal reactions, weight loss, and myelosuppression, were assessed. Serum carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), and liver and renal function indices were measured before and after chemotherapy. After completion of six chemotherapy cycles, fecal samples were collected and total DNA was extracted. High-throughput sequencing targeting the V3-V4 region of the 16S ribosomal RNA (16S rRNA) gene was performed. Alpha and beta diversity were evaluated, and differentially abundant taxa were identified using linear discriminant analysis effect size (LEfSe). Functional profiles were predicted using Phylogenetic Investigation of Communities by Reconstruction of Unobserved States 2 (PICRUSt2) and the Clusters of Orthologous Groups (COG) database.
After PSM, baseline characteristics were well balanced between the two groups. In terms of clinical efficacy, the combination group showed better chemotherapy continuation than the control group and had higher ORR (46.67% vs 16.67%) and DCR (90.00% vs 73.33%) (both P<0.05). The overall response rate for TCM syndromes was 73.3% in the combination group, significantly higher than 30.0% in the control group (P<0.05). At cycles 3 and 6, KPS scores were higher in the combination group than in the control group (both P<0.05). Regarding safety and adverse effects, by the end of cycle 6, the combination group showed less severe gastrointestinal reactions, less weight loss, and less myelosuppression than the control group (all P<0.05), whereas changes in liver and renal function indices did not differ significantly between the groups (all P>0.05). For serum biomarkers, CEA levels were lower and the reduction rate was greater in the combination group at the end of cycles 5 and 6 (all P<0.05), whereas no significant between-group differences were observed in CA19-9 levels or reduction rates (all P>0.05). Gut microbiota analysis showed no significant difference in alpha diversity between the 2 groups (P>0.05), whereas beta diversity showed significant separation (P<0.05). LEfSe analysis indicated decreased relative abundances of Bacteroidota, Fusobacteriota, and Campylobacterota in the combination group. At the genus level, the relative abundances of Bacteroides, Parabacteroides, and cancer-associated genus Fusobacterium were reduced, whereas the relative abundances of the short-chain fatty acid-producing genera Blautia and Ruminococcaceae-UCG-014 were increased (all P<0.05). COG-based functional prediction showed downregulation of pathways related to lipid transport and metabolism and cell wall/membrane/envelope biogenesis, together with activation of signal transduction functions, in the gut microbiota of the combination group.
In patients with stage III-IV CRC, adjunctive JPJDYHF may improve chemotherapy tolerance and short-term objective response, reduce myelosuppression and gastrointestinal adverse effects, promote reductions in serum CEA levels, and improve overall functional status. These effects may be related to remodeling of the gut microbial ecosystem, including reduced abundance of drug resistance-associated taxa such as Fusobacterium and enrichment of short-chain fatty acid-producing bacteria, thereby modulating lipid metabolism and signal transduction pathways. Future studies integrating multi-omics approaches with large multicenter cohorts are warranted to further clarify the specific molecular targets through which gut microbiota-derived metabolites regulate host immunity and enhance chemotherapy efficacy.