The effects of intentionally-induced leaky gut on metabolism and production in lactating Holstein dairy cows

Abstract Text: Presumably, intestinal barrier dysfunction negatively affects productivity, but it has never been studied in a controlled lactation experiment. Objectives were to elucidate consequences of leaky gut in otherwise healthy mid-lactation dairy cows.  Twelve Holstein cows (170.0 ± 15.1 DIM, 670 ± 13 kg BW, parity 1 to 5) were enrolled in two experimental periods.  Period 1 (P1) lasted 5d and served as baseline for period 2 (P2), which lasted 7d in which cows received one of two treatments I.V. twice daily: 1) sterile saline (control) or 2) gamma secretase inhibitor (GSI; 1.5 mg/kg BW). GSI specifically inhibits crypt stem cell differentiation into enterocytes via disrupting Notch signaling.  Control animals were pair-fed (PF) to GSI-treated cows (to eliminate the confounding effects of dissimilar feed intake). GSI administration caused a progressive reduction in DMI (P<0.01; 82%) and milk yield (P<0.01; 57%), but there was no treatment effect on milk components. Cows in both treatments lost a similar amount of BW (56 kg) by the end of P2. Histological analysis indicated GSI increased jejunum goblet cell area (3.3 vs. 1.0%; P=0.02), tended to: deepen villous crypts (P=0.06), reduce villous height (P=0.07) and alter villous height to crypt depth ratio (P=0.08). No treatment effects were detected in ileum or colon morphology, but manure score (a measure of fecal consistency) was decreased 36% (P<0.01) in the GSI-treated vs. PF controls. By d5-7 of P2, circulating lipopolysaccharide (LPS) was increased >3 fold in PF controls compared to GSI-treated cows. Plasma LPS binding protein (LPB) levels progressively increased in both treatments but were increased (42%, P<0.01) in GSI-treated vs. PF controls by d5-7 of P2. By the end of P2, the LPS:LPB ratio was increased 3.6 fold (P<0.05) in PF controls compared to GSI-treated cows. Haptoglobin and serum amyloid-A concentrations progressively increased (>400 and >5 fold, respectively) similarly in both treatments. Circulating IFNγ, TNFα and IL-6 were unaffected by treatment or time. GSI-treated cows tended to have increased plasma insulin (P=0.07) and decreased circulating NEFA (P=0.06) vs. PF cows. For both treatments, plasma glucose decreased with time (P=0.05), while BHBA progressively increased (87%; P=0.08). There were no treatment differences in spleen weight, liver weight, liver moisture, or liver lipid content. In summary, based upon all the data, GSI-treatment compromised intestinal integrity and markedly reduced feed intake and milk yield. Further, we have demonstrated progressive feed reduction also negatively influenced intestinal integrity.

Keywords: Lipopolysaccharide, insulin