A Novel Unconventional T Cell Population Enriched In Crohn's Disease

Identified and characterised a subpopulation of unconventional Crohn-associated invariant T (CAIT) cells. Multiple evidence suggests these cells to be part of the NKT type II population.

source: Gut

Summary

[Posted 23/Nov/2022]

AUDIENCE: Gastroenterology, Internal Medicine

KEY FINDINGS: Identified and characterised a subpopulation of unconventional Crohn-associated invariant T (CAIT) cells. Multiple evidence suggests these cells to be part of the NKT type II population. The potential implications of this population for CD or a subset thereof remain to be elucidated, and the immunophenotype and antigen reactivity of CAIT cells need further investigations in future studies.

BACKGROUND: One of the current hypotheses to explain the proinflammatory immune response in IBD is a dysregulated T cell reaction to yet unknown intestinal antigens. As such, it may be possible to identify disease-associated T cell clonotypes by analysing the peripheral and intestinal T-cell receptor (TCR) repertoire of patients with IBD and controls.

DETAILS: Bulk TCR repertoire profiling of both the TCR alpha and beta chains was performed using high-throughput sequencing in peripheral blood samples of a total of 244 patients with IBD and healthy controls as well as from matched blood and intestinal tissue of 59 patients with IBD and disease controls. It was further characterised specific T cell clonotypes via single-cell RNAseq. Identified a group of clonotypes, characterised by semi-invariant TCR alpha chains, to be significantly enriched in the blood of patients with Crohn's disease (CD) and particularly expanded in the CD8+ T cell population. Single-cell RNAseq data showed an innate-like phenotype of these cells, with a comparable gene expression to unconventional T cells such as mucosal associated invariant T and natural killer T (NKT) cells, but with distinct TCRs.

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Source: Rosati, E., Rios Martini G., Pogorelyy, M. V., et al. (2022). A Novel Unconventional T Cell Population Enriched In Crohn's Disease. Gut. 2022; 71(11): 2194-2204. Published: November, 2022. DOI: XXXXXXXX.



Effectiveness and Safety of Tofacitinib for Ulcerative Colitis

While the overall efficacy and safety of tofacitinib in moderate-severe UC is consistent with clinical trial data, the dose dependent increase in AEs highlights the significance of early dose de-escalation.

source: J Clin Gastro

Summary

Systematic Review and Meta-analysis

[Posted 10/Nov/2022]

AUDIENCE: Gastroenterology, Internal Medicine

KEY FINDINGS: While the overall efficacy and safety of tofacitinib in moderate-severe UC is consistent with clinical trial data, the dose dependent increase in AEs highlights the significance of early dose de-escalation. Rate of clinical response after tofacitinb induction was similar in biologic naive and biologic experienced patients.

BACKGROUND: The objective of our systematic review and meta-analysis was to evaluate the effectiveness and safety of tofacitinib in the treatment of moderate-severe ulcerative colitis (UC).

DETAILS: Authors searched Medline, Embase, Web of Science, and Cochrane Central to identify articles and abstracts reporting efficacy or safety data on tofacitinib use in UC. Primary outcome assessed was remission. Secondary outcomes included clinical response, steroid free remission, and adverse events (AEs). A total of 26 studies were included. The rates of remission were 29.81% [95% confidence interval (CI): 22.37%-37.25%, I2: 90%] at week 8, 32.27% (95% CI: 27.67%-36.88%, I2: 42%) at 6 months and 38.03% (95% CI: 33.59%-42.48%, I2: 0%) at 1-year. Clinical response rates were 59.41% (95% CI: 55.03%-63.94%, I2: 61%) at week 8, 48.99% (95% CI: 36.92%-61.06%, I2: 91%) at 6 months and 50.87% (95% CI: 42.16%-59.58%, I2: 67%) at 1-year. Odds ratio of clinical response at week 8 in biologic naive versus biologic experienced patients was 1.59 (95% CI: 0.54-4.63). Pooled incidence rate for serious infections, major adverse cardiovascular events, and nonmelanotic squamous cell malignancies across all doses was 4.41 per 100-patient years (PYs) (95% CI: 2.32-8.38 per 100-PY, I2: 78%), 0.91 per 100-PY (95% CI: 0.43-1.93 per 100-PY, I2: 37%) and 0.91 per 100-PY (95% CI: 0.61-1.34 per 100-PY, I2: 0%), respectively. Higher dose was associated with an increased frequency of AEs.

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Source: Taneja, V., El-Dallal, M., Haq, Z., et al. (2022). Effectiveness and Safety of Tofacitinib for Ulcerative Colitis: Systematic Review and Meta-analysis. J Clin Gastro. 2022; 56(10): e323-e333. Published: November/December, 2022. DOI: 10.1097/MCG.0000000000001608.



An Endoscopic and Histologic Study on Healing of Radiofrequency Ablation Wounds in Patients With Barrett's Esophagus

RFA wounds in BE are re-epithelialized, not just by squamous cells from the proximal wound margin but by scattered squamous islands.

source: Am J Gastro.

Summary

[Posted 26/Oct/2022]

AUDIENCE: Gastroenterology, Internal Medicine

KEY FINDINGS: RFA wounds in BE are re-epithelialized, not just by squamous cells from the proximal wound margin but by scattered squamous islands in which esophageal submucosal gland duct cells seem to redifferentiate into the squamous progenitors that fuel squamous re-epithelialization. SSIM can be found in most patients during the healing process. We speculate that this SSIM might underlie Barrett's recurrences after apparently successful eradication.

BACKGROUND: Radiofrequency ablation (RFA) of Barrett's esophagus (BE) inflicts a wound spanning 3 epithelial types (stratified squamous, Barrett's metaplasia, gastric epithelium), yet the esophageal injury heals almost completely with squamous epithelium. Knowledge of how this unique wound heals might elucidate mechanisms underlying esophageal metaplasia. We aimed to prospectively and systematically characterize the early endoscopic and histologic features of RFA wound healing.

DETAILS: Patients with nondysplastic BE had endoscopy with systematic esophageal photographic mapping, biopsy, and volumetric laser endomicroscopy performed before and at 1, 2, and 4 weeks after RFA. Seven patients (6 men; mean age 56.1 ± 10.9 years) completed this study. Squamous re-epithelialization of RFA wounds did not only progress exclusively through squamous cells extending from the proximal wound edge but also progressed through islands of squamous epithelium sprouting throughout the ablated segment. Volumetric laser endomicroscopy revealed significant post-RFA increases in subepithelial glandular structures associated with the squamous islands. In 2 patients, biopsies of such islands revealed newly forming squamous epithelium contiguous with immature-appearing squamous cells arising from esophageal submucosal gland ducts. Subsquamous intestinal metaplasia (SSIM) was found in biopsies at 2 and/or 4 weeks after RFA in 6 of 7 patients.

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Source: Konda, V., Souza, R. F., Dunbar, K. B. et al. (2022). An Endoscopic and Histologic Study on Healing of Radiofrequency Ablation Wounds in Patients With Barrett's Esophagus. Am J Gastro.. 2022; 17(10): 1583-1592. Published: October, 2022. DOI: 10.14309/ajg.0000000000001940.



Association of Celiac Serology Normalization With the Risk of Hypothyroidism

During the study it was reported that persistent-positive serology may be associated with the risk of hypothyroidism among the pediatric population.

source: Am J Gastro.

Summary

A Cohort Study

[Posted 27/Sep/2022]

AUDIENCE: Gastroenterology, Internal Medicine

KEY FINDINGS: In this retrospective, age-stratified analysis, it was reported that persistent-positive serology may be associated with the risk of hypothyroidism among the pediatric population. Prospective cohorts are needed to validate our findings.

BACKGROUND: During the study whether persistent-positive celiac serology is associated with the risk of hypothyroidism was evaluated.

DETAILS: Extracted a cohort of subjects aged 1-80 years with a positive IgA anti-tissue transglutaminase between January 1, 2008, and December 31, 2012, and a repeat anti-tissue transglutaminase test within 6-36 months from a large population-based electronic medical record database. Based on serology tests, categorized the pediatric (age <21 years) and adult cohorts into normalized or persistent-positive serology groups. All subjects were followed up for incident diagnosis of hypothyroidism from the last serology date up to December 31, 2017. Hazard ratio (HR) along 95% confidence intervals (CIs) were prepared to evaluate the association of celiac serology group with a diagnosis of hypothyroidism, crude, and adjusted for age, sex, and diagnosis of type 1 diabetes mellitus. Among the pediatric cohort (n = 2,687), during a median follow-up of 64 months (interquartile range 48-80), 2.3% (16/681) of the persistent-positive serology group and 1.0% (20/2,006) of the normalized serology group developed hypothyroidism (HR 2.07 [95% CI 1.07-4.44], adjHR 1.77 [95% CI 0.91-3.46]). The rate among the pediatric cohort with an established diagnosis of celiac disease was 3.4% (10/486) vs 1.0% (5/481), HR 2.83 (0.96-8.32). In the adult cohort (n = 1,286), 4.5% (20/442) of the persistent-positive group and 3.9% (33/811) of the normalized serology group developed hypothyroidism (HR 1.13 [95% CI 0.65-1.97]).

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Source: Golan, M. A., Feldman, B., Ollech, J. E., et al. (2022). Association of Celiac Serology Normalization With the Risk of Hypothyroidism: A Cohort Study. American Journal of Gastroenterology. 2022; 117(9): 1428-1436, 2022Published: September 2022. DOI: 10.14309/ajg.0000000000001872.



Integrated Metagenomic and Metabolomic Analysis Reveals Distinct Gut-Microbiome-Derived Phenotypes In Early-Onset Colorectal Cancer

Data suggests altered microbiome-metabolome interplay helps explain the pathogenesis of EO-CRC and LO-CRC.

source: Gut

Summary

[Posted 17/Aug/2022]

AUDIENCE: Gastroenterology, Oncology, Internal Medicine

KEY FINDINGS: The large-sample multiomics data suggest that altered microbiome–metabolome interplay helps explain the pathogenesis of EO-CRC and LO-CRC. The potential of microbiome-derived biomarkers as promising non-invasive tools could be used for the accurate detection and distinction of individuals with EO-CRC.

BACKGROUND: The incidence of early-onset colorectal cancer (EO-CRC) is steadily increasing. Here, we aimed to characterise the interactions between gut microbiome, metabolites and microbial enzymes in EO-CRC patients and evaluate their potential as non-invasive biomarkers for EO-CRC.

DETAILS: Metagenomic and metabolomic analyses was performed, identified multiomics markers and constructed CRC classifiers for the discovery cohort with 130 late-onset CRC (LO-CRC), 114 EO-CRC subjects and age-matched healthy controls (97 LO-Control and 100 EO-Control). An independent cohort of 38 LO-CRC, 24 EO-CRC, 22 LO-Controls and 24 EO-Controls was analysed to validate the results. Compared with controls, reduced alpha-diversity was apparent in both, LO-CRC and EO-CRC subjects. Although common variations existed, integrative analyses identified distinct microbiome–metabolome associations in LO-CRC and EO-CRC. Fusobacterium nucleatum enrichment and short-chain fatty acid depletion, including reduced microbial GABA biosynthesis and a shift in acetate/acetaldehyde metabolism towards acetyl-CoA production characterises LO-CRC. In comparison, multiomics signatures of EO-CRC tended to be associated with enriched Flavonifractor plauti and increased tryptophan, bile acid and choline metabolism. Notably, elevated red meat intake-related species, choline metabolites and KEGG orthology (KO) pldB and cbh gene axis may be potential tumour stimulators in EO-CRC. The predictive model based on metagenomic, metabolomic and KO gene markers achieved a powerful classification performance for distinguishing EO-CRC from controls.

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Source: Kong C., Liang L., Liu G., et al. (2022). Integrated Metagenomic and Metabolomic Analysis Reveals Distinct Gut-Microbiome-Derived Phenotypes In Early-Onset Colorectal Cancer. Gut. Published: August 11, 2022. DOI: 10.1136/gutjnl-2022-327156.



Inhibition of Carnitine Palmitoyltransferase 1A in HSC Protects Against Fibrosis

CPT1A is overexpressed in HSCs from patients with fibrosis and positively correlates with fibrosis and NAFLD activity score.

source: J Hepatology

Summary

[Posted 03/Aug/2022]

AUDIENCE: Gastroenterology, Internal Medicine

KEY FINDINGS: The results indicate that CPT1A plays a critical role in the activation of HSCs and is implicated in the development of liver fibrosis, making it a potentially actionable target for fibrosis treatment.

BACKGROUND: The pathogenesis of liver fibrosis requires activation of hepatic stellate cells (HSCs); once activated, HSCs lose intracellular fatty acids but the role of fatty acid oxidation and carnitine palmitoyltransferase 1A (CPT1A) in this process remains largely unexplored.

DETAILS: CPT1A was found in HSCs of patients with fibrosis. Pharmacological and genetic manipulation of CPT1A were performed in human HSC cell lines and primary HCSs. Finally, induced fibrosis in mice lacking CPT1A specifically in HSCs. Herein, study shows that CPT1A expression is elevated in HSCs of patients with non-alcoholic steatohepatitis, showing a positive correlation with the fibrosis score. This was corroborated in rodents with fibrosis, as well as in primary human HSCs and LX-2 cells activated by transforming growth factor ß1 (TGFß1) and fetal bovine serum (FBS). Furthermore, both pharmacological and genetic silencing of CPT1A prevent TGFß1- and FBS-induced HSC activation by reducing mitochondrial activity. The overexpression of CPT1A, induced by saturated fatty acids and reactive oxygen species, triggers mitochondrial activity and the expression of fibrogenic markers. Finally, mice lacking CPT1A specifically in HSCs are protected against fibrosis induced by a choline-deficient high-fat diet, a methionine- and choline-deficient diet, or treatment with carbon tetrachloride.

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Copyright © Elsevier Inc. All rights reserved.

Source: Fondevila, M. F., Fernandes, U., Heras, V., et al. (2022). Inhibition of Carnitine Palmitoyltransferase 1A in Hepatic Stellate Cells Protects Against Fibrosis. J Hepatology. 2022; 77(1): 15-28. Published: July, 2022. DOI: 10.1016/j.jhep.2022.02.003.



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