Yasmine Soubra

Introduction. Cancer cachexia is a highly prevalent metabolic condition characterized by muscle wasting, weight loss, and systemic inflammation. Depending on the type of cancer, 70-80% of cancer patients will be affected by cachexia, showing a decreased quality of life and increased morbidity and mortality rates.^3,4 Often associated with cachectic inflammation is systemic inflammation caused by an impaired gut barrier. Dysregulated microbiota has been shown to over activate the immune system through dysregulated blood flow and toxin translocation.¹ Methods. Many sources were reviewed to investigate a specific mechanism behind the progression of microbiota dysbiosis to cachectic inflammation and wasting. Multiple sources used colon cancer mouse models to study the impact and progression of cachexia. Subsequently, genetic material was extracted from stool samples and sequenced through qPCR to characterize fecal microbiota species.^2,3,6 The research was then focused on studying inflammatory markers (Interleukin (IL)-6), pair-feeding, and a highly prevalent species (Klebsiella oxytoca) to further delineate a causative mechanism, independently of confounding factors (i.e., anorexia, chemotherapy).^2,6 Results. Klebsiella oxytoca reported as the dominant species in the fecal samples of cachectic mice.³ A link between K. oxytoca expansion and upregulated IL-6 was found to play a major role in this pathway, whereby IL-6 induced markers of muscle atrophy, gut permeability, and antigen load, observed by a reduction in these markers when an IL-6 antibody was injected.⁶ Upregulation of IL-6 also induced Claudin-2 expression, a tight junction protein, indicating a link between IL-6 and trans-epithelial resistance across the gut barrier. Dysregulated Claudin-2 resulted in decreased resistance to the flow of ionic solutes across the epithelial barrier.⁷ When translated into clinical medicine, the above results were confirmed through demonstrating that cachectic lung cancer patients presented with significantly lower BMI, survival probability, and a significantly different microbiota profile with 51 abundant species identified, including K. oxytoca.⁸ Conclusion. Current treatments for cancer cachexia have been negatively impacted due to refractory cancer cachexia complicating chemotherapy.¹⁰ Focus has shifted to symptomatic alleviation through corticosteroid and progestin use, and nourishing and replacing microbiota composition with prebiotics and probiotics, respectively.^1,9 Fecal microbiota transplantation has also been discussed.⁵ Future work should aim at targeting a specific species, like K. oxytoca, in hopes of treating this debilitating disease from the source.

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2. Herremans KM, Riner AN, Cameron ME, Trevino JG. The Microbiota and Cancer Cachexia. Int J Mol Sci. 2019;20(24):6267. Published 2019 Dec 12. doi:10.3390/ijms20246267
3. Pötgens SA, Brossel H, Sboarina M, et al. Klebsiella oxytoca expands in cancer cachexia and acts as a gut pathobiont contributing to intestinal dysfunction. Sci Rep. 2018;8(1):12321. Published 2018 Aug 17. doi:10.1038/s41598-018-30569-5
4. Ni Y, Lohinai Z, Heshiki Y, et al. Distinct composition and metabolic functions of human gut microbiota are associated with cachexia in lung cancer patients. ISME J. 2021;15(11):3207-3220. doi:10.1038/s41396-021-00998-8
5. de Maria YNLF, Aciole Barbosa D, Menegidio FB, et al. Analysis of mouse faecal dysbiosis, during the development of cachexia, induced by transplantation with Lewis lung carcinoma cells. Microbiology (Reading). 2021;167(10):10.1099/mic.0.001088. doi:10.1099/mic.0.001088
6. Bindels LB, Neyrinck AM, Loumaye A, et al. Increased gut permeability in cancer cachexia: mechanisms and clinical relevance. Oncotarget. 2018;9(26):18224-18238. Published 2018 Apr 6. doi:10.18632/oncotarget.24804
7. Suzuki T, Yoshinaga N, Tanabe S. Interleukin-6 (IL-6) regulates claudin-2 expression and tight junction permeability in intestinal epithelium. J Biol Chem. 2011; 286:31263–71. https://doi.org/10.1074/jbc.M111.238147.
8. Ni Y, Lohinai Z, Heshiki Y, et al. Distinct composition and metabolic functions of human gut microbiota are associated with cachexia in lung cancer patients. ISME J. 2021;15(11):3207-3220. doi:10.1038/s41396-021-00998-8
9. Trivedi R, Barve K. Gut microbiome a promising target for management of respiratory diseases. Biochem J. 2020;477(14):2679-2696. doi:10.1042/BCJ20200426
10. Sørensen J. Lung Cancer Cachexia: Can Molecular Understanding Guide Clinical Management?. Integr Cancer Ther. 2018;17(3):1000-1008. doi:10.1177/1534735418781743