Phytochemical Compounds as Promising Therapeutics for Intestinal Fibrosis in Inflammatory Bowel Disease: A Critical Review

Abstract

Background/objective: Intestinal fibrosis, a prominent consequence of inflammatory bowel disease (IBD), presents considerable difficulty owing to the absence of licensed antifibrotic therapies. This review assesses the therapeutic potential of phytochemicals as alternate methods for controlling intestinal fibrosis. Phytochemicals, bioactive molecules originating from plants, exhibit potential antifibrotic, anti-inflammatory, and antioxidant activities, targeting pathways associated with inflammation and fibrosis. Compounds such as Asperuloside, Berberine, and olive phenols have demonstrated potential in preclinical models by regulating critical signaling pathways, including TGF-β/Smad and NFκB, which are integral to advancing fibrosis.

Results: The main findings suggest that these phytochemicals significantly reduce fibrotic markers, collagen deposition, and inflammation in various experimental models of IBD. These phytochemicals may function as supplementary medicines to standard treatments, perhaps enhancing patient outcomes while mitigating the adverse effects of prolonged immunosuppressive usage. Nonetheless, additional clinical trials are necessary to validate their safety, effectiveness, and bioavailability in human subjects.

Conclusions: Therefore, investigating phytochemicals may lead to crucial advances in the formulation of innovative treatment approaches for fibrosis associated with IBD, offering a promising avenue for future therapeutic development.

Keywords: IBD; TGF-beta; intestinal fibrosis; phytochemicals and health; polyphenols.

Figure 1

Activation of the components of the TGFβ/Smad canonical signaling pathway initiates the fibrosis process by inducing transcription of the downstream fibrotic genes. Abbreviations: α-SMA—alpha-smooth muscle actin, TIMP—tissue inhibitors metalloproteinases, N-Cad—Neural cadherin.

Figure 2

Activation of TGF-β stimulates NFκB and MAPK signaling pathways with the subsequent activation of the Wnt/β-catenin pathway. Abbreviations: TRAF—TNF receptor associated factor, TAK1—transforming growth factor-β activated kinase 1, MEKK1—mitogen-activated protein kinase kinase1, IKK—inhibitor of nuclear factor-κB (IκB) kinase, MKK—mitogen-activated protein kinase kinase, IKβ—I-kappaB kinase, ECM—extracellular matrix, EMT—epithelial–mesenchymal transition (↑—increased).

Figure 3

Activation and interaction of both canonical Wnt signaling and non-canonical Wnt/TGF-β. Abbreviations: LPR5/6—low density lipoprotein receptor-related proteins 5/6, FZD—seven-pass transmembrane receptor frizzled, CK1—casein kinase 1, APC—adenomatosis polyposis coli, GSK3β—glycogen synthase kinase 3β, DKK1—Dickkopf WNT signaling pathway inhibitor1, β-Cat—β-catenin, TCF/LEF—T cell factor/lymphoid enhancer factor, N-Cad—neural cadherin, E-Cad—Epithelial cadherin (↑—increased; ↓—decreased).

Figure 4

Interaction between non-canonical Wnt/β-catenin and TGFβ/Smad signaling pathways to stimulate the fibrogenesis process and transcription of the downstream fibrotic genes. Abbreviations: DKK1—Dickkopf WNT signaling pathway inhibitor 1, β-Cat—β-catenin, EMT—epithelial–mesenchymal transition, N-Cad—neural cadherin, E-Cad—epithelial cadherin. (↑—increased; ↓—decreased).

Figure 5

An overview of role of TGFβ in the pathogenesis of intestinal fibrosis. Additionally, ASP, Nobiletin, Olive phenols, TFA, and Huangqi decoction have an inhibitory effect on the MAPK pathway. Abbreviations: Rat sarcoma-small GTP-ase—Ras, Raf-1 proto-oncogene—Raf, mitogen-activated protein kinase kinase-1/2—MEK, extracellular signal-regulated kinases—ERK, phosphoinositide 3-kinase—PI3K, mammalian target of rapamycin—mTOR, epithelial–mesenchymal transition—EMT, phosphatase and tensin homolog—PTEN, tissue inhibitors metalloproteinases—TIMP, matrix metalloproteinases—MMP, collagen typeI alpha1/2—Col1A1/2 (↑—increased; ↓—decreased).