Rectal Insulin Instillation Inhibits Inflammation and Tumor Development in Chemically Induced Colitis

Yassin, Mohammad; Sadowska, Zuzanna; Tritsaris, Katerina; Kissow, Hannelouise; Hansen, Camilla Hartmann Friis; Forman, Julie Lyng; Rogler, Gerhard; Troelsen, Jesper T.; Pedersen, Anders Elm; Olsen, Jørgen

doi:10.1093/ecco-jcc/jjy112

Cited by 12 publications

(11 citation statements)

References 42 publications

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“…More recently, investigated sugar-induced exacerbation of colitis when adding 10% glucose or fructose in drinking water (mimicking sugar-sweetened beverages), dietary sugars quickly altered gut microbial ecology ( 13 ). In agreement with these findings, rectal insulin instillation inhibited inflammation in chemically-induced colitis in mice ( 14 ). Although growing evidence underpins the pro-inflammatory effect of sugars ( 15 , 16 ), the long-term impact of combined excessive intake of dietary sugar and fat due to ultra-processed food overconsumption (enriched in added sugars) on healthy intestine and the underlying molecular mechanisms remain poorly described ( 9 ).…”

Section: Introductionsupporting

confidence: 69%

Long-Term Overconsumption of Fat and Sugar Causes a Partially Reversible Pre-inflammatory Bowel Disease State

et al. 2021

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Nutrition appears to be an important environmental factor involved in the onset of inflammatory bowel diseases (IBD) through yet poorly understood biological mechanisms. Most studies focused on fat content in high caloric diets, while refined sugars represent up to 40% of caloric intake within industrialized countries and contribute to the growing epidemics of inflammatory diseases. Herein we aim to better understand the impact of a high-fat-high-sucrose diet on intestinal homeostasis in healthy conditions and the subsequent colitis risk. We investigated the early events and the potential reversibility of high caloric diet-induced damage in mice before experimental colitis. C57BL/6 mice were fed with a high-fat or high-fat high-sucrose or control diet before experimental colitis. In healthy mice, a high-fat high-sucrose diet induces a pre-IBD state characterized by gut microbiota dysbiosis with a total depletion of bacteria belonging to Barnesiella that is associated with subclinical endoscopic lesions. An overall down-regulation of the colonic transcriptome converged with broadly decreased immune cell populations in the mesenteric lymph nodes leading to the inability to respond to tissue injury. Such in-vivo effects on microbiome and transcriptome were partially restored when returning to normal chow. Long-term consumption of diet enriched in sucrose and fat predisposes mice to colitis. This enhanced risk is preceded by gut microbiota dysbiosis and transcriptional reprogramming of colonic genes related to IBD. Importantly, diet-induced transcriptome and microbiome disturbances are partially reversible after switching back to normal chow with persistent sequelae that may contribute to IBD predisposition in the general population.

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Section: Introductionsupporting

confidence: 69%

Long-Term Overconsumption of Fat and Sugar Causes a Partially Reversible Pre-inflammatory Bowel Disease State

et al. 2021

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“…Note that to avoid the influences of abundant gastrointestinal proteinase and peptidase, we directly injected these purified proteins to the colons of HFD-fed mice according to a previous study. 29 Because M. timonae is the corresponding bacteria of GSDMD-N proteins, we firstly examined the abundance of M. timonae every 2 days. We found that the abundance of M. timonae from the feces of HFD-fed mice treated with GSDMD-N WT were significantly decreased to 41% at day 10, when compared to the control group ( Figure 5(a,b) ).…”

Section: Resultsmentioning

confidence: 99%

Host Gasdermin D restrains systemic endotoxemia by capturing Proteobacteria in the colon of high-fat diet-feeding mice

et al. 2021

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Gasdermin D (GSDMD) functions as a key pyroptotic executor through its secreted N-terminal domain (GSDMD-N). However, the functional relevance and mechanistic basis of the precise roles of host colonic GSDMD in high-fat diet (HFD)-induced gut dysbiosis and systemic endotoxemia remain elusive. In this study, we demonstrate that HFD feeding triggers GSDMD-N secretion of both T-lymphocytes and enterocytes in mouse colons. GSDMD deficiency aggravates HFD-induced systemic endotoxemia, gut barrier impairment, and colonic inflammation. More importantly, active GSDMD-N kills the Proteobacteria phylum via directly interacting with Cardiolipin. Mechanistically, we identify that the Glu236 (a known residue for GSDMD protein cleavage) is a bona fide important site for the bacterial recognition of GSDMD. Collectively, our findings explain the mechanism by which colonic GSDMD-N maintains low levels of HFD-induced metabolic endotoxemia. A GSDMD-N mimetic containing an exposed Glu236 site could be an attractive strategy for the treatment of HFD-induced metabolic endotoxemia.

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“…Such switchers may be affected by previous therapydfor example, physicians may switch patients on metformin or glucagon-like peptide 1 receptor agonists to DPP4i due to development of gastrointestinal symptoms (which may be either drug adverse events [33] or early symptoms of IBD). Notably, in a head-to-head comparison of the CPRD study, a higher risk was also observed comparing DPP4i versus insulin (HR 2.28 [1.07-4.85]), which might be due to a speculative potential protective effect of insulin on UC (34).…”

Section: Comparison With Previous Studiesmentioning

confidence: 98%

Dipeptidyl Peptidase 4 Inhibitors and Risk of Inflammatory Bowel Disease: Real-world Evidence in U.S. Adults

et al. 2019

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A recent study raises concerns that dipeptidyl peptidase 4 inhibitors (DPP4i) are associated with increased risk of inflammatory bowel disease (IBD). We evaluated the association between new use of DPP4i and IBD risk compared with other secondline antihyperglycemics. RESEARCH DESIGN AND METHODS We implemented an active-comparator, new-user cohort design using two U.S. administrative claims databases for commercially insured (MarketScan) and older adult (Medicare fee-for-service, 20% random sample) patients from January 2007 to December 2016. We identified patients, aged ‡18 years, who initiated DPP4i versus sulfonylureas (SUs) or initiated DPP4i versus thiazolidinediones (TZDs) and were without prior diagnosis, treatment, or procedure for IBD. The primary outcome was incident IBD, defined by IBD diagnosis preceded by colonoscopy and biopsy and followed by IBD treatment. We performed propensity score weighting to control for measured baseline confounding, estimated adjusted hazard ratios (aHRs [95% CI]) using weighted Cox proportional hazards models, and used randomeffects meta-analysis models to pool aHRs across cohorts. RESULTS We identified 895,747 eligible patients initiating DPP4i, SU, or TZD; IBD incidence rates ranged from 11.6 to 32.3/100,000 person-years. Over a median treatment duration of 1.09-1.69 years, DPP4i were not associated with increased IBD risk across comparisons. The pooled aHRs for IBD were 0.82 (95% CI 0.41-1.61) when comparing DPP4i (n 5 161,612) to SU (n 5 310,550) and 0.76 (0.46-1.26) when comparing DPP4i (n 5 205,570) to TZD (n 5 87,543). CONCLUSIONS Our population-based cohort study of U.S. adults with diabetes suggests that shortterm DPP4i treatment does not increase IBD risk. Dipeptidyl peptidase 4 inhibitors (DPP4i), a commonly prescribed second-line glucose-lowering drug (GLD) class, reduce hyperglycemia by increasing the levels of incretin hormones, which in turn increase insulin and decrease glucagon in a glucose-dependent fashion (1). DPP4, also known as CD26, is expressed on leukocytes and can inactivate various cytokines as well as act as a costimulator of T lymphocytes (2), thus raising concerns about potential immunologic effects of DPP4i (3). A recent

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Rectal Insulin Instillation Inhibits Inflammation and Tumor Development in Chemically Induced Colitis

Abstract: Rectal insulin therapy could potentially be a novel treatment, targeting the epithelial layer to enhance mucosal healing in ulcerated areas. Our findings open up new possibilities for combination treatments to synergize with the existing anti-inflammatory therapies.

Cited by 12 publications

References 42 publications

Long-Term Overconsumption of Fat and Sugar Causes a Partially Reversible Pre-inflammatory Bowel Disease State

Long-Term Overconsumption of Fat and Sugar Causes a Partially Reversible Pre-inflammatory Bowel Disease State

Host Gasdermin D restrains systemic endotoxemia by capturing Proteobacteria in the colon of high-fat diet-feeding mice

Dipeptidyl Peptidase 4 Inhibitors and Risk of Inflammatory Bowel Disease: Real-world Evidence in U.S. Adults

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