Gut barrier dysfunction and microbial translocation in cancer cachexia: a new therapeutic target

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Abstract

Purpose of Review

Cachexia is a complex metabolic syndrome characterized by skeletal muscle and adipose tissue loss and is frequently associated with emaciation, anorexia, systemic inflammation, and metabolic dysfunction. Lack of a clear understanding of the cause of cancer cachexia has impeded progress in identifying effective therapeutic agents. This review summarizes recent publications on the role of gut barrier function, intestinal microbiota, and inflammation in the etiology of cancer cachexia and new therapeutic interventions that may benefit treatment strategies.

Recent Findings

Significant advances have been made in understanding the composition and metabolic capabilities of the intestinal microbiota and its impact on gut barrier function with implications for certain inflammatory-based diseases. Recent studies reported associations between intestinal permeability and endotoxemia with development of cancer cachexia and other metabolic disorders. Improvements in intestinal function and weight gain along with decreased inflammation have been reported for potential therapeutic agents such as eicosapentaenoic acid, immunoglobulin isolates, and probiotics.

Summary

Continued progress in the scientific understanding of the complex interplay between the intestinal microbiota, gut barrier function, and host inflammatory responses will uncover new therapeutic targets to help avoid the serious metabolic alterations associated with cachexia.

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Most cited references 49

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Regulation of human epithelial tight junction proteins by Lactobacillus plantarum in vivo and protective effects on the epithelial barrier.

Jurgen Karczewski, Freddy J. Troost, Irene B.M. Konings … (2010)

Lactobacillus plantarum, a commensal bacterium of humans, has been proposed to enhance the intestinal barrier, which is compromised in a number of intestinal disorders. To study the effect of L. plantarum strain WCFS1 on human barrier function, healthy subjects were administered L. plantarum or placebo in the duodenum for 6 h by means of a feeding catheter. The scaffold protein zonula occludens (ZO)-1 and transmembrane protein occludin were found to be significantly increased in the vicinity of the tight-junction (TJ) structures, which form the paracellular seal between cells of the epithelium. In an in vitro model of the human epithelium, L. plantarum induced translocation of ZO-1 to the TJ region; however, the effects on occludin were minor compared with those seen in vivo. L. plantarum was shown to activate Toll-like receptor 2 (TLR2) signaling, and treatment of Caco-2 monolayers with the TLR2 agonist Pam(3)-Cys-SK4(PCSK) significantly increased fluorescent staining of occludin in the TJ. Pretreatment of Caco-2 monolayers with L. plantarum or PCSK significantly attenuated the effects of phorbol ester-induced dislocation of ZO-1 and occludin and the associated increase in epithelial permeability. Our results identifying commensal bacterial stimulation of TLR2 in the gut epithelium as a regulator of epithelial integrity have important implications for understanding probiotic mechanisms and the control of intestinal homeostasis.

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Disease phenotype and genotype are associated with shifts in intestinal-associated microbiota in inflammatory bowel diseases.

Daniel Frank, Charles E. Robertson, Christina Hamm … (2011)

Abnormal host-microbe interactions are implicated in the pathogenesis of inflammatory bowel diseases. Previous 16S rRNA sequence analysis of intestinal tissues demonstrated that a subset of Crohn's disease (CD) and ulcerative colitis (UC) samples exhibited altered intestinal-associated microbial compositions characterized by depletion of Bacteroidetes and Firmicutes (particularly Clostridium taxa). We hypothesize that NOD2 and ATG16L1 risk alleles may be associated with these alterations. To test this hypothesis, we genotyped 178 specimens collected from 35 CD, 35 UC, and 54 control patients for the three major NOD2 risk alleles (Leu 1007fs, R702W, and G908R) and the ATG16L1T300A risk allele, that had undergone previous 16S rRNA sequence analysis. Our statistical models incorporated the following independent variables: 1) disease phenotype (CD, UC, non-IBD control); 2) NOD2 composite genotype (NOD2(R) = at least one risk allele, NOD2(NR) = no risk alleles); 3) ATG16L1T300A genotype (ATG16L1(R/R), ATG16L1(R/NR), ATG16L1(NR/NR)); 4) patient age at time of surgery and all first-order interactions. The dependent variable(s) were the relative frequencies of bacterial taxa classified by applying the RDP 2.1 classifier to previously reported 16S rRNA sequence data. Disease phenotype, NOD2 composite genotype and ATG16L1 genotype were significantly associated with shifts in microbial compositions by nonparametric multivariate analysis of covariance (MANCOVA). Shifts in the relative frequencies of Faecalibacterium and Escherichia taxa were significantly associated with disease phenotype by nonparametric ANCOVA. These results support the concept that disease phenotype and genotype are associated with compositional changes in intestinal-associated microbiota. Copyright © 2010 Crohn's & Colitis Foundation of America, Inc.

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Chronic intestinal inflammation: inflammatory bowel disease and colitis-associated colon cancer

DEBORAH RUBIN, Anisa Shaker, Marc S Levin (2012)

The inflammatory bowel diseases (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), are chronic inflammatory disorders of the intestine. The prevalence in the United States is greater than 200 cases per 100,000, with the total number of IBD patients between 1 and 1.5 million. CD may affect all parts of the gastrointestinal tract, from mouth to anus, but most commonly involves the distal part of the small intestine or ileum, and colon. UC results in colonic inflammation that can affect the rectum only, or can progress proximally to involve part of or the entire colon. Clinical symptoms include diarrhea, abdominal pain, gastrointestinal bleeding, and weight loss. A serious long-term complication of chronic inflammation is the development of colorectal cancer. A genetic basis for IBD had long been recognized based on the increased familial risk. However, significant discordance for CD in twins, and a much less robust phenotypic concordance for UC, suggested additional factors play a role in disease pathogenesis, including environmental factors. In the past several years, progress in understanding the molecular basis of IBD has accelerated, beginning with the generation of animal models of colitis and progressing to the identification of specific genetic markers from candidate gene, gene linkage, and genome-wide association analyses. Genetic studies have also resulted in the recognition of the importance of environmental factors, particularly the crucial role of the gut microbiota in CD and UC. Altered immune responses to the normal intestinal flora are key factors in IBD pathogenesis. In this research topic, the genetic basis of IBD, the genetic and cellular alterations associated with colitis-associated colon cancer, and the emerging role of the intestinal microbiota and other environmental factors will be reviewed.

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Journal

Journal ID (nlm-ta): Curr Opin Support Palliat Care

Journal ID (iso-abbrev): Curr Opin Support Palliat Care

Journal ID (publisher-id): COSPA

Title: Current Opinion in Supportive and Palliative Care

Publisher: Lippincott Williams & Wilkins

ISSN (Print): 1751-4258

ISSN (Electronic): 1751-4266

Publication date (Print): November 2013

Publication date (Electronic): 06 November 2013

Volume: 7

Issue: 4

Pages: 361-367

Affiliations

[a ]Entera Health, Inc, Cary, North Carolina, USA

Article

DOI: 10.1097/SPC.0000000000000017

PMC ID: 3819310

PubMed ID: 24157715

SO-VID: 663b07df-95c4-4d36-bb73-9d14cb78b76a

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This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivitives 3.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially.

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Keywords: cancer cachexia,cytokines,gut barrier,inflammation,microbiota,translocation

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Keywords: cancer cachexia, cytokines, gut barrier, inflammation, microbiota, translocation

Gut barrier dysfunction and microbial translocation in cancer cachexia: a new therapeutic target

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Abstract

Purpose of Review

Recent Findings

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Microbial Genomics

Most cited references 49

Regulation of human epithelial tight junction proteins by Lactobacillus plantarum in vivo and protective effects on the epithelial barrier.

Disease phenotype and genotype are associated with shifts in intestinal-associated microbiota in inflammatory bowel diseases.

Chronic intestinal inflammation: inflammatory bowel disease and colitis-associated colon cancer

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