The 2023 Impact of Inflammatory Bowel Disease in Canada: Access to and Models of Care.

Rising compounding prevalence of inflammatory bowel disease (IBD) (Kaplan GG, Windsor JW. The four epidemiological stages in the global evolution of inflammatory bowel disease. Nat Rev Gastroenterol Hepatol. 2021;18:56-66.) and pandemic-exacerbated health system resource limitations have resulted in significant variability in access to high-quality, evidence-based, person-centered specialty care for Canadians living with IBD. Individuals with IBD have identified long wait times, gaps in biopsychosocial care, treatment and travel expenses, and geographic and provider variation in IBD specialty care and knowledge as some of the key barriers to access. Care delivered within integrated models of care (IMC) has shown promise related to impact on disease-related outcomes and quality of life. However, access to these models is limited within the Canadian healthcare systems and much remains to be learned about the most appropriate IMC team composition and roles. Although eHealth technologies have been leveraged to overcome some access challenges since COVID-19, more research is needed to understand how best to integrate eHealth modalities (i.e., video or telephone visits) into routine IBD care. Many individuals with IBD are satisfied with these eHealth modalities. However, not all disease assessment and monitoring can be achieved through virtual modalities. The need for access to person-centered, objective disease monitoring strategies, inclusive of point of care intestinal ultrasound, is more pressing than ever given pandemic-exacerbated restrictions in access to endoscopy and cross-sectional imaging. Supporting learning healthcare systems for IBD and research relating to the strategic use of innovative and integrative implementation strategies for evidence-based IBD care interventions are greatly needed. Data derived from this research will be essential to appropriately allocating scarce resources aimed at improving person-centred access to cost-effective IBD care.

Butyrate's role in human health and the current progress towards its clinical application to treat gastrointestinal disease.

Butyrate is a key energy source for colonocytes and is produced by the gut microbiota through fermentation of dietary fiber. Butyrate is a histone deacetylase inhibitor and also signals through three G-protein coupled receptors. It is clear that butyrate has an important role in gastrointestinal health and that butyrate levels can impact both host and microbial functions that are intimately coupled with each other. Maintaining optimal butyrate levels improves gastrointestinal health in animal models by supporting colonocyte function, decreasing inflammation, maintaining the gut barrier, and promoting a healthy microbiome. Butyrate has also shown protective actions in the context of intestinal diseases such as inflammatory bowel disease, graft-versus-host disease of the gastrointestinal tract, and colon cancer, whereas lower levels of butyrate and/or the microbes which are responsible for producing this metabolite are associated with disease and poorer health outcomes. However, clinical efforts to increase butyrate levels in humans and reverse these negative outcomes have generated mixed results. This article discusses our current understanding of the molecular mechanisms of butyrate action with a focus on the gastrointestinal system, the links between host and microbial factors, and the efforts that are currently underway to apply the knowledge gained from the bench to bedside.

Resistant starch, microbiome, and precision modulation.

Resistant starch, microbiome, and precision modulation. Mounting evidence has positioned the gut microbiome as a nexus of health. Modulating its phylogenetic composition and function has become an attractive therapeutic prospect. Resistant starches (granular amylase-resistant α-glycans) are available as physicochemically and morphologically distinguishable products. Attempts to leverage resistant starch as microbiome-modifying interventions in clinical studies have yielded remarkable inter-individual variation. Consequently, their utility as a potential therapy likely depends predominantly on the selected resistant starch and the subject's baseline microbiome. The purpose of this review is to detail i) the heterogeneity of resistant starches, ii) how resistant starch is sequentially degraded and fermented by specialized gut microbes, and iii) how resistant starch interventions yield variable effects on the gut microbiome.

Compositional changes to the ileal microbiome precede the onset of spontaneous ileitis in SHIP deficient mice.

Inflammatory bowel disease, encompassing both ulcerative colitis and Crohn's disease, is characterized by chronic, relapsing-remitting gastrointestinal inflammation of unknown etiology. SHIP deficient mice develop fully penetrant, spontaneous ileitis at 6 weeks of age, and thus offer a tractable model of Crohn's disease-like inflammation. Since disruptions to the microbiome are implicated in the pathogenesis of Crohn's disease, we conducted a 16S rRNA gene survey of the ileum, cecum, colon, and stool contents of SHIP+/+ and SHIP-/- mice. We predicted that diversity and compositional changes would occur after, and possibly prior to, the onset of overt disease. No differences were found in alpha diversity, but significant changes in beta diversity and specific commensal populations were observed in the ileal compartment of SHIP deficient mice after the onset of overt disease. Specifically, reductions in the Bacteroidales taxa, Muribaculum intestinale, and an expansion in Lactobacillus were most notable. In contrast, expansions to bacterial taxa previously associated with inflammation, including Bacteroides, Parabacteroides, and Prevotella were observed in the ilea of SHIP deficient mice prior to the onset of overt disease. Finally, antibiotic treatment reduced the development of intestinal inflammation in SHIP-/- mice. Thus, our findings indicate that SHIP is involved in maintaining ileal microbial homeostasis. These results have broader implications for humans, since reduced SHIP protein levels have been reported in people with Crohn's disease.

SHIP negatively regulates type II immune responses in mast cells and macrophages.

SHIP is a hematopoietic-specific lipid phosphatase that dephosphorylates PI3K-generated PI(3,4,5)-trisphosphate. SHIP removes this second messenger from the cell membrane blunting PI3K activity in immune cells. Thus, SHIP negatively regulates mast cell activation downstream of multiple receptors. SHIP has been referred to as the "gatekeeper" of mast cell degranulation as loss of SHIP dramatically increases degranulation or permits degranulation in response to normally inert stimuli. SHIP also negatively regulates Mϕ activation, including both pro-inflammatory cytokine production downstream of pattern recognition receptors, and alternative Mϕ activation by the type II cytokines, IL-4, and IL-13. In the SHIP-deficient (SHIP-/- ) mouse, increased mast cell and Mϕ activation leads to spontaneous inflammatory pathology at mucosal sites, which is characterized by high levels of type II inflammatory cytokines. SHIP-/- mast cells and Mϕs have both been implicated in driving inflammation in the SHIP-/- mouse lung. SHIP-/- Mϕs drive Crohn's disease-like intestinal inflammation and fibrosis, which is dependent on heightened responses to innate immune stimuli generating IL-1, and IL-4 inducing abundant arginase I. Both lung and gut pathology translate to human disease as low SHIP levels and activity have been associated with allergy and with Crohn's disease in people. In this review, we summarize seminal literature and recent advances that provide insight into SHIP's role in mast cells and Mϕs, the contribution of these cell types to pathology in the SHIP-/- mouse, and describe how these findings translate to human disease and potential therapies.

Perspectives on the discovery of NOTCH2-specific inhibitors.

The Notch pathway is a cell-cell communication system where membrane-bound ligands interact with the extracellular region of Notch receptors to induce intracellular, downstream effects on gene expression. Aberrant Notch signaling promotes tumorigenesis, and the Notch pathway has tremendous potential for novel targeting strategies in cancer treatment. While γ-secretase inhibitors as Notch-inhibiting agents are already promising in clinical trials, they are highly non-specific with adverse side-effects. One of the underlying challenges is that two of the four known human Notch paralogs, NOTCH1 and 2, share very high structural similarity but play opposing roles in some tumorigenesis pathways. This perspective explores the feasibility of developing Notch-specific small molecule inhibitors targeting the anti-NOTCH2 antibody-binding epitopes or the "S2-Leu-plug-binding site" using a computer-aided drug discovery approach.