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As the largest immune organ with the greatest microbial burden, the gastrointestinal (GI) tract may change the speed and direction the patient follows along this pathway. The gut's influence is mediated by a complex process of cross\u2010talk immune signaling between the intestinal epithelium, the liver, and the microbiome. Agents that invoke this response vary from mitochondrial DNA, inflammatory cytokines, and bacterial organisms to short\u2010chain fatty acids and bile salts. The site of action of these agents again varies widely from pattern\u2010recognition receptors, G protein receptors, and farnesoid X receptors in the gut and liver to transcriptional factors in epithelial cells, hepatocytes, macrophages, and neutrophils. Whereas the initial focus of response may be local within the GI tract and liver, the process extends in a systemic manner to affect immune tissue and various organs at distant sites. The gut can modulate this cross\u2010talk signaling through numerous strategies in the design of nutrition therapy. The physiologic response to luminal nutrients and short\u2010chain fatty acids, and more novel approaches like using phosphorylated polyethylene glycol, bovine serum\u2013derived immunoglobulin, and specialized proresolving molecules, may help slow disease progression and even reverse the patient's course toward one of health and recovery. The optimal benefit to be derived from nutrition therapy may have more to do with the degree to which immune cross\u2010talk signaling can be modified by such innovative strategies.<\/jats:p>","DOI":"10.1002\/jpen.2260","type":"journal-article","created":{"date-parts":[[2021,9,3]],"date-time":"2021-09-03T08:05:34Z","timestamp":1630656334000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Can feeding strategies alter immune signaling and gut sepsis in critical illness?"],"prefix":"10.1002","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1140-7263","authenticated-orcid":false,"given":"Stephen A.","family":"McClave","sequence":"first","affiliation":[{"name":"Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine University of Louisville School of Medicine  Louisville Kentucky USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2021,12,13]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clnu.2017.07.015"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/ncp.10371"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40560-019-0372-6"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/ncp.10228"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1177\/014860719702100114"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2013.08.004"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro2297"},{"issue":"3","key":"e_1_2_6_9_1","first-page":"309","article-title":"Gut failure in critical care: old school versus new school","volume":"28","author":"Sertaridou E","year":"2015","journal-title":"Ann Gastroenterol"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2004.09.015"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.05.041"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/apt.13333"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcmgh.2014.11.004"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v21.i37.10487"},{"journal-title":"Nat Rev Gastro Hep. 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