| Summary: | Chorioamnionitis, clinically most frequently associated with <i>Ureaplasma</i>, is linked to intestinal inflammation and subsequent gut injury. No treatment is available to prevent chorioamnionitis-driven adverse intestinal outcomes. Evidence is increasing that plant sterols possess immune-modulatory properties. Therefore, we investigated the potential therapeutic effects of plant sterols in lambs intra-amniotically (IA) exposed to <i>Ureaplasma</i>. Fetal lambs were IA exposed to <i>Ureaplasma parvum</i> (<i>U. parvum</i>, UP) for six days from 127 d−133 d of gestational age (GA). The plant sterols β-sitosterol and campesterol, dissolved with β-cyclodextrin (carrier), were given IA every two days from 122 d−131 d GA. Fetal circulatory cytokine levels, gut inflammation, intestinal injury, enterocyte maturation, and mucosal phospholipid and bile acid profiles were measured at 133 d GA (term 150 d). IA plant sterol administration blocked a fetal inflammatory response syndrome. Plant sterols reduced intestinal accumulation of proinflammatory phospholipids and tended to prevent mucosal myeloperoxidase-positive (MPO) cell influx, indicating an inhibition of gut inflammation. IA administration of plant sterols and carrier diminished intestinal mucosal damage, stimulated maturation of the immature epithelium, and partially prevented <i>U. parvum</i>-driven reduction of mucosal bile acids. In conclusion, we show that β-sitosterol and campesterol administration protected the fetus against adverse gut outcomes following UP-driven chorioamnionitis by preventing intestinal and systemic inflammation.
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