Colon to Rectum
Gut. 2024;73(8):1292–301
Protective function of sclerosing cholangitis on IBD
Objective: There is a strong clinical association between inflammatory bowel disease (IBD) and primary sclerosing cholangitis (PSC), a chronic disease of the liver characterised by biliary inflammation that leads to strictures and fibrosis. Approximately 60–80% of people with PSC will also develop IBD (PSC-IBD). One hypothesis explaining this association would be that PSC drives IBD. Therefore, the authors’ aim was to test this hypothesis and to decipher the underlying mechanism. Design: Colitis severity was analysed in experimental mouse models of colitis and sclerosing cholangitis, and people with IBD and PSC-IBD. Foxp3+ regulatory T (Treg)-cell infiltration was assessed by quantitative polymerase chain reaction (qPCR) and flow cytometry. Microbiota profiling was carried out from faecal samples of people with IBD, PSC-IBD and mouse models recapitulating these diseases. Faecal microbiota samples collected from people with IBD and PSC-IBD were transplanted into germ-free mice followed by colitis induction. Results: The authors show that sclerosing cholangitis attenuated IBD in mouse models. Mechanistically, sclerosing cholangitis causes an altered intestinal microbiota composition, which promotes Foxp3+ Treg-cell expansion, and thereby protects against IBD. Accordingly, sclerosing cholangitis promotes IBD in the absence of Foxp3+ Treg cells. Furthermore, people with PSC-IBD have an increased Foxp3+ expression in the colon and an overall milder IBD severity. Finally, by transplanting faecal microbiota into gnotobiotic mice, it was shown that the intestinal microbiota of people with PSC protects against colitis.
Conclusion: This study shows that primary sclerosing cholangitis attenuates inflammatory bowel disease and provides a comprehensive insight into the mechanisms involved in this effect.
DOI: 10.1136/gutjnl-2023-330856
Dr. Lena Sophie Mayer
Specialist Internal Medicine, Department of Internal Medicine II, University Medical Center Freiburg (Germany)
Protective function of sclerosing cholangitis on IBD
The reciprocal relationship between the intestine and liver has been the focus of research for several years. In terms of anatomy, the “gut-liver axis” is represented by the portal vein and the biliary system, while functionally, it is represented by the microbiome and circulating metabolites. The clinical association between chronic inflammatory bowel disease (IBD) and primary sclerosing cholangitis (PSC) is just one of many examples highlighting a connection between the gut and the liver. Approximately 60–80% of patients with PSC develop IBD, while only about 5% of patients with IBD develop PSC. PSC induces changes in the intestinal microbiome, and these changes modulate the mucosal immune system.
Earlier studies have described the association between PSC-IBD and attenuated inflammation and changes in the microbiome compared to IBD without concomitant PSC. Bedke et al. confirmed this observation using various mouse models. A fecal microbiome transfer from patients with IBD and PSC-IBD to germ-free mice also showed attenuated inflammation in the presence of the PSC-IBD microbiota. An enrichment of Lachnospiraceae was found both in the mouse model and in human microbiome samples in patients with PSC-IBD. Limitations of such analyses include the heterogeneity of patient cohorts, different sampling sites, and differences in the sample type (stool, biopsy). However, this study shows an enrichment of Lachnospiraceae in both biopsies and stool samples from patients with PSC-IBD. The correlation of inflammatory activity with the microbiota at the family level is also of limited significance, as different species have distinct metabolic properties, and thus can have either proinflammatory or anti-inflammatory effects.
The microbiome and intestinal immune system constantly interact. While dysbiosis can lead to an excessive immune response and cause intestinal damage, a favorable composition of the microbiota contributes to immune homeostasis. The differentiation and expansion of regulatory T cells (Treg), which play a central role in limiting intestinal inflammation, are also largely influenced by the microbiome. Indeed, the authors found an enrichment of mucosal Foxp3+ Treg in the PSC-IBD mouse model and an increased expression of Foxp3 mRNA was detected in the mucosa of PSC-IBD patients. In a lymphocytopenic mouse model where Treg were absent, inflammation of PSC-IBD was more severe, proving that the attenuation of inflammation mechanistically depends on Treg. However, functional differences of Treg regarding their suppressive capacity in PSC-IBD versus IBD alone were not explored. Moreover it remains unclear whether Treg expansion occurs directly in the mucosa or in the cholestatic liver. In addition, it is yet to be determined whether other cholestatic liver diseases or treatment with ursodeoxycholic acid (UDCA) influence the development of IBD.
PSC increases the risk of various malignancies. In patients with PSC-IBD, the risk of developing colon cancer is significantly higher compared to patients with IBD alone, warranting annual screening colonoscopies. The fact that the PSC-associated microbiome modulates inflammation raises the question of whether modifications to the microbiome might also reduce cancer risk. However, this was not investigated in the present study.
In summary, this study suggests that PSC may positively influence the outcome of IBD by modulating the microbiome and promoting the expansion of regulatory T cells. However, more detailed microbiome analyses and functional immunological assessments are still needed. Moreover, the influence of cholestasis and its treatment on mucosal inflammation remain unexplored. In addition, the impact of the PSC-associated microbiome on the occurrence of IBD-related complications needs to be further investigated. At present, this study does not lead to any direct recommendations for clinical practice. Microbiome or immunological analyses do not yet provide a basis for specific therapeutic interventions and thus should not be routinely performed. However, fecal microbiome transfer as a potential treatment option for IBD patients with and without concomitant PSC is already under clinical investigation. Thus studies such as this one are particularly important for improving patient care.