Undernutrition Disrupts Cecal Microbiota and Epithelium Interactions, Epithelial Metabolism, and Immune Responses in a Pregnant Sheep Model.

Undernutrition may change cecal microbiota-epithelium interactions to influence cecal feed fermentation, nutrient absorption and metabolism, and immune function. Sixteen late-gestation Hu-sheep were randomly divided into control (normal feeding) and treatment (feed restriction) groups to establish an undernourished sheep model. Cecal digesta and epithelium were collected to analyze microbiota-host interactions based on 16S rRNA gene and transcriptome sequencing. Results showed that cecal weight and pH were decreased, volatile fatty acids and microbial proteins concentrations were increased, and epithelial morphology was changed upon undernutrition. Undernutrition reduced the diversity, richness, and evenness of cecal microbiota. The relative abundances of cecal genera involved in acetate production ( dgA-11 gut group, RC9 gut group, and ) and negatively correlated with butyrate proportion ( vadinBB60 group_norank) were decreased, while genera related to butyrate (_uncultured and _uncultured) and valerate (_uncultured) production were increased in undernourished ewes. These findings were consistent with the decreased molar proportion of acetate and the increased molar proportions of butyrate and valerate. Undernutrition changed the overall transcriptional profile and substance transport and metabolism in cecal epithelium. Undernutrition suppressed extracellular matrix-receptor interaction and intracellular phosphatidyl inositol 3-kinase (PI3K) signaling pathway then disrupted biological processes in cecal epithelium. Moreover, undernutrition repressed phagosome antigen processing and presentation, cytokine-cytokine receptor interaction, and intestinal immune network. In conclusion, undernutrition affected cecal microbial diversity and composition and fermentation parameters, inhibited extracellular matrix-receptor interaction and the PI3K signaling pathway, and then disrupted epithelial proliferation and renewal and intestinal immune functions. Our findings exposed cecal microbiota-host interactions upon undernutrition and contribute to their further exploration. Undernutrition is commonly encountered in ruminant production, especially during pregnancy and lactation in females. Undernutrition not only induces metabolic diseases and threatens pregnant mothers' health, but also inhibits fetal growth and development, leading to weakness or even death of fetuses. Cecum works importantly in hindgut fermentation, providing volatile fatty acids and microbial proteins to the organism. Intestinal epithelial tissue plays a role in nutrient absorption and transport, barrier function, and immune function. However, little is known about cecal microbiota and epithelium interactions upon undernutrition. Our findings showed that undernutrition affected bacterial structures and functions, which changed fermentation parameters and energy regimens, and therefore affected the substance transport and metabolism in cecal epithelium. Extracellular matrix-receptor interactions were inhibited, which repressed cecal epithelial morphology and cecal weight via the PI3K signaling pathway and lowered immune response function upon undernutrition. These findings will help in further exploring microbe-host interactions.