High-Fat Diet Accelerates Carcinogenesis in a Mouse Model of Barrett’s Esophagus via Interleukin 8 and Alterations to the Gut Microbiome

Münch, Natasha Stephens; Fang, Hsin-Yu; Ingermann, Jonas; Maurer, H. Carlo; Anand, Akanksha; Kellner, Victoria; Sahm, Vincenz; Wiethaler, Maria; Baumeister, Theresa; Wein, Frederik; Einwächter, Henrik; Bolze, Florian; Klingenspor, Martin; Haller, Dirk; Kavanagh, Maria E.; Lysaght, Joanne; Friedman, Richard A.; Dannenberg, Andrew J.; Pollak, Michael; Holt, Peter R.; Muthupalani, Sureshkumar; Fox, James G.; Whary, Mark T.; Lee, Yoomi; Ren, Tony Y.; Elliot, Rachael; Fitzgerald, Rebecca; Steiger, Katja; Schmid, Roland M.; Wang, Yichen; Quante, Michael

doi:10.1053/j.gastro.2019.04.013

Cited by 105 publications

(99 citation statements)

References 62 publications

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“…The role of IL-8 in Barrett’s progression was recently described in a paper by Münch et al, which demonstrated that a high-fat diet induces IL-8 secretion and plays a role in accelerated dysplastic growth in a mouse model of BE ( 32 ). This model also demonstrated increased recruitment of immature myeloid cells and neutrophils.…”

Section: Discussionmentioning

confidence: 92%

Immune determinants of Barrett’s progression to esophageal adenocarcinoma

Lagisetty¹,

McEwen²,

Nancarrow³

et al. 2021

JCI Insight

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Section: Discussionmentioning

confidence: 92%

Immune determinants of Barrett’s progression to esophageal adenocarcinoma

Lagisetty¹,

McEwen²,

Nancarrow³

et al. 2021

JCI Insight

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“…Indeed, multiple studies have suggested that obesity per se may not be the culprit; instead, certain dietary and/or metabolic factors in obese patients may increase the risk of EAC. Particularly, across different cohorts of patients, both high-fat diet (HFD) (8)(9)(10) and metabolic syndrome have been consistently associated with increased risk of EAC (11)(12)(13)(14) . Supporting the importance of fatty-acid metabolism in the pathophysiology of EAC, among the metabolites from various categories (carbohydrate, amino acid, xenobiotics, lipid), fatty-acids accounted for a large faction of increased molecules in the serum of EAC patients compared with normal individuals (14).…”

Section: Introductionmentioning

confidence: 99%

A Transcriptional Regulatory Loop of Master Regulator Transcription Factors, PPARG, and Fatty Acid Synthesis Promotes Esophageal Adenocarcinoma

Zhou

Yang

et al. 2021

Cancer Research

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Although obesity is one of the strongest risk factors for esophageal adenocarcinoma, the molecular mechanisms underlying this association remain unclear. We recently identified four esophageal adenocarcinoma–specific master regulator transcription factors (MRTF) ELF3, KLF5, GATA6, and EHF. In this study, gene-set enrichment analysis of both esophageal adenocarcinoma patient samples and cell line models unbiasedly underscores fatty acid synthesis as the central pathway downstream of three MRTFs (ELF3, KLF5, GATA6). Further characterizations unexpectedly identified a transcriptional feedback loop between MRTF and fatty acid synthesis, which mutually activated each other through the nuclear receptor, PPARG. MRTFs cooperatively promoted PPARG transcription by directly regulating its promoter and a distal esophageal adenocarcinoma–specific enhancer, leading to PPARG overexpression in esophageal adenocarcinoma. PPARG was also elevated in Barrett’s esophagus, a recognized precursor to esophageal adenocarcinoma, implying that PPARG might play a role in the intestinal metaplasia of esophageal squamous epithelium. Upregulation of PPARG increased de novo synthesis of fatty acids, phospholipids, and sphingolipids as revealed by mass spectrometry–based lipidomics. Moreover, ChIP-seq, 4C-seq, and a high-fat diet murine model together characterized a novel, noncanonical, and cancer-specific function of PPARG in esophageal adenocarcinoma. PPARG directly regulated the ELF3 super-enhancer, subsequently activating the transcription of other MRTFs through an interconnected regulatory circuitry. Together, elucidation of this novel transcriptional feedback loop of MRTF/PPARG/fatty acid synthesis advances our understanding of the mechanistic foundation for epigenomic dysregulation and metabolic alterations in esophageal adenocarcinoma. More importantly, this work identifies a potential avenue for prevention and early intervention of esophageal adenocarcinoma by blocking this feedback loop. Significance: These findings elucidate a transcriptional feedback loop linking epigenomic dysregulation and metabolic alterations in esophageal adenocarcinoma, indicating that blocking this feedback loop could be a potential therapeutic strategy in high-risk individuals.

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“…Recently, microbiome alterations have been implicated in the pathogenesis of inflammatory and neoplastic conditions in the gastrointestinal tract, especially in the esophagus [21]. Very recently, scholars have studied the alterations of the microbiome in BE, which mainly focused on Campylobacter, Proteobacteria, Firmicutes, Streptococcus, Bacteroidetes, and Actinobacteria [22,23].…”

Section: Introductionmentioning

confidence: 99%

A Meta-Analysis of the Impact of Obesity, Metabolic Syndrome, Insulin Resistance, and Microbiome on the Diagnosis of Barrett’s Esophagus

Jia

Cheng

Chang

et al. 2019

Dig Dis

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Background and Aim: The etiology and pathogenesis of Barrett's esophagus (BE) have been widely studied during recent decades. However, the association between BE and possible risk factors, including abdominal obesity (AO), metabolic syndrome (MetS), insulin resistance (IR), and the microbiome has not reached a consensus and lacks a systematic assessment. The purpose of our study is to evaluate, quantify, and summarize the association between these factors and BE risk. Methods: A systematic search of Pubmed, Embase, and Cochrane Library databases was performed to identify relevant studies before September 2018. Studies were estimated with the OR, the weighted mean difference (WMD), and the 95% CI by using a random effects model. Subgroup analysis and publication bias were also performed. Results: A total of 46 citations were included in the analysis, and 119,273 subjects were analyzed (AO 13, MetS 15, IR 9, and microbiome: 9). The pooled results showed that AO (p < 0.01, OR 1.30, 95% CI 1.11-1.52, I 2 = 31.9%), MetS (p < 0.01, OR 1.68, 95% CI 1.40-2.01, I 2 = 87.6%), and IR (p < 0.01, WMD 0.23, 95% CI 0.11-0.35, I 2 = 55.8%) were all significantly associated with an increased risk of BE, but except for the mi-crobiome (p > 0.05, OR 1.27, 95% CI 0.66-2.43, I 2 = 46.7%). In addition, subgroup analyses were stratified by waist-to-hip ratio, waist circumference, body mass index, diagnosis criteria, strain type, geographical region, and study design, respectively. Moreover, we observed no evidence of publication bias in Egger's and Begg's tests. Conclusions: Our study reveals that AO, MetS, and IR are significantly associated with BE risk, except for the microbiome. The mechanism of BE induced by 3 risk factors should be further explored.

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High-Fat Diet Accelerates Carcinogenesis in a Mouse Model of Barrett’s Esophagus via Interleukin 8 and Alterations to the Gut Microbiome

Cited by 105 publications

References 62 publications

Immune determinants of Barrett’s progression to esophageal adenocarcinoma

Immune determinants of Barrett’s progression to esophageal adenocarcinoma

A Transcriptional Regulatory Loop of Master Regulator Transcription Factors, PPARG, and Fatty Acid Synthesis Promotes Esophageal Adenocarcinoma

A Meta-Analysis of the Impact of Obesity, Metabolic Syndrome, Insulin Resistance, and Microbiome on the Diagnosis of Barrett’s Esophagus

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