Novel Insights into the Pathogenesis of Inflammatory Bowel Diseases

Abstract

Inflammatory bowel diseases (IBDs), encompassing Crohn's disease and ulcerative colitis, are complex chronic disorders characterized by an intricate interplay between genetic predisposition, immune dysregulation, gut microbiota alterations, and environmental exposures. This review aims to synthesize recent advances in IBD pathogenesis, exploring key mechanisms and potential avenues for prevention and personalized therapy. A comprehensive literature search was conducted across major bibliographic databases, selecting the most recent and impactful studies on IBD pathogenesis. The review integrates findings from multi-omics analyses, single-cell transcriptomics, and longitudinal cohort studies, focusing on immune regulation, gut microbiota dynamics, and environmental factors influencing disease onset and progression. Immune dysregulation, including macrophage polarization (M1 vs. M2) and Th17 activation, emerges as a cornerstone of IBD pathogenesis. Dysbiosis, as a result of reduced alpha and beta diversity and overgrowth of harmful taxa, is one of the main contributing factors in causing inflammation in IBD. Environmental factors, including air and water pollutants, maternal smoking, and antibiotic exposure during pregnancy and infancy, significantly modulate IBD risk through epigenetic and microbiota-mediated mechanisms. While recent advances have supported the development of new therapeutic strategies, deeply understanding the complex dynamics of IBD pathogenesis remains challenging. Future efforts should aim to reduce the burden of disease with precise, personalized treatments and lower the incidence of IBD through early-life prevention and targeted interventions addressing modifiable risk factors.

Keywords: air pollution; exposome; genetics; gut microbiota; immune system; inflammatory bowel disease; pathogenesis; water pollution.

Figure 1

Dysregulated immune responses contributing to inflammation and tissue damage in IBD pathogenesis. Epithelial barrier disruption and neutrophil recruitment trigger the release of S100A9, which activates Toll-like receptor 4 (TLR4) signaling in M1 macrophages. These macrophages produce pro-inflammatory cytokines (TNFα, IL-6, IL-12, IL-1β), promoting inflammation and reducing phagocytosis (A). Altered production and glycosylation of mucin molecules contribute to amplify inflammation via NFkB (B). Dysregulated T-cell responses include reduced regulatory T cell (Treg) activity (C) and increased Th1, Th17, and mixed Th1/Th17 responses, producing IFNγ, TNFα, IL-17, and IL-22. These cytokines induce recruitment of inflammatory cells and expression of chemokines (CCL20, GZMA, ITGA1, etc.), amplifying tissue damage (D). NK cells with impaired mTORC1 signaling show reduced cytotoxicity, further aggravating inflammation (E). Innate lymphoid cells (ILC3) produce IL-17 and IL-22, enhancing CD8⁺ T cell activation and exacerbating tissue injury (F).

Figure 2

The impact of gut microbiota dysregulation on IBD pathogenesis. Reduced microbial diversity, depletion of beneficial taxa such as Faecalibacterium prausnitzii and Roseburia intestinalis, and enrichment of pathogenic taxa like Proteobacteria are the core features of gut dysbioisis. This disruption impairs gut permeability by reducing key amino acids and altering microbial composition, allowing microbial components to penetrate the intestinal barrier (A). Translocated microbial peptides and metabolites, such as flagellins and LPS, enter systemic circulation, triggering IgG production and amplifying inflammation (B). Immune system activation involves increased inflammatory cytokine production following exposure to microbial products, as observed in germ-free mice receiving fecal transplants from IBD patients. Pathogenic bacteria, including Klebsiella spp. and Ruminococcus gnavus, further stimulate macrophages and dendritic cells to release pro-inflammatory cytokines like IL-1β, IL-18, and TNF (C). Additionally, dysbiosis disrupts TRPV1⁺ nociceptor signaling, reducing levels of the anti-inflammatory mediator Substance P. This impairment compromises vagus nerve-mediated tissue repair, enhances inflammation, and deranges pain perception (D).

Figure 3

Environmental exposures contributing to IBD pathogenesis across the lifespan. The figure highlights risk factors at different life stages—childhood exposure, including maternal smoking, lack of breastfeeding, and reduced microbial diversity associated with the “hygiene theory”; cumulative lifetime exposure, such as antibiotic use, infections, stressful events, and urban living; and adulthood exposure, including air and water pollution, smoking, Western diets, and sleep disturbances. These exposures may influence immune responses and gut microbiome composition, increasing susceptibility to inflammation and IBD development.