Herbal medicine beyond probiotics: Yiyi Fuzi Baijiang powder and the holistic regulation of gut microbiota in ulcerative colitis

Abstract

We read with great interest the study by Zhang et al on Yiyi Fuzi Baijiang powder (YFB), which exemplifies the power of modern methods to validate traditional Chinese medicine (TCM). The key insight is that YFB doesn’t merely alter “good” or “bad” bacteria but restores the gut microbiota’s holistic equilibrium. This is powerfully shown by its paradoxical reduction of anaerobic probiotics like Bifidobacterium, rectifying the diseased, hypoxic environment, causing their aberrant overgrowth. This challenges the conventional probiotic paradigm and underscores a core TCM principle: Herbal formulas treat disease by restoring the body’s overall functional balance. Future research should focus on the interplay between herbal components, intestinal oxygen, and microbial metabolites to further unravel this sophisticated dialogue.

Key Words: Yiyi Fuzi Baijiang powder; Ulcerative colitis; Gut microbiota; Network pharmacology; Short-chain fatty acids; Multi-omics integration; Nuclear factor kappa-B signaling pathway; Synergistic mechanism

Core Tip: Yiyi Fuzi Baijiang powder (YFB) represents a paradigm shift in treating ulcerative colitis. Unlike conventional probiotics, YFB restores gut ecosystem equilibrium via a dual pathway: Its compounds directly mitigate inflammation while normalizing the intestinal oxygen landscape. This rectifies the hypoxic environment, explaining the paradoxical reduction of overgrown anaerobes like Bifidobacterium as a sign of ecosystem recovery, not a drawback. Integrating multi-omics techniques reveals YFB’s holistic, synergistic mechanism. Future work should employ molecular dynamics and metabolite assays to further decipher this sophisticated system-rebalancing approach.

TO THE EDITOR

We read with great interest the article by Zhang et al[1], who combined gut microbiomics and network pharmacology to elucidate the mechanisms of Yiyi Fuzi Baijiang powder (YFB) in treating ulcerative colitis (UC). Their multi-omics approach provides a robust model for researching complex traditional medicine formulae. The finding that YFB restores the dynamic equilibrium of the gut ecosystem rather than unidirectionally promoting “beneficial” bacteria is particularly insightful and aligns with the holistic philosophy of traditional Chinese medicine (TCM).

THE PARADOX OF PROBIOTIC REGULATION: BEYOND SIMPLE “GOOD VS BAD” BACTERIA

The most striking finding of Zhang et al[1] is the demonstration that YFB’s therapeutic effect cannot be simplistically attributed to an increase in “beneficial” bacteria and a decrease in “harmful” ones. Instead, YFB appears to restore the dynamic equilibrium of the intestinal microecology. This is powerfully illustrated by its paradoxical regulation of anaerobic probiotics such as Bifidobacterium, Ruminococcus, and Enterorhabdus. In dextran sulfate sodium-induced UC mice, the relative abundance of these typically beneficial bacteria increased under disease conditions but decreased after YFB intervention. The authors reasonably hypothesize that this reflects a normalization of the intestinal environment: The hypoxic, inflammatory state in UC promotes the overgrowth of anaerobic bacteria, while YFB counteracts this by alleviating inflammation and improving tissue oxygenation, thereby reducing the niche for these organisms. This finding challenges the conventional probiotic paradigm, which often seeks to increase specific “good” bacteria maximally, and instead underscores a core TCM principle herbal formulae treat disease by restoring the body’s overall functional balance[2,3], with the gut ecosystem being a critical target of this holistic regulation[4,5].

First and foremost, we wish to delve deeper into one of the most intriguing and seemingly paradoxical findings: The significant increase in the anaerobic probiotics Ruminococcus, Enterorhabdus, and Bifidobacterium in dextran sulfate sodium-induced mice and their subsequent decrease following YFB intervention. The authors provide a compelling hypothesis that dextran sulfate sodium-induced hypoxia created a favorable niche for these anaerobic bacteria and that YFB’s anti-inflammatory and anti-oxidative effects (e.g., upregulating superoxide dismutase) improved the intestinal oxygen environment, thereby suppressing their overgrowth.

However, it raises a critical follow-up question: Does the reduction of these specific probiotics represent a genuine therapeutic outcome, or could it potentially hinder long-term mucosal recovery? While their overgrowth in a dysbiotic, hypoxic environment may be a consequence of disease, Bifidobacterium and others are well-established for their role in producing short-chain fatty acids (SCFAs) like butyrate[6], which is crucial for epithelial energy supply and anti-inflammatory responses[7,8]. Could the YFB-induced reduction of these genera inadvertently delay the full restoration of a healthy microbiome capable of sustaining mucosal homeostasis? This is a question worth pondering. It is plausible that YFB first acts through direct molecular mechanisms to “extinguish the fire” (control inflammation), followed by microbial ecological regulation to “rebuild the home” (restore microbiota balance). After inflammation is effectively brought under control, a microbial community reshaped by YFB, which is more resilient and includes normalized levels of Bifidobacterium and increased abundance of Lachnospiraceae, will be better equipped to perform its functions, thereby supporting long-term mucosal homeostasis.

Lastly, we propose that future studies could greatly benefit from directly measuring SCFA concentrations (e.g., butyrate, acetate) and intestinal oxygen levels in the colonic lumen. Correlating these direct measurements with the observed microbial shifts would powerfully validate the “oxygen hypothesis” and clarify the functional impact of reducing these anaerobic probiotics. Furthermore, it would be fascinating to investigate if YFB’s action ultimately promotes a more balanced, resilient microbial community where the functions of these probiotics (SCFA production) are preserved or even enhanced, even if their relative abundance is normalized from a state of hypoxic overgrowth.

In conclusion, the work by Zhang et al[1] is commendable. Their observation forces us to move beyond a simplistic “more probiotics are better” paradigm and to appreciate the nuanced restoration of microbial function and equilibrium over mere composition. Addressing the role of oxygen and SCFAs will be the next critical step in fully unraveling the sophisticated mechanism by which YFB achieves its therapeutic effect.

THE PRIMARY MECHANISM DEBATE: GUT MICROBIOTA MODULATION VS DIRECT MOLECULAR TARGETING

The sophisticated multi-omics approach employed by Zhang et al[1] inevitably raises a fundamental question: Is YFB’s therapeutic effect primarily mediated through gut microbiota remodeling or through direct interactions between its bioactive compounds and host signaling pathways? A critical examination of their data suggests these are not mutually exclusive mechanisms, but rather interconnected components of YFB’s holistic therapeutic strategy.

The microbiota modulation hypothesis gains substantial support from the 16S rDNA sequencing data, which demonstrate that YFB administration significantly alters microbial community structure. The restoration of β diversity and specific taxonomic changes, particularly the reduction of pathogenic bacteria (e.g., Turicibacter and Clostridium_sensu_stricto_1), and the promotion of beneficial bacteria (e.g., unclassified_f_Lachnospiraceae), strongly suggest that microbial remodeling is a crucial mechanism. The functional predictions derived from microbiome analysis further support this perspective, showing significant alterations in key metabolic pathways.

On the other hand, network pharmacology and molecular docking results also provide evidence for direct molecular mechanisms. The identification of 52 common targets between the components of YFB and pathways related to UC, along with the verification of binding scores greater than 5.0 between key compounds and regulatory proteins, indicates that the active ingredients of YFB can modulate host signaling pathways. However, although these docking scores demonstrate potential binding affinity, the evidence remains at the static structural level.

To enhance the robustness of molecular-level evidence, the introduction of molecular dynamics simulations would significantly strengthen the proof of direct target binding[9]. While docking studies primarily assess static binding affinity, they cannot capture the dynamic stability of protein-ligand complexes under physiological conditions[10]. Conducting molecular dynamics simulations over 100-200 nanoseconds would enable researchers to evaluate binding stability and interaction persistence, and obtain more accurate binding free energy values using methods such as molecular mechanics energies combined with the Poisson-Boltzmann or generalized Born and surface area continuum solvation, which correlate better with experimental data than docking scores alone[11,12]. For the key compounds of YFB and their targets, molecular dynamics simulations would be particularly helpful in validating the biological relevance of docking predictions. Given that these compounds need to modulate inflammatory signaling pathways, demonstrating stable target binding through dynamic simulations would provide crucial evidence for their proposed mechanisms of action. The addition of molecular dynamics simulations would establish a more comprehensive validation pipeline: Starting with network pharmacology predictions, followed by initial screening through molecular docking, and culminating with dynamic validation via molecular dynamics simulations. This approach would substantially strengthen the persuasiveness of direct molecular targeting as a complementary mechanism to microbial regulation.

Rather than viewing these mechanisms as competitive, the enhanced evidence would support an integrated model of synergistic interaction, where both processes operate in coordination. The gut microbiota serves as both a target and a mediator of the effects of YFB, with the herbal compounds directly regulating host inflammatory pathways and creating an intestinal environment conducive to the growth of beneficial microorganisms. This bidirectional relationship is particularly evident in the paradoxical regulation of anaerobic probiotics, where the reduction in Bifidobacterium following YFB powder treatment may result from improved intestinal oxygenation due to reduced inflammation, which itself might be initiated by direct molecular targeting of inflammatory pathways. The integration of 16S rDNA sequencing, network pharmacology, and molecular docking reveals a synergistic model where microbial remodeling and direct molecular targeting coexist as complementary mechanisms. Furthermore, the systemic impact of YFB is likely not confined to the nuclear factor kappa-B pathway alone; its holistic nature suggests a broader regulatory scope that may encompass other critical pathways in UC pathogenesis, such as the hypoxia-sensing hypoxia inducible factor-1α and the nutrient-sensing mammalian target of rapamycin signaling axes, which are intimately linked to gut barrier integrity, immune metabolism, and the inflammatory cascade. Future work probing these additional dimensions will be crucial to fully appreciate the system-level therapeutic strategy of YFB.

The therapeutic implications of this integrated mechanism are significant. The combination of immediate anti-inflammatory effects achieved through direct pathway modulation and long-term ecological stabilization via microbiome restoration represents a comprehensive treatment strategy that aligns with the fundamental principle of TCM to restore systemic balance. Future research combining molecular dynamics simulations with microbial ecology analysis will provide more robust evidence for this complex, multi-level therapeutic action. However, current relevant clinical studies are indeed very sparse, and the future design of randomized, double-blind, placebo-controlled clinical trials, which collect patient feces for metagenomic, metabolomic, and serum inflammatory factor detection, will further establish the bridge between YFB’s basic mechanistic discoveries and clinical practice.

CONCLUSION

The study by Zhang et al[1] represents a significant advancement in bridging TCM with modern multi-omics approaches, offering a nuanced understanding of YFB therapeutic mechanisms in UC. Their work compellingly demonstrates that YFB operates not through simplistic microbial manipulation but by restoring dynamic equilibrium to the gut ecosystem, which aligns with the holistic principles of TCM. The paradoxical regulation of anaerobic probiotics, such as Bifidobacterium and Ruminococcus, underscores the complexity of microbiome-host interactions and highlights the limitations of conventional “good vs bad” bacteria paradigms. By integrating 16S rDNA sequencing, network pharmacology, and molecular docking, the authors reveal a synergistic model where microbial remodeling and direct molecular targeting coexist as complementary mechanisms. However, to further validate these interactions, future studies should incorporate molecular dynamics simulations to assess binding stability under physiological conditions, with direct measurements of SCFAs and intestinal oxygen levels. Such approaches would clarify the functional impact of YFB-induced microbial shifts and strengthen the evidence for its multi-target actions. Ultimately, this research not only deepens our appreciation of TCM’s systemic therapeutic strategies but also sets a precedent for integrating traditional wisdom with contemporary scientific rigor to address complex diseases like UC.