From Dysbiosis to Precision Medicine: Targeting the Microbial–Metabolic Axis in IBD Management
核心洞察
Global IBD burden reached approximately 4.9 million cases in 2019, with China and the United States reporting the highest numbers, while newly industrialized regions in Asia, South America, and Africa are experiencing rapid incidence increases.
Intestinal dysbiosis in IBD is characterized by reduced Firmicutes and SCFA-producing bacteria alongside increased pro-inflammatory bacteria, driving impaired epithelial barrier function and chronic mucosal inflammation.
Emerging microbiome-targeted therapies including fecal microbiota transplantation, engineered probiotics, bacteriophage therapy, and helminth-based immunomodulation aim to restore the microbial-metabolic axis rather than merely suppressing immune responses.
Inflammatory bowel disease (搜索) (IBD), encompassing ulcerative colitis (搜索) (UC) and Crohn's disease (搜索) (CD), represents a chronic relapsing inflammatory condition of the gastrointestinal tract that has imposed a considerable and increasing global health burden. In 2019, approximately 4.9 million cases of IBD were reported worldwide, with the highest number of cases in China (911,405 cases; 66.9 per 100,000) and the United States (762,890 cases; 245.3 per 100,000). According to the Global Burden of Disease (GBD) 2021 analysis, approximately 3.83 million people were living with IBD worldwide, with 375,140 new cases and 42,423 deaths, resulting in 1.51 million disability-adjusted life years (DALYs). A recent comprehensive review published in Frontiers in Cellular and Infection Microbiology integrates the pathomechanistic implications of the microbiome-metabolic axis in gut homeostasis and its disruption in IBD, while evaluating emerging therapeutic strategies aimed at restoring this axis.
Global Epidemiology and Shifting Disease Patterns
IBD has emerged as a global health problem with increasing prevalence worldwide, especially in newly industrialized regions such as Asia, despite initially being perceived as a predominantly Western disease. Epidemiological studies reveal a significant geographic shift in the distribution of IBD, with an instantaneous increase now observed in emerging industrialized countries in Asia, South America, Eastern Europe, and Africa. A large-scale study reviewing data from more than 500 population-based studies across 82 regions over more than one hundred years found that IBD development traverses through various epidemiologic stages: emergence, accelerating incidence, compounding prevalence, and a potential future fourth stage involving prevalence stability.
Industrialized areas are now progressing toward incidence stabilization, but prevalence rises due to demographic aging, while newly industrialized regions are currently witnessing fast-rising incidences. Early industrialized countries are expected to transition toward prevalence equilibrium within the next decade, with more than 1% of their populations projected to live with IBD. In the Asian population, incidence is highest in the 30–34 age group, while prevalence peaks in the 45–49 age group.
Quantitative evidence indicates that smoking increases Crohn's disease (搜索) risk by approximately 2.0-fold, while ulcerative colitis (搜索) risk increases by nearly 1.2-fold. Early-life antibiotic exposure is associated with a 2.0-fold higher risk of IBD development, and adherence to a Western dietary pattern confers nearly a 2-fold increased risk. Conversely, breastfeeding reduces concomitant risk factors by 20–25%, and Mediterranean dietary adherence lowers progression risk by 20–30%.
Microbial Dysbiosis and Inflammatory Imbalance
Patients with IBD commonly exhibit intestinal dysbiosis, generally characterized by reduced levels of beneficial Firmicutes and increased presence of opportunistic pathogenic microorganisms. The gut microbiota of individuals with IBD shows a characteristic compositional shift with greater prevalence of Bacteroidetes and Proteobacteria, including increased abundance of E. coli, while there is a notable reduction in Firmicutes genera such as Lactobacillus compared to healthy controls.
SCFA-producing bacteria, including Faecalibacterium prausnitzii (搜索), are markedly diminished in individuals with IBD. This reduction coincides with a substantial decrease in the production of short-chain fatty acids, particularly propionic acid, which are crucial for their anti-inflammatory properties. Adherent-invasive E. coli (AIEC) has been implicated in both CD and UC, with the strain E. coli p19A shown to secrete α-hemolysin that induces apoptosis in dendritic cells and promotes expression of pro-inflammatory cytokines including IL-6, IL-23, and TNF-α (搜索).
At the epithelial interface, the AhR-NR4A1 signaling pathway represents a fundamental mechanism promoting epithelial homeostasis, with downstream transcriptional upregulation of claudin-4, occludin, and ZO-1 promoting junction formation and inhibiting paracellular permeability. Recent studies in pediatric UC showed that lower baseline gut bacterial diversity characterized by fewer butyrate-producing bacteria and an increase in oral-associated bacteria like Veillonella parvula is strongly associated with future relapse.
Diet as a Therapeutic Signal
Among modifiable environmental factors, diet has emerged as a critical regulator of intestinal inflammation. The prospective DELECTABLE study demonstrated the feasibility of implementing the Crohn's Disease (搜索) Exclusion Diet (CDED), the whole-food additive-free diet (WFD), and the low-sulphur plant-based diet in clinical practice, with high patient adherence and satisfaction over 12 weeks. Both CDED and WFD resulted in significant improvement in quality of life (p < 0.001). In patients with CD, CDED resulted in significant reduction in objective inflammatory indices, including C-reactive protein and fecal calprotectin, as well as CD Activity Index scores (p < 0.045).
A randomized controlled trial evaluating a Mediterranean and low FODMAP diet combination with partial enteral nutrition in active UC showed significant reduction in disease activity index compared with baseline (p < 0.001) and with the control diet (p = 0.043), along with marked improvements in quality of life (p < 0.001) and significant reduction in high-sensitivity CRP (p < 0.01).
Probiotics, SCFAs, and Microbiome-Targeted Interventions
Probiotics have emerged as a promising therapeutic strategy, with strains including Saccharomyces boulardii, lactobacilli, and bifidobacteria demonstrating the ability to modulate the inflammatory cytokine profile in IBD patients. Probiotic administration leads to reduction in pro-inflammatory markers like TNF-α (搜索), IL-8, and IFN-γ while elevating anti-inflammatory cytokines TGF-β and IL-10. Genetically engineered probiotics represent a novel targeted delivery platform; a systematic review of twelve preclinical studies demonstrated that genetically modified probiotics engineered to produce IL-10 exhibited superior efficacy in attenuating intestinal inflammation compared to non-recombinant counterparts.
Short-chain fatty acids (SCFAs)—acetate, propionate, and butyrate—modulate their functions primarily through G protein-coupled receptors (GPR43/FFAR2, GPR41/FFAR3, GPR109A). A randomized study in UC patients supplemented with 600 mg/kg of sodium butyrate demonstrated effective decrease of disease severity, supported by significant decrease in the partial Mayo score and lowered systemic inflammatory markers including erythrocyte sedimentation rate (ESR) and neutrophil-to-lymphocyte ratio (NLR).
Fecal Microbiota Transplantation
Fecal microbiota transplantation (FMT) has undergone a significant shift in perception, transitioning from a limited, evidence-deficient alternative therapy to a potentially effective first-line treatment option. A meta-analysis of four randomized controlled trials in UC demonstrated significantly higher remission rates with FMT, with 28% (39/140) of patients achieving remission compared to 9% (13/137) in the placebo group. A larger systematic review and meta-analysis of 27 studies comprising 596 adult and pediatric IBD patients reported a clinical remission rate of 28.8% (132/459) and an overall clinical response rate of 53% (241/459). In Crohn's disease (搜索), a study of 174 patients found a remission rate of 20.1% and a response rate of 43.7% following FMT via mid-gut routes.
Bacteriophage and Helminth-Based Therapies
The gut virome, dominated by bacteriophages, plays a crucial role in maintaining gut homeostasis. Specific alterations in IBD include increased phages targeting Faecalibacterium prausnitzii (搜索), enrichment of Caudovirales, Picornaviridae, and Anelloviridae, and reduced Microviridae abundance. Studies targeting adherent-invasive Escherichia coli and Klebsiella pneumoniae have shown significant pathobiont depletion in DSS-induced colitis models and attenuation of histopathological and clinical disease severity following phage therapy intervention.
Helminth-mediated immunomodulation represents another emerging strategy. Studies involving Trichuris suis ova have shown symptomatic improvement in Crohn's disease (搜索), while Nippostrongylus brasiliensis-derived extracellular vesicles have demonstrated potent immunomodulatory effects in reducing colitis-associated inflammation and cytokines such as IL-6, IL-1β, IFN-γ, and IL-17A.
Machine Learning and Multi-Omics Integration
Machine learning algorithms integrating clinical data and biomarkers have demonstrated significant efficacy (AUC ~0.80) in diagnosing non-invasive IBD. Multi-omics integration has revealed a Crohn's disease (搜索)-specific 20-species microbial signature with high diagnostic performance (AUC = 0.94), together with functional perturbations in microbial fermentation pathways explaining butyrate depletion. Global multi-omics integration has identified consistently dysregulated species and enabled discovery of globally validated biomarkers with AUROC values ranging from 0.92 to 0.98.
Despite these advancements, several obstacles hinder clinical implementation, including retrospective design of training datasets, over-reliance on internal validation methods, variability between microbiome sampling and sequencing protocols, and differences between study cohorts affecting model generalizability.
The review concludes that the fusion of microbiome science and AI-powered precision medicine represents a promising frontier in IBD management, with the potential to move beyond disease management toward correction of the immunomicrobial imbalance, leading to true disease modification.