Disruption of the intestinal epithelial barrier is a hallmark of mucosal inflammation. It increases exposure of the immune system to luminal microbes, triggering a perpetuating inflammatory response. ...For several decades, the inflammatory stimuli-induced breakdown of the human gut barrier was studied
by using colon cancer derived epithelial cell lines. While providing a wealth of important data, these cell lines do not completely mimic the morphology and function of normal human intestinal epithelial cells (IEC) due to cancer-related chromosomal abnormalities and oncogenic mutations. The development of human intestinal organoids provided a physiologically-relevant experimental platform to study homeostatic regulation and disease-dependent dysfunctions of the intestinal epithelial barrier. There is need to align and integrate the emerging data obtained with intestinal organoids and classical studies that utilized colon cancer cell lines. This review discusses the utilization of human intestinal organoids to dissect the roles and mechanisms of gut barrier disruption during mucosal inflammation. We summarize available data generated with two major types of organoids derived from either intestinal crypts or induced pluripotent stem cells and compare them to the results of earlier studies with conventional cell lines. We identify research areas where the complementary use of colon cancer-derived cell lines and organoids advance our understanding of epithelial barrier dysfunctions in the inflamed gut and identify unique questions that could be addressed only by using the intestinal organoid platforms.
FOXP3.sup.+ Tregs are expanded within the inflamed intestine of human Crohn's disease, yet FOXP3-mediated gene repression within these cells is lost. The polycomb repressive complexes play a role in ...FOXP3 target gene regulation, but deeper mechanistic insight is incomplete. We have now specifically identified the polycomb-repressive complex 1 (PRC1) family member, BMI1 in the regulation of a proinflammatory enhancer network in both human and murine Tregs. Using human Tregs and lamina propria T cells, we inferred PRC1 to regulate Crohn's associated gene networks through assays of chromatin accessibility. Conditional deletion of BMI1 in murine FOXP3.sup.+ cells led to systemic inflammation. BMI1- deficient Tregs beared a TH1/TH17-like phenotype as assessed by assays of genome wide transcription, chromatin accessibility and proteomic techniques. Finally, BMI1 mutant FOXP3.sup.+ cells did not suppress colitis in the adoptive transfer model of human inflammatory bowel disease. We propose that BMI1 plays an important role in enforcing Treg identity in vitro and in vivo. Loss of Treg identity via genetic or transient BMI1 depletion perturbs the epigenome and converts Tregs into Th1/Th17- like proinflammatory cells, a transition relevant to human Crohn's disease associated CD4.sup.+ T cells.
Turning Purple with Pain Fredrick, Thomas W; Neto, Manuel B. Braga; Johnsrud, Daniel O ...
The New England journal of medicine,
08/2021, Letnik:
385, Številka:
6
Journal Article
Recenzirano
A 32-year-old woman presented with a 10-year history of intermittent episodes of severe diffuse abdominal pain, occurring every month or two and usually lasting several days, with no apparent ...precipitant.
It has been suggested that distal gastric carcinoma (GC) in younger patients has a more aggressive outcome than in older patients, however this is a controversial issue. The aim of this study was to ...compare clinicopathological features between younger and older patients with GC in Northeastern Brazil.
A total of 207 patients with distal GC (41 patients ≤45 years, considered younger group, and 166 > 45 years, considered older group) were evaluated prospectively during a 6 year period.
The mean patient age in the young group was 37.41 years old and 64.43 years in the older group. No significant difference was found regarding gender, area of residence, history of alcohol consumption, chronic tobacco smoking. Prevalence of first-degree GC history was 12.5% (7.3% in younger group vs. 13.9% in older; p < 0.46). The most frequent symptom was gastric pain and weight loss. Diffuse infiltrative cancer was more frequently seen in younger patients (70.70% vs. 33.70%, respectively; p < 0.01), as was histologically less differentiated tumors (63.40% vs. 33.10%; p < 0.01) and stage IV of GC (48.80% vs. 30.70%; p < 0.015). Five-year survival, evaluated in 82 patients, was lower in younger patients (p = 0.045); however, after adjusting for stage of GC in the multivariate analysis, this association did not remain significant. Family history of GC and gender had no impact on survival.
Younger patients showed higher prevalence of diffuse type of Lauren and lower survival that was attributed to higher rate of advanced stage of GC. Gastric cancer screening strategies should also be considered in younger individuals, especially in areas of high prevalence. Further studies are warranted to determine risk factors associated with gastric cancer in young adults.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Although T-cell intrinsic expression of G9a has been associated with murine intestinal inflammation, mechanistic insight into the role of this methyltransferase in human T-cell differentiation is ill ...defined, and manipulation of G9a function for therapeutic use against inflammatory disorders is unexplored.
Human naive T cells were isolated from peripheral blood and differentiated in vitro in the presence of a G9a inhibitor (UNC0642) before being characterized via the transcriptome (RNA sequencing), chromatin accessibility (assay for transposase-accessible chromatin by sequencing), protein expression (cytometry by time of flight, flow cytometry), metabolism (mitochondrial stress test, ultrahigh performance liquid chromatography–tandem mas spectroscopy) and function (T-cell suppression assay). The in vivo role of G9a was assessed using 3 murine models.
We discovered that pharmacologic inhibition of G9a enzymatic function in human CD4 T cells led to spontaneous generation of FOXP3+ T cells (G9a-inibitors–T regulatory cells Tregs) in vitro that faithfully reproduce human Tregs, functionally and phenotypically. Mechanistically, G9a inhibition altered the transcriptional regulation of genes involved in lipid biosynthesis in T cells, resulting in increased intracellular cholesterol. Metabolomic profiling of G9a-inibitors–Tregs confirmed elevated lipid pathways that support Treg development through oxidative phosphorylation and enhanced lipid membrane composition. Pharmacologic G9a inhibition promoted Treg expansion in vivo upon antigen (gliadin) stimulation and ameliorated acute trinitrobenzene sulfonic acid–induced colitis secondary to tissue-specific Treg development. Finally, Tregs lacking G9a expression (G9a-knockout Tregs) remain functional chronically and can rescue T-cell transfer–induced colitis.
G9a inhibition promotes cholesterol metabolism in T cells, favoring a metabolic profile that facilitates Treg development in vitro and in vivo. Our data support the potential use of G9a inhibitors in the treatment of immune-mediated conditions including inflammatory bowel disease.
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Abstract
Background
An association between inflammatory bowel disease (IBD) and obesity has been observed. Little is known about the effect of weight loss on IBD course. Our aim was to determine the ...impact of bariatric surgery on long-term clinical course of obese patients with IBD, either Crohn's disease (CD) or ulcerative colitis (UC).
Methods
Patients with IBD who underwent bariatric surgery subsequent to IBD diagnosis were identified from 2 tertiary IBD centers. Complications after bariatric surgery were recorded. Patients were matched 1:1 for age, sex, IBD subtype, phenotype, and location to patients with IBD who did not undergo bariatric surgery. Controls started follow-up at a time point in their disease similar to the disease duration in the matched case at the time of bariatric surgery. Inflammatory bowel disease medication usage and disease-related complications (need for corticosteroids, hospitalizations, and surgeries) among cases and controls were compared.
Results
Forty-seven patients met inclusion criteria. Appropriate matches were found for 25 cases. Median follow-up among cases (after bariatric surgery) and controls was 7.69 and 7.89 years, respectively. Median decrease in body mass index after bariatric surgery was 12.2. Rescue corticosteroid usage and IBD-related surgeries were numerically less common in cases than controls (24% vs 52%; odds ratio OR, 0.36; 95% confidence interval CI, 0.08–1.23; 12% vs 28%; OR, 0.2; 95% CI, 0.004–1.79). Two cases and 1 control were able to discontinue biologics during follow-up.
Conclusions
Inflammatory bowel disease patients with weight loss after bariatric surgery had fewer IBD-related complications compared with matched controls. This observation requires validation in a prospective study design.
We matched 1:1 on 5 variables, 25 patients with inflammatory bowel disease (IBD) who underwent bariatric surgery matched to 25 controls who did not. Rescue corticosteroid usage and IBD-related surgeries were numerically less common in cases, whereas 2 cases and 1 control were able to discontinue biologics during follow-up.
Video Abstract
10.1093/ibd/izz236_video1
Video Abstract
izz236_video1
6095050202001
The implementation of biologic therapy has improved the treatment and clinical course of patients with inflammatory bowel disease since the initial approval of infliximab for Crohn’s disease in 1998. ...However, the efficacy and safety profiles of currently available therapies are still less than optimal in several ways, highlighting the need for novel therapeutic targets. Several new drug classes (Janus kinase inhibitors, anti-integrins, sphingosine-1-phosphate receptor modulators, anti–interleukin-23 antibodies, and stem cell therapies) are currently being studied in Crohn’s disease and ulcerative colitis with promising results. This article reviews the current literature and provides an updated overview of the emerging therapies.
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