Commentary: Pingwei Powder Alleviates High-Fat Diet-Induced Colonic Inflammation by Modulating Microbial Metabolites SCFAs

Kangxiao GUO^1*Xuehuan He²Junping Zou¹Tang Yuan¹

• ¹Changsha Health Vocational College, Changsha, China
• ²Changjun Bilingual Xingsha School, Changsha, Hunan Province, China

Ulcerative colitis (UC), a major subtype of inflammatory bowel disease (IBD), is characterized by chronic relapsing inflammation of the colonic mucosa, presenting with symptoms such as persistent diarrhea, hematochezia, and abdominal pain (Wangchuk et al., 2024). By 2023, the global prevalence of UC had exceeded 5 million cases, imposing a substantial burden on healthcare systems and patient quality of life (Wangchuk et al., 2024). While the pathogenesis of UC remains incompletely understood, accumulating evidence highlights the critical role of environmental factors, especially particularly dietary patterns, in disease initiation and progression. High-fat diets (HFDs), defined as diets containing>30% energy from fat, have emerged as a key risk factor: epidemiological studies involving 170,805 participants demonstrated that high intake of trans-unsaturated fatty acids increases the risk of UC by 40% (Ananthakrishnan et al., 2014). Mechanistically, HFDs disrupt gut homeostasis by inducing gut microbiota dysbiosis, impairing intestinal barrier function, and triggering low-grade systemic inflammation (Fritsch et al., 2021;Hyun, 2021).Current therapeutic options for UC are limited by efficacy gaps and high costs: conventional medications such as 5-aminosalicylic acid (5-ASA) only induce remission in 40-50% of patients, while biological agents are prohibitively expensive for most populations (Gao et al., 2019). In contrast, traditional Chinese medicine (TCM) formulas have gained attention for their cost-effectiveness and multi-target therapeutic effects in UC management. Pingwei Powder (PWP), a classic TCM formula first documented in the Taiping Huimin Heji Jufang, which is Formulas from the Imperial Pharmacy for Universal Relief, of the Song Dynasty, consists of four herbs, Cang Zhu, Hou Po, Chen Pi and Gan Cao. For over a millennium, PWP has been used to treat digestive disorders associated with "dampness retention" in TCM, and modern studies have confirmed its anti-inflammatory, intestinal barrier-protective, and gut microbiota-regulating properties (Fan et al., 2023;Zhang et al., 2023;Zhang et al., 2019).A recent landmark study by Liu et al. (2025) Notably, compared with other TCM formulas for UC, PWP exhibits unique advantages in targeting HFD-related pathogenesis. For example, Huangqin Decoction primarily exerts therapeutic effects by regulating amino acid metabolism and inhibiting the mTOR pathway (Li et al., 2022), but it lacks a direct regulatory effect on SCFA-producing bacteria-a core mechanism of PWP in counteracting HFD-induced gut dysbiosis. Sishen Pill, while requiring SCFA synergy to enhance efficacy (Guo et al., 2025), focuses on "kidney-yang deficiency" syndrome and is less targeted at the "dampness retention" associated with HFD-induced metabolic disturbances, which PWP is traditionally indicated for. This Subsequent animal experiments validated this prediction: PWP significantly downregulated the expression of PI3K protein and the phosphorylation ratios of AKT and mTOR in colonic tissues of UC mice .This integrative approach not only provides a scientific basis for PWP's "multi-component, multi-target" effects but also avoids the limitations of traditional experimental research. Similar network pharmacology-based strategies have been successfully applied to other TCM formulas for UC, such as Huangqin Decoction, confirming its reliability (Li et al., 2022). Axis A major contribution of Liu et al.'s study is its systematic exploration of the "gut microbiota-SCFAs-PI3K/AKT/mTOR-autophagy" regulatory axis, a core mechanism of PWP's therapeutic effect. The authors employed a multimodal approach to characterize this axis. 16S rDNA sequencing showed that PWP reversed HFD-DSS-induced gut dysbiosis by reducing the abundance of opportunistic pathogens and increasing the levels of SCFA-producing bacteria. Linear discriminant effect size (LEfSe) analysis further confirmed these taxonomic shifts, highlighting PWP's selective modulation of gut microbiota. Gas chromatography-mass spectrometry (GC/MS) revealed that PWP significantly increased intestinal levels of butyric acid, valeric acid, and isovaleric acid which is the key SCFAs with anti-inflammatory and barrier-protective effects.Correlation analysis showed that the abundance of AlistipesandParabacteroides was positively correlated with SCFA levels and negatively correlated with colonic pro-inflammatory cytokine expression, establishing a link between microbiota and metabolite changes. Notably, this SCFA-mediated microbiota regulation is not unique to PWP, Guo et al. (2025) However, it is important to note that TCM quality control was not fully addressed in this study. PWP's efficacy is highly dependent on the quality of its constituent herbs, which can vary significantly due to factors such as geographical origin, harvesting time, and processing methods. For instance, Hou Po exhibits substantial batch-to-batch variation in the content of its active components magnolol and honokiol (Luo et al., 2019), which are key anti-inflammatory constituents of PWP. Similarly, Cang Zhu (Atractylodes lancea) from different regions shows differences in atractyloside A levels, a component linked to PWP's gut microbiota-regulating effects (Zhang et al., 2023). Without standardized quality control protocols, the reproducibility of PWP's clinical efficacy may be compromised. This gap weakens the practical guidance for PWP's clinical application and warrants attention in future research. Despite its significant contributions, Liu et al.'s study has several limitations that warrant consideration:1. Incomplete Analysis of Gut Microbiota Function While 16S rDNA sequencing provided insights into microbial community structure, the study did not employ metagenomic sequencing-atechnique that reveals the functional potential of the gut microbiome. For example, metagenomic sequencing could identify changes in genes encoding butyrate-producing enzymes or LPS biosynthesis genes in pathogenic bacteria (Ma et al., 2024). A recent study by Ma et al. (2024) demonstrated that metagenomic analysis of gut microbiota from pregnant women uncovered functional pathways not detected by 16S rRNA sequencing. For PWP research, metagenomics would clarify whether PWP modulates SCFA levels by altering microbial functional genes or simply by changing taxonomic abundance.Additionally, the study focused on bacterial communities but ignored other gut microbes such as fungi and archaea. Emerging evidence suggests that fungal dysbiosis contributes to UC pathogenesis by triggering immune responses (Wang et al., 2023), and future studies should include multi-kingdom microbiota profiling.2. Insufficient Exploration of SCFA-Mediated Signaling Pathways Liu et al. (2025) demonstrated that PWP increases intestinal SCFA levels and upregulates the SCFA receptor GPR43, but they did not investigate the downstream signaling pathways by which SCFAs exert their effects.SCFAs exert anti-inflammatory and barrier-protective effects through multiple mechanisms. In the GPR43/GPR41 signaling pathway, activation of G protein coupled receptors inhibits NF-κ B mediated inflammation and enhances expression of tight junction proteins (Kreuter et al., 2019). By inhibiting histone deacetylase (HDAC), particularly butyrate can inhibit HDAC activity and promote the expression of anti-inflammatory genes and autophagy-related genes (Donohoe et al. 2011). Besides, SCFAs serve as energy substrates for colonocytes, maintaining mitochondrial function and barrier integrity (Hamed et al., 2023).A recent study by Hamed et al. (2023) showed that butyrate protects intestinal epithelial barrier function by activating GPR43 and restoring mitochondrial morphology. Liu et al.'s study could have strengthened its mechanistic insights by investigating these pathways-for example, by using GPR43 knockout mice to determine whether PWP's effects are dependent on GPR43. Furthermore, given the synergistic effect of SCFAs with TCM formulas observed by Guo et al. (2025), future studies could explore whether combining PWP with SCFAs (e.g., sodium propionate) enhances the activation of these signaling pathways, thereby improving therapeutic efficacy. The study evaluated PWP's efficacy over a short period and did not assess long-term outcomes such as relapse rates or potential side effects.In clinical practice, UC is a chronic disease requiring long-term management, and short-term animal studies may not reflect the durability of PWP's effects. Additionally, while PWP is generally considered safe, high doses of its components may have hepatotoxic or neurotoxic effects (Luo et al., 2019). Future studies should include long-term administration and monitor serum biochemical markers to evaluate safety.Furthermore, the study used a single dose of PWP without exploring dose-response relationships. Dose optimization is critical for clinical translation, as excessive doses may increase side effects while suboptimal doses may reduce efficacy. Drawing inspiration from Guo et al.'s (2025) finding that SCFAs reduce TCM formula dosage, future studies could investigate whether combining PWP with SCFAs allows for dose reduction, minimizing potential side effects while maintaining efficacy. While Liu et al. showed that PWP promotes colonic autophagy, they did not clarify the specific type of autophagy involved or its upstream regulators. Autophagy in UC includes Xenophagy (Sharma et al., 2018), Mitophagy (Wang et al., 2024a). The PI3K/AKT/mTOR pathway inhibits autophagy by phosphorylating ULK1 (Kim et al., 2011), but Liu et al. did not measure ULK1 phosphorylation or mitophagy markers . Additionally, the study did not determine whether autophagy is required for PWP's effects-for example, by using autophagy-deficient mice to test if PWP's efficacy is abrogated. Liu et al.'s study was conducted in mice, and the authors did not provide data on PWP's efficacy in human UC patients. While animal models are valuable for mechanistic research, they have limitations:HFD-DSS-induced UC in mice does not fully recapitulate the chronic, relapsing nature of human UC, and interspecies differences in gut microbiota composition may affect PWP's efficacy (Thomas et al., 2023). Use GPR43 or GPR41 knockout mice to determine whether PWP's effects on barrier function and inflammation require these receptors (Kreuter et al., 2019). Measure HDAC activity in colonic tissues and use HDAC inhibitors/activators to test if PWP's autophagy-promoting effects are mediated by HDAC inhibition (Donohoe et al., 2011). Inspired by Guo et al.'s (2025) work, test the efficacy of PWP combined with sodium propionate or other SCFAs, evaluating whether this combination enhances GPR43 activation, HDAC inhibition, or mitochondrial function (Hamed et al., 2023). Use a chronic DSS model to evaluate PWP's ability to prevent relapse (Li et al., 2022). Monitor serum liver and kidney function markers, and perform histopathological analysis of major organs to evaluate long-term safety (Luo et al., 2019). Test multiple PWP doses alone and in combination with sodium propionate to identify the minimum effective dose and optimal therapeutic window (Guo et al., 2025). Measure markers of xenophagy and mitophagy to determine the specific type of autophagy promoted by PWP (Sharma et al., 2018;Wang et al., 2024a). Use Atg5 or ULK1 knockout mice to test if PWP's anti-inflammatory effects are abrogated in the absence of autophagy (Kim et al., 2011). Treat human colonic organoids with PWP or PWP-modulated fecal microbiota to validate its effects on barrier function and inflammation (Thomas et al., 2023). Conduct phase II randomized controlled trials (RCTs) to evaluate PWP's efficacy in UC patients, with endpoints including clinical remission rate, endoscopic improvement, and changes in fecal SCFA levels and microbiota composition (Haskey et al., 2023).Include an arm testing PWP + sodium propionate to evaluate dosage reduction and synergistic efficacy (Guo et al., 2025). Given the role of HFD in UC pathogenesis, test the efficacy of PWP combined with a low-fat, high-fiber diet (e.g., Mediterranean diet) in both animal models and clinical trials (Fritsch et al., 2021;Haskey et al., 2023).