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.



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.



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.



AKD is Common and Associated with Poor Outcomes In Patients with Cirrhosis and AKI

AKD develops in 1 in 3 hospitalized patients with cirrhosis and AKI and it is associated with worse 90- and 180-day survival and de novo CKD.

source: J Hepatology

Summary

Acute Kidney DiseaseiIs Common and Associated with Poor Outcomes In Patients with Cirrhosis and Acute Kidney Injury

[Posted 11/Jul/2022]

AUDIENCE: Gastroenterology, Nephrology, Internal Medicine

KEY FINDINGS: AKD develops in 1 in 3 hospitalized patients with cirrhosis and AKI and it is associated with worse survival and de novo CKD. Interventions that target AKD may improve outcomes of patients with cirrhosis and AKI.

BACKGROUND: Acute kidney disease (AKD) is the persistence of acute kidney injury (AKI) for up to 3 months, which is proposed to be the time-window where critical interventions can be initiated to alter downstream outcomes of AKI. In cirrhosis, AKD and its impact on outcomes have been scantly investigated. Study aim was to define the incidence and outcomes associated with AKD in a nationwide US cohort of hospitalized patients with cirrhosis and AKI.

DETAILS: Hospitalized patients with cirrhosis and AKI in the Cerner-Health-Facts database from 1/2009-09/2017 (n = 6,250) were assessed for AKD and were followed-up for 180 days. AKI and AKD were defined based on KDIGO and ADQI AKD and renal recovery consensus criteria, respectively. The primary outcome measure was mortality, and the secondary outcome measure was de novo chronic kidney disease (CKD). Competing-risk multivariable models were used to determine the independent association of AKD with primary and secondary outcomes. AKD developed in 32% of our cohort. On multivariable competing-risk analysis adjusting for significant confounders, patients with AKD had higher risk of mortality at 90 (subdistribution hazard ratio [sHR] 1.37; 95% CI 1.14-1.66; p = 0.001) and 180 (sHR 1.37; 95% CI 1.14-1.64; p = 0.001) days. The incidence of de novo CKD was 37.5%: patients with AKD had higher rates of de novo CKD (64.0%) compared to patients without AKD (30.7%; p 0.001). After adjusting for confounders, AKD was independently associated with de novo CKD (sHR 2.52; 95% CI 2.01-3.15; p 0.001) on multivariable competing-risk analysis.

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Source: Patidar, K. R., Naved, M. A., Grama, A., et al. (2022). Acute Kidney Disease Is Common and Associated with Poor Outcomes In Patients With Cirrhosis And Acute Kidney Injury. J Hepatology. 2022; 77(1): 108-115. Published: July, 2022. DOI: 10.1016/j.jhep.2022.02.009.



Hepatitis B Surface Antigen Levels

Hepatitis B virus genotype-specific HBsAg cutoffs may have utility in ruling out presence of cirrhosis in HBeAg-positive patients with genotypes B, C, and D and can be an adjunct to FIB-4 to reduce the need for further testing.

source: J Infect Disease

Summary

Hepatitis B Surface Antigen Levels Can Be Used to Rule Out Cirrhosis in Hepatitis B e Antigen-Positive Chronic Hepatitis B: Results From the SONIC-B Study

[Posted 14/Jun/2022]

AUDIENCE: Infectious Disease, Internal Medicine

KEY FINDINGS: Hepatitis B virus genotype-specific HBsAg cutoffs may have utility in ruling out presence of cirrhosis in HBeAg-positive patients with genotypes B, C, and D and can be an adjunct to FIB-4 to reduce the need for further testing.

BACKGROUND: Serum hepatitis B surface antigen (HBsAg) levels correlate with the duration of chronic hepatitis B virus (HBV) infection and may predict the extent of hepatic fibrosis.

DETAILS: Analyzed data from the SONIC-B database, which contains data from 8 global randomized trials and 2 large hepatology centers. Relationship between HBsAg levels and presence of significant fibrosis (Ishak 3-4) or cirrhosis (Ishak 5-6) were explored, and clinically relevant cutoffs were identified to rule out cirrhosis. The dataset included 2779 patients: 1866 hepatitis B e antigen (HBeAg)-positive; 322 with cirrhosis. Among HBeAg-positive patients, lower HBsAg levels were associated with higher rates of significant fibrosis (odds ratio [OR], 0.419; P < .001) and cirrhosis (OR, 0.435; P < .001). No relationship was observed among HBeAg-negative patients. Among HBeAg-positive patients, genotype-specific HBsAg cutoffs had excellent negative predictive values (>97%) and low misclassification rates (<=7.1%) and may therefore have utility in ruling out cirrhosis. Diagnostic performance of the HBsAg cutoffs was comparable among patients in whom cirrhosis could not be ruled out with fibrosis 4 (FIB-4).

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Copyright © Oxford University Press for the Infectious Diseases Society of America. All rights reserved.

Source: Sonneveld, M. J., Hansen, B. H., Brouwer, W. P., et al. (2022). Hepatitis B Surface Antigen Levels Can Be Used to Rule Out Cirrhosis in Hepatitis B e Antigen-Positive Chronic Hepatitis B: Results From the SONIC-B Study. J Infect Disease. 2022; 225(11): 1967-1973. Published: June 6, 2022. DOI: 10.1093/infdis/jiaa192.



Pickle Juice Intervention for Cirrhotic Cramps Reduction

Study shows sips of pickle brine consumed at cramp onset improve cramp severity without adverse events.

source: Am J Gastro.

Summary

The PICCLES Randomized Controlled Trial

[Posted 13/Jun/2022]

AUDIENCE: Gastroenterology, Internal Medicine

KEY FINDINGS: In a randomized trial, sips of pickle brine consumed at cramp onset improve cramp severity without adverse events.

BACKGROUND: Muscle cramps are common among persons with cirrhosis and associated with poor health-related quality of life. Treatment options are limited. We sought to determine whether pickle juice can improve muscle cramp severity.

DETAILS: There were 82 patients were enrolled with cirrhosis and a history of >4 muscle cramps in the previous month from December 2020 to December 2021. Patients were randomized 1:1 to sips of pickle juice vs tap water at cramp onset. Our primary outcome assessed at 28 days was the change in cramp severity measured by the visual analog scale for cramps (VAS-cramps, scaled 0-10). Cramps were assessed 10 times over 28 days using interactive text messages. Secondary outcomes included the proportion of days with VAS-cramps <5, change in sleep quality, and global health-related quality of life measured using the EQ-5D. Overall, 74 patients completed the trial, aged 56.6 ± 11.5 years, 54% male, 41% with ascites, 38% with encephalopathy, and model for end-stage liver disease—sodium score 11.2 ± 4.9. Many patients were receiving other cramp therapies at baseline. The baseline VAS for cramps was 4.2 ± 3.4, the EQ-5D was 0.80 ± 0.10, and 43% rated sleep as poor. At trial completion, the respective values for the pickle juice and control arms were -2.25 ± 3.61 points on the VAS for cramps, compared with control tap water (-0.36 ± 2.87), P = 0.03; a proportion of cramp-days with VAS-cramps <5 were 46% vs 35% (P = 0.2); and the change in sleep quality was not different (P = 0.1). The end-of-trial EQ-5D was 0.78 ± 0.10 vs 0.80 ± 0.10 (P = 0.3). No differences in weight change were observed for those with and without ascites.

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Source: Tapper, E. B., Salim J., Baki, J., et al. (2022). Pickle Juice Intervention for Cirrhotic Cramps Reduction: The PICCLES Randomized Controlled Trial. Am J Gastro.. 2022; 117(6): 895-901. Published: June, 2022. DOI: 10.14309/ajg.0000000000001781.



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