Protective function of sclerosing cholangitis on IBD

Objective
There is a strong clinical association between 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, our 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+ Treg-cell infiltration was assessed by 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
We 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, we showed that the intestinal microbiota of people with PSC protects against colitis.

Conclusion
This study shows that PSC attenuates IBD and provides a comprehensive insight into the mechanisms involved in this effect.

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Gastrointestinal biofilms – Endoscopic detection, disease relevance and therapeutic strategies

Gastrointestinal biofilms are highly heterogenic and spatially organised polymicrobial communities that can expand and cover large areas in the gastrointestinal tract. Gut microbiota dysbiosis, mucus disruption, and epithelial invasion are associated with pathogenic biofilms that have been linked to gastrointestinal disorders such as irritable bowel syndrome (IBS), inflammatory bowel diseases (IBD), gastric cancer, and colon cancer. Intestinal biofilms are highly prevalent in ulcerative colitis and IBS patients, and most endoscopists will have observed such biofilms during colonoscopy, maybe without appreciating their biological and clinical importance.

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GI highlights from the literature

Basic scienceSpatiotemporally resolved colorectal oncogenesis in mini-colons ex vivo Lorenzo-Martín L, Hübscher T, Bowler A, et al. Spatiotemporally resolved colorectal oncogenesis in mini-colons ex vivo. Nature 2024; 629(8011): 450-457. doi: 10.1038/s41586-024-07330-2. The use of organoid cultures has become prevalent in studies attempting to understand intestinal biology and disease. However, such systems have limitations, in particular, modelling of tumours has proved problematic due to cystic structures that do not compare with tissue histology. Here, Lorenzo-Martin et al use a ‘mini-colon’ model that incorporates previously engineered crypt-like structures composed of Matrigel and collagen in a flow-luminal system that reflects the basic intestinal structure. Lorenzo-Martin et al lined these with epithelial cells derived from mice that expressed inducible adenomatous polyposis coli (Apc) loss, Kirsten rat sarcoma virus (Kras) mutations and tumour protein P53 (Tp53) mutations (AKP) when exposed to blue light. Tumours with the triad of mutations developed rapidly compared…

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Clinical, experimental and pathophysiological effects of Yaq-001: a non-absorbable, gut-restricted adsorbent in models and patients with cirrhosis

Objective
Targeting bacterial translocation in cirrhosis is limited to antibiotics with risk of antimicrobial resistance. This study explored the therapeutic potential of a non-absorbable, gut-restricted, engineered carbon bead adsorbent, Yaq-001 in models of cirrhosis and acute-on-chronic liver failure (ACLF) and, its safety and tolerability in a clinical trial in cirrhosis.

Design
Performance of Yaq-001 was evaluated in vitro. Two-rat models of cirrhosis and ACLF, (4 weeks, bile duct ligation with or without lipopolysaccharide), receiving Yaq-001 for 2 weeks; and two-mouse models of cirrhosis (6-week and 12-week carbon tetrachloride (CCl4)) receiving Yaq-001 for 6 weeks were studied. Organ and immune function, gut permeability, transcriptomics, microbiome composition and metabolomics were analysed. The effect of faecal water on gut permeability from animal models was evaluated on intestinal organoids. A multicentre, double-blind, randomised, placebo-controlled clinical trial in 28 patients with cirrhosis, administered 4 gr/day Yaq-001 for 3 months was performed.

Results
Yaq-001 exhibited rapid adsorption kinetics for endotoxin. In vivo, Yaq-001 reduced liver injury, progression of fibrosis, portal hypertension, renal dysfunction and mortality of ACLF animals significantly. Significant impact on severity of endotoxaemia, hyperammonaemia, liver cell death, systemic inflammation and organ transcriptomics with variable modulation of inflammation, cell death and senescence in the liver, kidneys, brain and colon was observed. Yaq-001 reduced gut permeability in the organoids and impacted positively on the microbiome composition and metabolism. Yaq-001 regulated as a device met its primary endpoint of safety and tolerability in the clinical trial.

Conclusions
This study provides strong preclinical rationale and safety in patients with cirrhosis to allow clinical translation.

Trial registration number
NCT03202498.

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