This editorial refers to "Effects and mechanism of Bifidobacterium on intestinal inflammation resulting from deoxycholic acid-induced M1 polarization of macrophages" by Yang et al, 2026; https://doi.org/10.3748/wjg.v32.i6.113010.
INTRODUCTION
This editorial comments on the recently published manuscript by Yang et al[1] in the World Journal of Gastroenterology, which investigates the mechanistic link between a high-fat diet (HFD), the gut microbial metabolite deoxycholic acid (DCA), macrophage polarization, and colonic inflammation, while evaluating the protective role of Bifidobacterium. In this study with mouse model, macrophage populations were characterized using F4/80 as a pan-macrophage marker, inducible nitric oxide synthase as a marker for pro-inflammatory (M1-like) macrophages, and CD206 as a marker for anti-inflammatory (M2-like) macrophages[1]. The investigation represents a significant contribution to understanding how dietary patterns perturb gut homeostasis to initiate inflammation. By employing a logical sequence of interventions in a mouse model, the authors delineate a clear pathogenic axis: A HFD alters the gut microbiota to elevate levels of the secondary bile acid DCA, which subsequently promotes the infiltration and pro-inflammatory M1 polarization of colonic macrophages, culminating in tissue damage and the expression of cytokines like tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-1β. The demonstration that both antibiotic (vancomycin) and probiotic (Bifidobacterium) interventions can break this chain, primarily by reducing DCA, offers a compelling narrative for microbial metabolite-driven immunopathology. This work successfully focuses scientific inquiry on the “gut microbiota-DCA-macrophage” nexus in diet-induced colitis. However, to fully realize the therapeutic potential implied by these findings, we further reviewed the mechanisms of macrophage polarization, and its role in metabolic disorder, and inflammatory bowel diseases (IBDs), and conducted a deeper exploration of the mechanistic intricacies and contextual limitations.
FUNDAMENTAL ASPECTS OF MACROPHAGES POLARIZATION
Macrophages are versatile immune cells that play a central role in maintaining tissue homeostasis, defending against pathogens, and regulating inflammatory responses[2-4]. Their functional plasticity is largely governed by a process known as polarization[5,6], through which macrophages adopt distinct phenotypes in response to microenvironmental cues. The two classic polarization states are the pro-inflammatory M1 phenotype and the anti-inflammatory M2 phenotype[7,8].
M1 macrophages are typically activated by interferon-gamma and lipopolysaccharide (LPS). They produce high levels of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6, and generate reactive oxygen and nitrogen species to eliminate pathogens[9]. M1 polarization is associated with Th1 immune responses and is crucial for host defense but can also contribute to tissue damage if dysregulated[10,11]. In contrast, M2 macrophages are induced by cytokines such as IL-4, IL-10, and IL-13. They produce anti-inflammatory mediators like IL-10 and transforming growth factor-beta (TGF-β), promote tissue repair, angiogenesis, and extracellular matrix remodeling. M2 macrophages are involved in resolving inflammation, wound healing, and maintaining immune tolerance[12,13].
The balance between M1 and M2 polarization is essential for immune homeostasis. Dysregulation of this balance is implicated in a wide range of diseases including in metabolic disorders, colitis, and IBDs.
MACROPHAGE POLARIZATION IN METABOLIC DISORDERS
In metabolic disorders like metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH), macrophage polarization is a pivotal process connecting metabolic stress to tissue inflammation and fibrosis. The shift from a simple fatty liver to inflammatory MASH involves hepatic macrophages adopting a pro-inflammatory, M1-like state. This polarization is triggered by multiple signals, including exosomal microRNAs (e.g., miR-192-5p[14]) from damaged hepatocytes and metabolites like lactate, which can epigenetically promote M2-associated genes via histone lactylation, revealing a complex feedback mechanism[15].
Key regulators of this inflammatory switch have been identified. The transcription factor XBP1 drives M1 polarization, and its macrophage-specific deletion reduces inflammation and fibrosis[16,17]. Similarly, the glycoprotein CD44 promotes inflammatory activation, and its deficiency enhances protective M2 polarization[18]. Recruitment of inflammatory monocytes, mediated by CCR2, is another critical node, with CCR2/CCR5 antagonism showing therapeutic benefit[19]. Disruption of the gut-liver axis, such as through CX3CR1 deficiency, also exacerbates disease by increasing hepatic inflammation[20].
Therapeutically, strategies aim to reprogram macrophages toward an anti-inflammatory state. Aging worsens MASH by promoting M1 polarization[21], while chronic inflammation impairs the liver's regenerative capacity[22]. Repurposed drugs like metformin can mitigate disease progression by altering macrophage subsets, reducing pro-inflammatory populations in models of MASLD-associated cancer[6].
In summary, macrophage polarization is a central mechanism in MASLD/MASH progression, where metabolic insults drive hepatic macrophages toward a pro-inflammatory M1 phenotype. This shift is regulated by specific signals (exosomal miRNAs, lactate), intracellular regulators (XBP1, CD44), and recruitment pathways (CCR2). Disruption of the gut-liver axis further fuels inflammation. Therapeutic approaches focus on reversing this polarization, with evidence showing that targeting recruitment (e.g., CCR2 inhibition) or reprogramming macrophages (e.g., with metformin) can reduce inflammation and fibrosis, highlighting macrophages as a key therapeutic target.
MACROPHAGE POLARIZATION IN IBD
In IBD, persistent M1 polarization drives chronic inflammation and tissue destruction[23,24]. Infiltrating macrophages exhibit an M1-like phenotype, secreting TNF-α and IL-1β that damage the epithelium[25]. Conversely, promoting M2 polarization ameliorates experimental colitis by enhancing tissue repair. In metabolic inflammation, HFD-induced dysbiosis elevates DCA, which promotes M1 polarization in colonic macrophages, exacerbating colitis. High fructose consumption may amplify this by disrupting the intestinal barrier and increasing LPS translocation, promoting metabolic endotoxemia and further favoring M1 polarization.
Under the combined impact of HFD and DCA, the phenotypic balance of intestinal macrophages normally in a tolerogenic, homeostatic state is broken, tilting toward a pro-inflammatory direction. DCA drives M1 polarization through key mechanisms. First, the DCA-S1PR2-NLRP3 inflammatory cascade is a clearly elucidated pathway where DCA binding to S1PR2 induces lysosomal rupture, cytoplasmic cathepsin B release, and subsequent NLRP3 inflammasome activation, leading to IL-1β maturation and release[26]. Second, a synergistic effect of TLR4 and DCA occurs via a “double hit” mechanism: HFD-induced gut leakiness elevates LPS, which primes macrophages via TLR4/NF-κB, upregulating NLRP3 and pro-IL-1β. DCA then acts as the second signal to trigger full inflammasome activation[27]. Third, suppression of anti-inflammatory TGR5/FXR signaling occurs as pro-inflammatory S1PR2 signals overwhelm the anti-inflammatory TGR5 pathway, while HFD-induced dysbiosis and inflammation downregulate protective FXR signaling, removing brakes on inflammation[28].
Polarized M1 macrophages undergo a metabolic shift to aerobic glycolysis, producing high levels of TNF-α, IL-1β, IL-6, and reactive species, which contribute to tissue damage in colitis thus providing potential therapeutic targets[9,29,30]. In contrast, M2 macrophages, induced by IL-4, IL-10, and IL-13, produce anti-inflammatory mediators like IL-10 and TGF-β to promote tissue repair and resolve inflammation[12,13]. Interventions like Bifidobacterium can reverse HFD-related colitis by harnessing macrophage polarization through multi-target strategies: Upstream interception by inhibiting DCA-producing flora; midstream blockade by inhibiting TLR4/NF-κB pathways; downstream remodeling by secreting metabolites (e.g., acetate, lactate) to induce M2 polarization via STAT6/PPARγ activation and histone lactylation[31-33]; and barrier reinforcement by synergizing with epithelial repair to cut off LPS influx.
These studies highlighted the specific molecular pathways (S1PR2-NLRP3, TLR4 synergy, TGR5/FXR suppression) by which HFD and DCA drive M1 polarization and elaborates on the multi-target strategies (upstream, midstream, downstream) through which interventions like Bifidobacterium might work, which the original study did not fully delineate and further studies with more specific molecular targets such as FXR/TGR5 are recommended to explore this topic.
ANALYSIS OF THE PRIMARY RESEARCH: EXPERIMENTAL MERITS AND EXISTING GAPS
The experimental architecture of Yang et al's study[1] is a key strength, enabling the dissection of complex host-microbe interactions. The sequential use of HFD to induce dysbiosis, vancomycin to selectively deplete gram-positive bacteria and lower DCA, and exogenous DCA supplementation to restore inflammation establishes a robust causal relationship. This approach effectively isolates DCA from the myriad of other HFD-induced changes. The inclusion of Bifidobacterium supplementation then provides a proof-of-concept that a microbial intervention can therapeutically target this specific metabolite-driven pathway.
Despite this elegant design, the study appropriately underscores two fundamental challenges in translational microbiome science. Firstly, the efficacy of the intervention was context-dependent; Bifidobacterium failed to fully restore the gut microbial diversity that was disrupted by vancomycin[1]. This observation is crucial, as it highlights that the success of probiotic therapies is not absolute but is contingent upon the baseline ecological state of the resident microbiota, which is influenced by prior antibiotic exposure, diet, and host genetics. Secondly, while the data strongly correlate Bifidobacterium supplementation with reduced DCA levels and improved outcomes, the direct molecular mechanism remains a “black box”. The authors reasonably hypothesize about the role of bacterial bile salt hydrolase activity, but this was not experimentally verified[1]. Furthermore, the reduction of DCA is likely only one component of Bifidobacterium's protective effect, which probably involves a broader network of immunomodulatory signals that directly engage host immune cells like macrophages[34,35]. Moreover, the enzymatic activity of bacteria may modulate the bile acid pool, these mechanisms remain unverified experimentally and a significant gap in the current understanding.
ELABORATING THE MECHANISTIC NETWORK: SYNERGISTIC PATHWAYS OF BIFIDOBACTERIUM-MEDIATED MACROPHAGE REGULATION
The protection afforded by Bifidobacterium in HFD-induced colitis is best understood not as a single-action therapy but as a multi-pronged strategy that synergistically corrects the dysregulated macrophage response. The pathway highlighted by Yang et al[1], reduction of the pro-inflammatory ligand DCA, is a pivotal upstream event. DCA acts as a potent inflammatory signal in macrophages, primarily by activating the S1PR2, which triggers NF-κB and ERK1/2 signaling, and by promoting NLRP3 inflammasome assembly, leading to IL-1β maturation[27,36]. By diminishing the luminal and tissue concentration of DCA, Bifidobacterium directly removes this major driver of M1 polarization.
Concurrently and independently, Bifidobacterium engages at least two other major immunomodulatory pathways that actively promote an anti-inflammatory milieu. A primary mechanism is the production of microbial metabolites, particularly short-chain fatty acids (SCFAs) like acetate and lactate. These metabolites are not merely waste products but key signaling molecules. TLR237 and SCFAs such as butyrate function as histone deacetylase inhibitors, epigenetically reprogramming macrophage gene expression toward an M2 phenotype[35]. They also act as agonists for host G-protein-coupled receptors (e.g., GPR43, GPR109a), signaling that suppresses NF-κB activity and induces the production of anti-inflammatory IL-10[34,35]. Notably, lactate has recently been shown to induce a novel form of epigenetic regulation and histone lactylation, that can directly promote the expression of genes involved in wound healing and M2-like functions[15].
In parallel, Bifidobacterium engages in direct molecular dialogue with the host immune system. Through structural components interacting with pattern recognition receptors such as TLR2 on epithelial cells and antigen-presenting cells, certain Bifidobacterium strains can induce a state of immunological tolerance[36]. This signaling can promote the differentiation of regulatory T cells and the production of IL-10, thereby shaping a mucosal environment that favors the alternative activation of macrophages toward an M2, tissue-reparative phenotype[12,13].
The power of Bifidobacterium as an intervention likely lies in the synergy of these pathways. The reduction of DCA (pathway 1) eliminates a key inflammatory trigger. The production of SCFAs (pathway 2) and the engagement of tolerogenic immune signaling (pathway 3) then actively push macrophage polarization toward a resolution program while also reinforcing epithelial barrier integrity. This integrated action explains the significant therapeutic effect observed, which likely surpasses what could be achieved by targeting any single node in this network.
BROADER RELEVANCE: THE AXIS IN INTESTINAL INFLAMMATORY DISEASE
The mechanistic cascade elucidated by Yang et al[1], dietary insult - dysbiosis - pathogenic metabolite (DCA) - macrophage dysregulation - inflammation, provides a paradigmatic framework with relevance extending beyond experimental HFD-colitis to human IBD. In conditions like Crohn’s disease and ulcerative colitis, a chronic imbalance in macrophage polarization, skewed toward a pro-inflammatory M1 state, is a well-established feature of disease pathology that correlates with tissue destruction and impaired healing[23,25].
While the initial triggers in IBD are multifactorial, involving genetic susceptibility and aberrant immune responses, environmental factors like diet can act as potent disease modifiers by engaging the same axis. A Western-style diet high in fats may exacerbate or perpetuate inflammation in susceptible individuals by enriching for DCA-producing bacteria and elevating this pro-inflammatory metabolite, thereby fueling the M1 macrophage response[15,22]. Consequently, the therapeutic strategy demonstrated by Yang et al[1] using a probiotic to modulate a specific microbial metabolite and rebalance macrophage polarization, holds significant translational promise. It suggests that adjunctive microbiome-targeted therapies, designed to dampen pro-inflammatory metabolite production and promote anti-inflammatory signals, could be beneficial in managing intestinal inflammation where macrophage phenotype is a central pathological determinant[29].
TRANSLATIONAL ROADMAP AND CONCLUDING PERSPECTIVE
The research by Yang et al[1] provides a strong preclinical foundation for targeting the “gut microbiota-DCA-macrophage” axis. To translate this into clinical benefit, a concerted effort is required. Future work must first validate these mechanisms in human subjects, correlating fecal and serum bile acid profiles with macrophage phenotypes in intestinal biopsies and clinical disease activity. Secondly, well-designed clinical trials are needed to assess the efficacy of specific, mechanism-based probiotics (or their defined products, “postbiotics”) in patient populations with diet-associated intestinal complaints or as adjuncts in IBD. Finally, developing predictive biomarkers, such as specific microbial metabolic signatures or host gene expression profiles in macrophages, will be essential to stratify patients and personalize these interventions.
CONCLUSION
In conclusion, Yang et al[1] have skillfully identified and validated a critical pathway in diet-induced colitis, centering on DCA as a microbial mediator of macrophage dysfunction. Their work shifts the therapeutic focus toward microbial metabolite modulation and immune cell reprogramming. Expanding on this foundation by deciphering the precise molecular mechanisms of probiotic action and testing their efficacy in relevant human contexts will be the crucial next steps in harnessing the gut microbiome to treat intestinal inflammatory diseases.
Peer review: Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Gastroenterology and hepatology
Country of origin: China
Peer-review report’s classification
Scientific quality: Grade B, Grade B
Novelty: Grade B, Grade B
Creativity or innovation: Grade B, Grade B
Scientific significance: Grade B, Grade B
P-Reviewer: Jin Y, PhD, Associate Chief Physician, Professor, China; Kieliszek K, Academic Fellow, Professor, Poland S-Editor: Lin C L-Editor: A P-Editor: Yu HG
