{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T08:29:05Z","timestamp":1792225745224,"version":"4.4.0"},"reference-count":40,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2022,10,27]],"date-time":"2022-10-27T00:00:00Z","timestamp":1666828800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2022,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Cachexia\u2010anorexia syndrome is a complex metabolic condition characterized by skeletal muscle wasting, reduced food intake and prominent involvement of systemic and central inflammation. Here, the gut barrier function was investigated in pancreatic cancer\u2010induced cachexia mouse models by relating intestinal permeability to the degree of cachexia. We further investigated the involvement of the gut\u2013brain axis and the crosstalk between tumour, gut and hypothalamus in vitro.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Two distinct mouse models of pancreatic cancer cachexia (KPC and 4662) were used. Intestinal inflammation and permeability were assessed through fluorescein isothiocyanate dextran (FITC\u2010dextran) and lipopolysaccharide (LPS), and hypothalamic and systemic inflammation through mRNA expression and plasma cytokines, respectively. To simulate the tumour\u2013gut\u2013brain crosstalk, hypothalamic (HypoE\u2010N46) cells were incubated with cachexia\u2010inducing tumour secretomes and LPS. A synthetic mimic of C26 secretome was produced based on its secreted inflammatory mediators. Each component of the mimic was systematically omitted to narrow down the key mediator(s) with an amplifying inflammation. To substantiate its contribution, cyclooxygenase\u20102 (COX\u20102) inhibitor was used.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In vivo experiments showed FITC\u2010dextran was enhanced in the KPC group (362.3 vs. sham 111.4\u00a0ng\/mL, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001). LPS was increased to 140.9\u00a0ng\/mL in the KPC group, compared with sham and 4662 groups (115.8 and 115.8\u00a0ng\/mL, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05). Hypothalamic inflammatory gene expression of <jats:italic>Ccl2<\/jats:italic> was up\u2010regulated in the KPC group (6.3 vs. sham 1, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.0001, 4662 1.3, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001), which significantly correlated with LPS concentration (<jats:italic>r<\/jats:italic>\u00a0=\u00a00.4948, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.0226). These data suggest that intestinal permeability is positively related to the cachexic degree. Prostaglandin E2 (PGE2) was confirmed to be present in the plasma and PGE2 concentration (log10) in the KPC group was much higher than in 4662 group (1.85 and 0.56\u00a0ng\/mL, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001), indicating a role for PGE2 in pancreatic cancer\u2010induced cachexia.<\/jats:p><jats:p>Parallel to in vivo findings, in vitro experiments revealed that the cachexia\u2010inducing tumour secretomes (C26, LLC, KPC and 4662) amplified LPS\u2010induced hypothalamic IL\u20106 secretion (419%, 321%, 294%, 160%). COX\u20102 inhibitor to the tumour cells reduced PGE2 content (from 10<jats:sup>5<\/jats:sup> to 10<jats:sup>2<\/jats:sup>\u00a0pg\/mL) in the secretomes and eliminated the amplified hypothalamic IL\u20106 production. Moreover, results could be reproduced by addition of PGE2 alone, indicating that the increased hypothalamic inflammation is directly related to the PGE2 from tumour.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>PGE2 secreted by the tumour may play a role in amplifying the effects of bacteria\u2010derived LPS on the inflammatory hypothalamic response. The cachexia\u2010inducing potential of tumour mice models parallels the loss of intestinal barrier function. Tumour\u2010derived PGE2 might play a key role in cancer\u2010related cachexia\u2010anorexia syndrome via tumour\u2013gut\u2013brain crosstalk.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.13093","type":"journal-article","created":{"date-parts":[[2022,10,28]],"date-time":"2022-10-28T01:43:41Z","timestamp":1666921421000},"page":"3014-3027","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Lipopolysaccharide\u2010induced hypothalamic inflammation in cancer cachexia\u2010anorexia is amplified by tumour\u2010derived prostaglandin E2"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9570-8631","authenticated-orcid":false,"given":"Xiaolin","family":"Li","sequence":"first","affiliation":[{"name":"Nutritional Biology, Division of Human Nutrition Wageningen University  Wageningen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tosca","family":"Holtrop","sequence":"additional","affiliation":[{"name":"Nutritional Biology, Division of Human Nutrition Wageningen University  Wageningen The Netherlands"},{"name":"Pap\u00e9 Family Pediatric Research Institute Oregon Health &amp; Science University (OHSU)  Portland OR USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fleur A.C.","family":"Jansen","sequence":"additional","affiliation":[{"name":"Nutritional Biology, Division of Human Nutrition Wageningen University  Wageningen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brennan","family":"Olson","sequence":"additional","affiliation":[{"name":"Pap\u00e9 Family Pediatric Research Institute Oregon Health &amp; Science University (OHSU)  Portland OR USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pete","family":"Levasseur","sequence":"additional","affiliation":[{"name":"Pap\u00e9 Family Pediatric Research Institute Oregon Health &amp; Science University (OHSU)  Portland OR USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinxia","family":"Zhu","sequence":"additional","affiliation":[{"name":"Pap\u00e9 Family Pediatric Research Institute Oregon Health &amp; Science University (OHSU)  Portland OR USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mieke","family":"Poland","sequence":"additional","affiliation":[{"name":"Nutritional Biology, Division of Human Nutrition Wageningen University  Wageningen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Winni","family":"Schalwijk","sequence":"additional","affiliation":[{"name":"Nutritional Biology, Division of Human Nutrition Wageningen University  Wageningen The 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