Commentary: Synergistic treatment of sodium propionate and Sishen Pill for diarrhea mice with kidney-yang deficiency syndrome

A Commentary on
Synergistic treatment of sodium propionate and Sishen Pill for diarrhea mice with kidney-yang deficiency syndrome

By Guo M, Di J and Lei Z (2025) Front. Cell. Infect. Microbiol. 15:1608271. doi: 10.3389/fcimb.2025.1608271

Introduction

Kidney-yang deficiency syndrome (KYDS), a fundamental concept in Traditional Chinese Medicine (TCM), manifests clinically as chronic diarrhea, cold intolerance, and fatigue with high prevalence among aging populations. Modern biomedical research has established that KYDS correlates with hypothalamic-pituitary-adrenal (HPA) axis dysregulation and intestinal barrier compromise (Zhang et al., 2019). Crucially, emerging evidence implicates gut dysbiosis as a pathological mediator, where depleted short-chain fatty acid (SCFA) production—particularly propionate—impairs colonic mucosal integrity and immune homeostasis (Smith et al., 2021). Sishen Pill (SSP), a classical TCM formula documented in Sheng Ji Zong Lu (1100 AD), contains bioactive compounds like psoralen and evodiamine that demonstrate anti-inflammatory and microbiota-modulating properties (Ge et al., 2020). The innovative integration of sodium propionate (SP) with SSP represents a paradigm-shifting strategy targeting both microbial ecology and mucosal healing. This synergy is theoretically anchored in TCM’s “kidney governing water metabolism” principle and Western medicine’s gut-kidney axis concept, offering unprecedented potential for refractory diarrhea management.

General comments

In a recent study entitled “Synergistic Treatment of Sodium Propionate and Sishen Pill for Diarrhea Mice with Kidney-Yang Deficiency Syndrome” was published in Frontiers in Cellular and lnfection Microbiology”.Synergistic Treatment of Sodium Propionate and Sishen Pill for Diarrhea Mice with Kidney-Yang Deficiency Syndrome” (Guo et al., 2025) pioneers an integrative therapeutic strategy combining sodium propionate—a gut microbiota-modulating short-chain fatty acid—with Sishen Pill, a classic TCM formula, to address diarrhea in murine models of kidney-yang deficiency syndrome. The authors investigated the synergistic potential of metabolic regulation and TCM principles in restoring intestinal homeostasis. Key strengths include an innovative combination therapy design, comprehensive validation of TCM syndromes in animal models, and multi-faceted biomarker analysis spanning intestinal enzymes, immune organ indices, and microbial composition. Their systematic evaluation demonstrated robust synergistic efficacy in alleviating diarrhea and restoring microbiota balance. Critically, the 75% Sishen Pill + 60 mg/kg sodium propionate group exhibited normalization of fecal water content, bacterial overgrowth, and immune dysfunction, underscoring the importance of mechanistic synergy and precise dose optimization for therapeutic outcomes. This work offers novel insights into microbiota-TCM interactions and paves the way for optimized integrative interventions.

First, several limitations should be acknowledged. While the study identifies shifts in Bifidobacterium and Escherichia coli populations, the causal link between these changes and diarrhea resolution remains unclear. Functional assays, such as metabolomics profiling of short-chain fatty acids, could strengthen mechanistic interpretations (He et al., 2022). Additionally, the empirical determination of the optimal Sishen Pill-to-sodium propionate ratio lacks exploration of pharmacokinetic interactions or receptor-mediated signaling pathways, leaving the basis for this specific combination unexplained. The study’s exclusive focus on murine models also restricts immediate translational relevance, necessitating clinical validation to confirm safety and efficacy in humans.

Second, several mechanistic ambiguities warrant critical examination. While the reported microbial alterations offer correlative insights, the absence of functional validation leaves unresolved whether these taxonomic changes directly mediate therapeutic effects or merely represent secondary phenomena. Metabolomic profiling of luminal SCFA dynamics—particularly quantification of propionate flux and butyrate reciprocation—would substantially strengthen causal attribution, especially given butyrate’s established role as the primary colonocyte energy source (Anderson et al., 2022).

Furthermore, the empirically determined optimal ratio lacks pharmacokinetic substantiation regarding potential herb-metabolite interactions. Unanswered questions persist concerning whether bioactive SSP constituents such as psoralen competitively inhibit monocarboxylate transporter (MCT1)-mediated propionate absorption, or conversely potentiate GPR43 receptor signaling in enteroendocrine cells. The exclusive reliance on antibiotic-induced murine models also constrains clinical extrapolation, as human KYDS involves distinctive neuroendocrine signatures including cortisol rhythm disruption and adrenocortical insufficiency that remain inadequately recapitulated in rodents.

Discussion

The groundbreaking work by Guo et al. inaugurates a transformative approach to KYDS management by synergizing ancient herbal wisdom with microbial metabolome modulation. Their demonstration that SP potentiates SSP’s efficacy aligns with contemporary understanding of the gut-kidney axis, where SCFAs directly influence renal water handling through olfactory receptor 78 (Olfr78) activation in juxtaglomerular apparatus. Nevertheless, three fundamental questions demand resolution to advance this therapeutic strategy. First, the causal relationship between specific microbial shifts and clinical improvement requires validation through fecal microbiota transplantation studies in germ-free models (He et al., 2019). Second, the pharmacokinetic interplay between SSP polyphenols and SP absorption necessitates investigation via Caco-2 transwell assays and hepatic microsomal stability testing (Zhang et al., 2015). Third, the neuroendocrine dimension of KYDS—particularly HPA axis modulation—remains unexplored; future research should assess corticosterone rhythms and adrenal glucocorticoid output in treated models.

1. SP serving as a histone deacetylase (HDAC) inhibitor, enhances SSP-induced Nrf2 activation. Existing evidence suggests that HDAC inhibition enhances negative feedback regulation by upregulating glucocorticoid receptor (GR) expression, and this process may be further amplified by gut-derived SCFAs (such as butyrate) through the GPR43-HDAC inhibition axis, exacerbating gut-kidney inflammation in Nrf2-deficient mice (Wang et al., 2012). Additionally, the renal protective effect of vagus nerve stimulation depends on the α7nAChR-Nrf2 pathway, suggesting that Nrf2 is a core target for neuro-immune regulation.

2. The gut microbiota is closely associated with KYDS (Chen et al., 2019). Braune (Braune, 2025) demonstrated that SSP isoflavones promote the conversion of propionic acid to butyric acid via bacteria expressing butyryl-CoA transferase.

3. The vagus nerve afferent fibers regulate colonic motility through the gut-brain axis. Muller et al (Muller et al., 2020)’s research revealed that the specific mechanism involves vagus nerve afferent fibers sensing intestinal signals via 5-HT₃ receptors and SCFAs/GPR41/43, enhancing parasympathetic output through the NTS-DMV pathway, and promoting colonic peristalsis. Gut microbiota metabolites (butyrate, tryptophan) regulate this process through epigenetic regulation (HDAC-BDNF) and neurotransmitter regulation.

To validate these hypotheses, multi-omics integration is crucial—metabolomics sequencing combined with mucosal proteomics can reveal microbial functional pathways and host receptor responses. Crucially, clinical translation requires phased human trials: first, precise stratification based on traditional Chinese medicine syndromes (KYDS) combined with biomarkers (24-hour urinary cortisol, ACTH) and gut type (metagenomic typing); Phase I trials assess SP/SSP pharmacokinetics (blood-brain barrier permeability, TGF-β1 safety monitoring) to determine dosing regimens; Phase II adopts a randomized double-blind design, with the experimental group receiving SP/SSP combined with microbial-targeted intervention (e.g., Prevotella-type anti-inflammatory fiber supplementation), and the control group receiving a placebo. Primary endpoints include colon transit time (SmartPill), neuropeptide levels (ELISA/MS), and microbial function (metagenomics + metabolomics), secondary endpoints assess autonomic nervous function (heart rate variability) and psychological scores (HADS); ultimately, through multi-omics integration (mucosal proteomics-fecal metagenomics), the regulatory mechanisms of the HDAC3/Nrf2 pathway will be elucidated to provide evidence for personalized treatment.

Author contributions

ZZ: Writing – original draft, Conceptualization. HW: Writing – review & editing. XL: Writing – review & editing.

Funding

The author(s) declare that no financial support was received for the research, and/or publication of this article.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Generative AI statement

The author(s) declare that no Generative AI was used in the creation of this manuscript.

Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

References

Anderson, E. M., Rozowsky, J. M., Fazzone, B. J., Schmidt, E. A., Stevens, B. R., O’Malley, K. A., et al. (2022). Temporal dynamics of the intestinal microbiome following short-term dietary restriction. Nutrients 14 (14), 2785. doi: 10.3390/nu14142785

PubMed Abstract | Crossref Full Text | Google Scholar

Braune, A. (2025). Flavonoid-converting capabilities of Clostridium butyricum. Appl. Microbiol. Biotechnol. 109, 53. doi: 10.1007/s00253-025-13434-0

PubMed Abstract | Crossref Full Text | Google Scholar

Chen, R., Wang, J., Zhan, R., Zhang, L., and Wang, X. (2019). Fecal metabonomics combined with 16S rRNA gene sequencing to analyze the changes of gut microbiota in rats with kidney-yang deficiency syndrome and the intervention effect of You-gui pill. J. Ethnopharmacol. 244, 112139. doi: 10.1016/j.jep.2019.112139

PubMed Abstract | Crossref Full Text | Google Scholar

Ge, W., Wang, H. Y., Zhao, H. M., Liu, X. K., Zhong, Y. B., Long, J., et al. (2020). Effect of Sishen pill on memory T cells from experimental colitis induced by dextran sulfate sodium. Front. Pharmacol. 11, 908. doi: 10.3389/fphar.2020.00908

PubMed Abstract | Crossref Full Text | Google Scholar

Guo, M., Di, J., and Lei, Z. (2025). Synergistic treatment of sodium propionate and Sishen Pill for diarrhea mice with kidney-yang deficiency syndrome. Front. Cell. Infect. Microbiol. 15. doi: 10.3389/fcimb.2025.1608271

PubMed Abstract | Crossref Full Text | Google Scholar

He, J., Luo, X., Xin, H., Lai, Q., Zhou, Y., and Bai, Y. (2022). The effects of fatty acids on inflammatory bowel disease: A two-sample Mendelian randomization study. Nutrients 14 (14), 2883. doi: 10.3390/nu14142883

PubMed Abstract | Crossref Full Text | Google Scholar

He, C., Wang, H., Liao, W. D., Peng, C., Shu, X., Zhu, X., et al. (2019). Characteristics of mucosa-associated gut microbiota during treatment in Crohn’s disease. World J. Gastroenterol. 25 (18), 2204–2216. doi: 10.3748/wjg.v25.i18.2204

PubMed Abstract | Crossref Full Text | Google Scholar

Muller, P. A., Schneeberger, M., Matheis, F., Wang, P., Kerner, Z., Ilanges, A., et al. (2020). Microbiota modulate sympathetic neurons via a gut-brain circuit. Nature 583 (7816), 441–446. doi: 10.1038/s41586-020-2474-7

PubMed Abstract | Crossref Full Text | Google Scholar

Smith, S. A., Ogawa, S. A., Chau, L., Whelan, K. A., Hamilton, K. E., Chen, J., et al. (2021). Mitochondrial dysfunction in inflammatory bowel disease alters intestinal epithelial metabolism of hepatic acylcarnitines. J. Clin. Invest. 131 (1), e133371. doi: 10.1172/JCI133371

PubMed Abstract | Crossref Full Text | Google Scholar

Wang, B., Zhu, X., Kim, Y., Li, J., Huang, S., Saleem, S., et al. (2012). Histone deacetylase inhibition activates transcription factor Nrf2 and protects against cerebral ischemic damage. Free Radic. Biol. Med. 52 (5), 928–936. doi: 10.1016/j.freeradbiomed.2011.12.006

PubMed Abstract | Crossref Full Text | Google Scholar

Zhang, J. Y., Hong, C. L., Chen, H. S., Zhou, X. J., Zhang, Y. J., Efferth, T., et al. (2019). Target identification of active constituents of Shen Qi Wan to treat kidney yang deficiency using computational target fishing and network pharmacology. Front. Pharmacol. 10, 650. doi: 10.3389/fphar.2019.00650

PubMed Abstract | Crossref Full Text | Google Scholar

Zhang, Y., Zhao, K. T., Fox, S. G., Kim, J., Kirsch, D. R., Ferrante, R. J., et al. (2015). Tertiary amine pyrazolones and their salts as inhibitors of mutant superoxide dismutase 1-dependent protein aggregation for the treatment of amyotrophic lateral sclerosis. J. Med. Chem. 58 (15), 5942–5949. doi: 10.1021/acs.jmedchem.5b00561

PubMed Abstract | Crossref Full Text | Google Scholar