Written by Nick Trompeter, Ph.D., Cole Toohey, Payton Olson, Peter Li, and Ken Dorko.
Pathophysiology: Inflammatory Bowel Disease alters homeostasis.
Histological staining of primary human intestinal crypt cells differentiated as monolayer on 96-well transwell inserts. Healthy donor HI230007, left, exhibit characteristic columnar formation after 7 days in culture. The monolayer on the right, from donor HI230009 (Crohn's Disease), displays a thin monolayer, indicating a diseased phenotype.
While the intestine absorbs and digests food, it must also serve as a protective barrier against food-borne pathogen, and the microbiome residing within the mucosal barrier. Thus, dysfunction and/or disruption of the intestinal barrier elicits wide-ranging effects on whole-system physiology. Inflammatory Bowel Disease (IBD) consists of a heterogenous spectrum of pathologies divided into two distinct clinical subtypes, Crohn’s Diseases (CD) and Ulcerative Colitis (UC). These diseases are defined based upon the manifestation of their symptoms; however, many patients present with overlapping symptoms from both classifications. CD traditionally presents as transmural disease, hallmarked by thickening of the intestinal lining and granulomas (clusters of white blood cells), and can present anywhere within the gastrointestinal tract. As the name indicates, UC symptoms generally appear in the colon as ulcers, edema, hemorrhage, and chronic inflammation of the mucosa caused by both mononuclear and polymorphonuclear leukocytes. The precise etiology and pathogenesis of IBD remains to be elucidated, but genetics, environmental factors, and microbiota composition contribute to the disease.(69–71)
The overarching symptoms of IBD include diarrhea, pain, the appearance of blood in the stool (UC predominantly), and postprandial discomfort. Extra-intestinal complications include fever, undernutrition, arthralgias and arthritis, kidney stones, and liver disease. In fact, approximately 30% of IBD patients suffer from MASLD.(72) Ultimately, disruptions to the intestinal epithelium in both UC and CD permit the excess accumulation of fat within the liver, leading to steatosis. Understanding the underlying biological mechanisms responsible for the etiopathology of IBD will advance therapeutic interventions, as currently approved treatments treat the underlying inflammatory cascade and may not target the root cause of IBD.
Implicated in the progression of IBD is the microbiota. Support for this hypothesis stems from the observation that gnotobiotic (germ-free) and antibiotic treated Murine models of IBD, both CD and UC, fail to develop the inflammatory phenotype observed in normal mice. (73) Indeed, treatment with metronidazole or ciprofloxacin, both antibiotics, are used to treat mild-moderate IBD.(70) While pathogens may indeed cause the initial occurrence of IBD, a maladaptive response by the intestinal innate immune system to enteric microflora has been postulated to drive chronic inflammation in IBD.
As the first line of defense during pathogen infections, the innate immune system recognizes PAMPs, such as bacterial metabolites and DNA, via PRRs displayed on the surface of innate immune cells. TLRs, a heavily studies subset of PRRs, mediate the response to PAMPs through the nuclear translocation of NF-κb and the subsequent production of inflammatory cytokines.(74) Linking TLR activation to NF-κb translocation are the Caterpillar‐(CARD)/NOD intracellular receptors. Evidence strongly supports the role of variants of the CARD15/NOD2 gene as drivers of inflammation in CD, with increasing evidence indicating a contribution of CARD15 to the pathogenesis of UC.(75)
Without the capability to mount a proper inflammatory response to cues from commensal bacteria by the innate immune system, infection and subsequent morphological changes appear to induce IBD.(76) Production of IL-1β, IL-6, and IL-23 by mononuclear phagocytes stimulates secretion of IL-22 by lymphoid cells. IL-22 acts on intestinal epithelial cells to enhance the integrity of the intestinal barrier.76 Highlighting the importance of cytokine networks to maintain homeostasis, deficiency of the anti-inflammatory cytokine IL-10 leads to colitogenic effects. Because of IL-10 deficiency, levels of IL-1β increase within the colon and the absence of IL-10 mediated mononuclear phagocyte signaling leads to fewer macrophages with an anti-inflammatory phenotype. Conversely, the pro-inflammatory IL-18 cytokine impairs goblet cells maturation, leading to the hallmark of mucus depletion observed in UC.(74) The complex network of cytokine signaling, in conjunction with the initial health status of patients with IBD, contributes to the responsiveness of patients to therapeutic interventions.
Inflammatory cytokines that elicit both direct and effector function, such as TNF-α, TGF-β, and interferons, also contribute significantly to IBD disease progression. Studies implicate TNF-α in augmenting inflammation within the intestine, in addition to causing intestinal epithelial cell apoptosis and concomitant intestinal barrier disruption.(77) The pleiotropic action of TNF-α signaling culminates in the proliferation of T-cells, inflammatory macrophages, and myofibroblasts. These TNF-α-mediated effects cause morphological changes that include ulcer formation, fibrosis (in CD), and white blood cell aggregation in IBD.(76,78) Anti-TNF antibodies treatment continues as the first line of intervention for patients with CD and IBD,(79) however, failure of some anti-TNF antibodies to prevent CD and the relapse of other patients necessitates further understanding of the mechanism of action. Indeed, when Derkx and team first leveraged TNF-α antibodies to treat CD patients, little information existed regarding the mechanism of action responsible for the observed clinically efficacy. Thus, with additional studies into the molecular signaling pathways by which TNF antibodies work, research has tested blocking other inflammatory cytokines, in conjunction with TNF- α antibodies, to avoid the roughly 40% of patients unresponsive to initial anti-TNF therapy.(76)
TGF-β has also been studied as a therapeutic target for IBD, specifically for its role in myofibroblast differentiation and the secretion of ECM during CD. However, the failure of blocking of TGF-β with antibodies in the clinic, and the finding that TGF-β deficiency leads to IBD in humans,(80) suggests that TGF-β mediates both pro- and anti-inflammatory effects in the intestine. TGF-β promotes intestinal T-cell differentiation to regulatory T-cells cells via the induction of Foxp3 expression.(81) Furthermore, in the presence of IL-6, TGF-β drives T-helper 17 (Th17) cell differentiation and the production of IL-22 to maintain epithelial integrity.(81 )
Interferons elicit similar responses as TGF-β, by stimulating proliferation and differentiation of innate immune cell populations, while also promoting integrity of the intestinal barrier. When produced by mononuclear phagocytes, type I interferon signaling activates STAT1/2 signaling in epithelial cells to stimulate guanylate-binding protein 1 in tight junctions. Guanylate-binding protein 1 maintain intestinal permeability, as knockdown of GBP1 in human IBD-derived intestinal cells increased permeability and apoptosis.(82) NK cells, cytotoxic lymphocytes that eliminate infected or stressed cells, secrete large amounts of IFN when activated. A subtype of NK cells lacking the expression of the nuclear receptor RORγt produce IFN, which has been implicated in colitis.(83)
Pathophysiology: IBD opens the gateway to the liver
Many of the morphological changes observed in patients with IBD can influence the noted co-morbidity of MASLD. Disruption and defects to the intestinal barrier cascade to exta-intestinal targets, with the entry of bacterial metabolites, PAMPs, xenobiotics, and pathogens into the hepatic portal vein. Furthermore, the frequent appearance of small intestine bacterial overgrowth in IBD, commonly observed in obesity and MASLD patients, increases the bacterial burden of metabolites and LPS. As mentioned in previously, the emergence of LPS in the hepatic portal vein binds to TLRs in KCs, as well as hepatocytes, to activate innate and adaptive immunity. The appearance of LPS within the liver sinusoid notifies NPCs and hepatocytes that bacteria may have entered the blood stream, stimulating an innate and adaptive immune response through antigen presentation by KCs, HSCs, and even hepatocytes against the potential foreign substance.
Beyond MASLD, IBD patients are more susceptible to other liver disease, including auto-immune hepatitis, primary sclerosis cholangitis (scarring of the bile ducts), hepatic granuloma formation, and gall stones (cholelithiasis).(69) Moreover, the occurrence of auto-immune hepatitis in UC patients can exacerbate disease progression, frequently requiring these patients to undergo proctocolectomy or experience refraction to treatments.(69) Overlapping clinical presentation of hepatic liver disease also occurs frequently in UC and CD patients, with auto-immune hepatitis and primary sclerosing cholangitis observed.(84)
In the upcoming section, the molecular mechanism and consequence of intestinal permeability on MASLD will be discussed and provide context to the pathogenesis of fatty liver disease in IBD patients.
References
69. Gaspar, R., Macedo, G., and Branco, C.C. (2021). Liver manifestations and complications in inflammatory bowel disease: A review. World J Hepatol 13, 1956–1967. https://doi.org/10.4254/wjh.v13.i12.1956.
70. Hendrickson, B.A., Gokhale, R., and Cho, J.H. (2002). Clinical aspects and pathophysiology of inflammatory bowel disease. Preprint, https://doi.org/10.1128/CMR.15.1.79-94.2002 https://doi.org/10.1128/CMR.15.1.79-94.2002.
71. Goyette, P., Labbé, C., Trinh, T.T., Xavier, R.J., and Rioux, J.D. (2007). Molecular pathogenesis of inflammatory bowel disease: Genotypes, phenotypes and personalized medicine. Preprint, https://doi.org/10.1080/07853890701197615 https://doi.org/10.1080/07853890701197615.
72. Kodali, A., Okoye, C., Klein, D., Mohamoud, I., Olanisa, O.O., Parab, P., Chaudhary, P., Mukhtar, S., Moradi, A., and Hamid, P. (2023). Crohn’s Disease is a Greater Risk Factor for Nonalcoholic Fatty Liver Disease Compared to Ulcerative Colitis: A Systematic Review. Cureus 15. https://doi.org/10.7759/CUREUS.42995.
73. Sartor, R.B. (2004). Therapeutic manipulation of the enteric microflora in inflammatory bowel diseases: Antibiotics, probiotics, and prebiotics. Gastroenterology 126, 1620–1633. https://doi.org/10.1053/j.gastro.2004.03.024.
74. Nowarski, R., Jackson, R., Gagliani, N., De Zoete, M.R., Palm, N.W., Bailis, W., Low, J.S., Harman, C.C.D., Graham, M., Elinav, E., et al. (2015). Epithelial IL-18 Equilibrium Controls Barrier Function in Colitis. Cell 163, 1444–1456. https://doi.org/10.1016/j.cell.2015.10.072.
75. Lesage, S., Zouali, H., Cézard, J.-P., Almer, S., Tysk, C., O’morain, C., Gassull, M., Binder, V., Finkel, Y., Modigliani, R., et al. (2002). CARD15/NOD2 Mutational Analysis and Genotype-Phenotype Correlation in 612 Patients with Inflammatory Bowel Disease.
76. Friedrich, M., Pohin, M., and Powrie, F. (2019). Cytokine Networks in the Pathophysiology of Inflammatory Bowel Disease. Preprint at Cell Press, https://doi.org/10.1016/j.immuni.2019.03.017 https://doi.org/10.1016/j.immuni.2019.03.017.
77. Garrett, W.S., Lord, G.M., Punit, S., Lugo-Villarino, G., Mazmanian, S.K.K., Ito, S., Glickman, J.N., and Glimcher, L.H. (2007). Communicable Ulcerative Colitis Induced by T-bet Deficiency in the Innate Immune System. Cell 131, 33–45. https://doi.org/10.1016/j.cell.2007.08.017.
78. Di Sabatino, A., Pender, S.L.F., Jackson, C.L., Prothero, J.D., Gordon, J.N., Picariello, L., Rovedatti, L., Docena, G., Monteleone, G., Rampton, D.S., et al. (2007). Functional Modulation of Crohn’s Disease Myofibroblasts by Anti-Tumor Necrosis Factor Antibodies. Gastroenterology 133, 137–149. https://doi.org/10.1053/j.gastro.2007.04.069.
79. Targan, S.R., Hanauer, S.B., van Deventer, S.J.H., Mayer, L., Present, D.H., Braakman, T., DeWoody, K.L., Schaible, T.F., and Rutgeerts, P.J. (1997). A Short-Term Study of Chimeric Monoclonal Antibody cA2 to Tumor Necrosis Factor α for Crohn’s Disease. New England Journal of Medicine 337, 1029–1036. https://doi.org/10.1056/NEJM199710093371502/ASSET/C67921B3-BF6D-4E96-AC89-C2EAC2AD76D3/ASSETS/IMAGES/LARGE/NEJM199710093371502_T3.JPG.
80. Kotlarz, D., Marquardt, B., Barøy, T., Lee, W.S., Konnikova, L., Hollizeck, S., Magg, T., Lehle, A.S., Walz, C., Borggraefe, I., et al. (2018). Human TGF-β1 deficiency causes severe inflammatory bowel disease and encephalopathy. Nat Genet 50, 344–348. https://doi.org/10.1038/s41588-018-0063-6.
81. Li, M.O., and Flavell, R.A. (2008). Contextual Regulation of Inflammation: A Duet by Transforming Growth Factor-β and Interleukin-10. Preprint, https://doi.org/10.1016/j.immuni.2008.03.003 https://doi.org/10.1016/j.immuni.2008.03.003.
82. Schnoor, M., Betanzos, A., Weber, D.A., and Parkos, C.A. (2009). Guanylate-binding protein-1 is expressed at tight junctions of intestinal epithelial cells in response to interferon-γ and regulates barrier function through effects on apoptosis. Mucosal Immunol 2, 33–42. https://doi.org/10.1038/mi.2008.62.
83. Vonarbourg, C., Mortha, A., Bui, V.L., Hernandez, P.P., Kiss, E.A., Hoyler, T., Flach, M., Bengsch, B., Thimme, R., Hölscher, C., et al. (2010). Regulated expression of nuclear receptor RORγt confers distinct functional fates to NK cell receptor-expressing RORγt+ innate lymphocytes. Immunity 33, 736–751. https://doi.org/10.1016/j.immuni.2010.10.017.
84. Restellini, S., Chazouillères, O., and Frossard, J.L. (2017). Hepatic manifestations of inflammatory bowel diseases. Preprint at Blackwell Publishing Ltd, https://doi.org/10.1111/liv.13265 https://doi.org/10.1111/liv.13265.
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