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Two major factors known to influence immune function and mortality in animals and people are early life stress and biological sex. How these two factors interact to shape long-term immune development and later life disease risk is poorly understood. Here we investigated how early weaning, a common early life stressor in pigs, and biological sex impacts long-term systemic inflammatory responses and hypothalamic\u2013pituitary\u2013adrenal axis (HPA axis) activation later in life. Ten-week-old female (F), intact-male (IM) and castrated-male (CM) pigs that were randomly assigned to early weaning (EW) and later weaning (LW) (at 15 or 28\u00a0days of age, respectively) were intramuscularly injected with either saline vehicle or lipopolysaccharide (LPS) to induce a systemic inflammatory response. Complete blood counts (CBC), proinflammatory cytokines, cortisol, testosterone, estradiol, and rectal temp were measured at 0\u00a0h, 2\u00a0h, and 4\u00a0h post-LPS challenge. At 4\u00a0h post-LPS, peritoneal fluid (PF) and white blood cells (WBC) were collected for differential analysis. LPS challenge significantly increased rectal temp and plasma cortisol level in all treatment groups. Together, the CBC results and immune cell counts in peritoneal cavity indicated that EW-F exhibited greater systemic immune response characterized by increased neutrophils to lymphocytes ratio (NLR) and enhanced neutrophil trafficking to the peritoneal cavity. Early weaning had an opposite effect on IM and CM pigs, which exhibited a suppressed LPS-induced neutrophil migration. Early weaning induced significantly greater cortisol responses only in IM pigs indicating a heightened HPA axis responses in EW-IM. how early weaning and biological sex affect immune and stress responses in pigs. Together, these results demonstrate that early weaning and biological sex and castration shape later life immune responses in pigs and provides insight into potential mechanisms driving sex differences in later life inflammatory disease risk and mortality.<\/jats:p>","DOI":"10.1038\/s41598-023-42553-9","type":"journal-article","created":{"date-parts":[[2023,9,23]],"date-time":"2023-09-23T10:02:01Z","timestamp":1695463321000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Early weaning and biological sex shape long-term immune and metabolic responses in pigs"],"prefix":"10.1038","volume":"13","author":[{"given":"Mahsa","family":"Fardisi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyan","family":"Thelen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allegra","family":"Groenendal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mrigendra","family":"Rajput","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimberly","family":"Sebastian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G. 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