Opening the doors of precision medicine: novel tools to assess intestinal barrier in inflammatory bowel disease and colitis-associated neoplasia

Abstract

Mounting evidence underscores the pivotal role of the intestinal barrier and its convoluted network with diet and intestinal microbiome in the pathogenesis of inflammatory bowel disease (IBD) and colitis-associated colorectal cancer (CRC). Moreover, the bidirectional association of the intestinal barrier with the liver and brain, known as the gut-brain axis, plays a crucial role in developing complications, including extraintestinal manifestations of IBD and CRC metastasis. Consequently, barrier healing represents a crucial therapeutic target in these inflammatory-dependent disorders, with barrier assessment predicting disease outcomes, response to therapy and extraintestinal manifestations.New advanced technologies are revolutionising our understanding of the barrier paradigm, enabling the accurate assessment of the intestinal barrier and aiding in unravelling the complexity of the gut-brain axis. Cutting-edge endoscopic imaging techniques, such as ultra-high magnification endocytoscopy and probe-based confocal laser endomicroscopy, are new technologies allowing real-time exploration of the 'cellular' intestinal barrier. Additionally, novel advanced spatial imaging technology platforms, including multispectral imaging, upconversion nanoparticles, digital spatial profiling, optical spectroscopy and mass cytometry, enable a deep and comprehensive assessment of the 'molecular' and 'ultrastructural' barrier. In this promising landscape, artificial intelligence plays a pivotal role in standardising and integrating these novel tools, thereby contributing to barrier assessment and prediction of outcomes.Looking ahead, this integrated and comprehensive approach holds the promise of uncovering new therapeutic targets, breaking the therapeutic ceiling in IBD. Novel molecules, dietary interventions and microbiome modulation strategies aim to restore, reinforce, or modulate the gut-brain axis. These advancements have the potential for transformative and personalised approaches to managing IBD.

Keywords: BRAIN/GUT INTERACTION; ENDOSCOPY; GASTROINTESTINAL CANCER; INFLAMMATORY BOWEL DISEASE; INTESTINAL BARRIER FUNCTION.

Figure 1. Intestinal barrier components in health and inflammation. This figure schematically represents the intestinal barrier, depicting a healthy barrier on the left and an impaired barrier in inflammatory bowel disease (IBD) on the right. In healthy conditions, the mucus layer and the epithelial barrier, fortified by tight junctions (represented in the upper left circle), prevent microbial translocation. Other components of the intestinal barrier include immune cells in the lamina propria and the vascular barrier (represented in the lower left circle). An immunofluorescence image provided on the left shows staining for the tight junction ZO-1, demonstrating an intact epithelial barrier (EB) and vascular barrier (VB). In IBD, a compromised intestinal barrier, with a reduced mucin layer and disrupted tight junctions, permits harmful microbes to enter the lamina propria (as represented in the upper right circle). Microbes trigger inflammation and can translocate across the impaired vascular barrier into the bloodstream. Barrier impairment is associated with IBD and colorectal cancer (CRC) development and complications. The immunofluorescence image on the right, stained for ZO-1, illustrates a disrupted EB and VB in IBD. Created with ‘Biorender.com’.

Figure 2. The gut-brain axis. This figure illustrates the complex interplay of the gut-brain axis in healthy conditions (left) and in inflammatory bowel disease (IBD) (right). In healthy conditions, the gut and microbiome interact bidirectionally with the brain through the vagus nerve and hormones and with the liver via nutrients and bile acids. A possible bilateral connection between liver and brain has also been hypothesised. Preserved intestinal barrier, as shown by endocytoscopy and confocal laser endomicroscopy images, maintains systemic homeostasis by preventing microbe dissemination. Simultaneously, intact blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB), as shown in immunofluorescence slides, hinder microbe and metabolite entry. In IBD, compromised intestinal barrier (epithelial damage at endocytoscope and fluorescein leakage at confocal laser endomicroscopy are shown) allows microbes and metabolite translocation into the bloodstream. Pro-inflammatory signals, microbes, metabolites and hormonal imbalance across the gut-brain and gut-liver axes led to neurological and liver disorders, and colorectal cancer metastasis. Correspondingly, impaired BBB and BCSFB (as evidenced by immunofluorescence images) exacerbate complications. Created with ‘Biorender.com’. CRC, colorectal cancer; CSF, cerebrospinal fluid.

Figure 3. Advanced tools for assessing the intestinal barrier. This figure shows various innovative tools available for assessing the intestinal barrier. Endocytoscopy and probe-based confocal laser endomicroscopy (pCLE) enable evaluation of the barrier at the cellular level (‘cellular‘ barrier), while cutting-edge laboratory techniques, like multispectral imaging of multiplex immunofluorescence depicted here, go deep into the ultrastructural level (‘molecular’ barrier). Additionally, the central circle highlights some artificial intelligence (AI) applications in barrier assessment, including computer-aided imaging analysis of pCLE and automated evaluation of multiplex immunofluorescence for assessing tight junction expressions. AI can assist in integrating these tools, offering a precise, real-time and standardised barrier assessment, thereby facilitating a comprehensive understanding of the gut-brain axis and identifying promising therapeutic targets and agents. Created with ‘Biorender.com’.

Figure 4. Intestinal barrier as therapeutic target in inflammatory bowel disease. This schematic illustration depicts various compounds currently available or under investigation for targeting different components of the intestinal barrier. Agents capable of targeting the epithelial, endothelial, immune barriers and microbiome are listed. Additionally, the potential of dietary interventions to impact multiple barrier targets is highlighted. Created with ‘Biorender.com’. FMT, faecal microbial transplant; FXR, farnesoid X receptor.