Repurposing losartan for fibrostenosing Crohn’s disease: a compelling preclinical rationale

The manuscript “The angiotensin receptor blocker, losartan, reduces inflammation and fibrosis, and prevents relapse of fibrosis after steroid-induced remission, in mice prone to Crohn’s disease-like ileitis” by Artone et al. investigates the potential of losartan, an angiotensin receptor blocker (ARB), as a therapeutic agent for intestinal fibrosis in Crohn’s disease (CD).1 Intestinal fibrosis, characterized by excessive deposition of extracellular matrix and muscle hypertrophy, is a common and severe complication of CD, often leading to strictures and requiring invasive procedures like surgery, and current treatments are not effective against it. In this study, a comprehensive, multimodal approach was adopted, integrating in vitro and in vivo models with analyses of human patient data. ­Initially, the authors interrogated a large publicly available RNA-Seq dataset of intestinal biopsies from patients with CD and healthy controls to assess the expression of key RAS effector molecules, subsequently validated at the protein level using immunohistochemistry on full-thickness intestinal tissue samples. In human CD patients, angiotensinogen, an upstream regulator of RAS, was found to be increased in inflamed gut mucosa. Conversely, downstream modulators like angiotensin-converting enzyme (ACE) and angiotensin II receptor type 1 (AT1) were decreased, possibly due to negative feedback. Importantly, AT1, the receptor that ARBs like losartan target, was markedly increased in the muscularis propria of involved areas in CD patients. This suggests that blocking RAS components could interfere with pro-fibrogenic processes. Taken together, the results demonstrate RAS dysregulation in CD patients. The efficacy of losartan in altering mediators of the RAS and fibrosis was tested using activated human intestinal fibroblasts stimulated with angiotensin II (Ang II), the primary effector ligand of the RAS, and then treated with losartan or a vehicle. Losartan effectively suppressed the expression of pro-fibrotic molecules (including insulin-like growth factor-1 [IGF-1], transforming growth factor [TGF]-β, matrix metalloproteinase [MMP]-9, thrombospondin [THBS]-2, eotaxin/CCL11, and Collagen Type I Alpha 1 Chain [COL1A1]) and inhibited fibroblast-to-myofibroblast differentiation and collagen deposition in Ang II-stimulated human intestinal fibroblasts, thus confirming Losartan’s anti-­fibrotic effects in vitro. The beneficial effects of losartan were also investigated in SAMP1/YitFc (SAMP) mice, a well-characterized and translationally relevant model of CD-like ileitis. In SAMP mice with established disease, losartan treatment significantly decreased both inflammation and fibrosis severity. It reduced inflammatory cell infiltrates, restored villous structure, and decreased the presence of collagen I and the thickness of the muscularis propria. Losartan also significantly decreased the expression of profibrogenic genes (Col1a1, Mmp9, Igf1) and interleukin-13, a cytokine involved in fibrosis. Using the relapse protocol, losartan prevented the reoccurrence of fibrosis following steroid-induced remission, significantly reducing its severity and the thickness of the muscularis propria, while inflammation was marginally impacted. Finally, the study observed a diminished AT1 expression across the ileal wall layers in losartan-treated SAMP mice, suggesting a mechanistic downregulation of this key receptor. Garg et al. previously highlighted the established role of the RAS in fibrosis and inflammation in renal and cardiovascular diseases, and noted that high concentrations of ACE and renin, along with Ang II, are elevated in the inflamed colonic tissue of patients with inflammatory bowel disease (IBD). Their study demonstrated lower rates of hospitalization and surgery among IBD patients receiving ACE inhibitors or ARBs.2 Similarly, Mantaka et al. also linked Ang II to IBD pathogenesis and found that ARBs were associated with a milder IBD course and lower rates of immunomodulator and steroid use.3 Wengrower et al. provided early preclinical evidence that captopril, an ACE inhibitor, could prevent colonic fibrosis in experimental colitis by blocking TGF-β1 overexpression and/or directly downregulating its transcript.4 This supports the mechanistic insights provided by Artone et al. regarding losartan’s impact on profibrogenic pathways. Garg et al. also showed that Ang (1-7) reduced, and Ang II increased, collagen secretion in human colonic myofibroblasts, with these effects being modulated by ACE inhibition and AT1 receptor blockade.2 While Artone et al. focus on preclinical models, their conclusions align with clinical observations from retrospective studies. In a large cohort of 764 IBD patients, treatment with ACE inhibitors or ARBs was associated with reduced flares, hospitalizations, and intestinal resections in univariate analysis, although these associations did not remain statistically significant after multivariable adjustment. It was suggested that a longer follow-up may be necessary to clarify these potential effects. These findings underscore the challenges of establishing causal relationships in observational research, particularly due to confounding factors and sample size limitations.2,3 Further supporting a role for the RAS pathway, another study reported that reduced ACE2 expression in the small intestine was associated with inflammation and severe CD, whereas increased colonic ACE2 expression correlated with active ulcerative colitis (UC).5 Notably, treatment with anti-cytokine agents such as infliximab and ustekinumab appeared to restore ACE2 levels, particularly in clinical responders, underscoring the anti-inflammatory role of ACE2 and its potential as a therapeutic target. These findings complement the preclinical evidence by demonstrating that current IBD therapies may also influence RAS pathway activity. Despite the lack of a standardized scoring system for intestinal fibrosis in humans and mice, this study highlights the anti-fibrotic effects of losartan. These findings support the need for clinical trials to explore RAS-targeting therapies, particularly as adjuncts to anti-inflammatory treatments in IBD.2,3 In summary, Artone et al. provide strong preclinical evidence that, via the RAS pathway, losartan effectively reduces established intestinal inflammation and fibrosis, and prevents fibrosis reoccurrence after steroid-induced remission in vivo. This positions RAS inhibition as a promising, cost-effective, and safe adjunctive therapeutic strategy for managing fibrostenosing CD. Imagine the RAS as a complex network of roads and traffic signals regulating gut health. In IBD, some of these signals (like Ang II via AT1) are stuck on “go” for destructive processes like inflammation and fibrosis, leading to intestinal scarring and blockages. Losartan acts like a traffic controller, effectively switching that specific signal to “stop,” thereby easing the congestion and allowing the gut to heal and prevent further “traffic jams” of fibrosis (Figure 1). Graphical representation of the losartan effects in the gut. L.M., V.S., and F.U. wrote the manuscript. All authors agreed with the final version of the manuscript submitted. None declared. V.S. declares consulting fees from J&J, speaker’s fees from Pfizer, Giuliani, Tillotts, and travel grant from AbbVie. L.M. and F.U. declare no conflict of interest. No new data were generated.

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