Abstract
The spread of bacterial resistance to antimicrobials (AMA) have intensified efforts to discontinue the non-therapeutic use of AMA in animal production. Finding alternatives to AMA, however, is currently encumbered by the obscure mechanism that underlies their growth-promoting action. In this report, we demonstrate that combinations of antibiotics and zinc oxide at doses commonly used for stimulating growth or preventing post-weaning enteritis in pigs converge in promoting microbial production of bile acids (BA) in the intestine. This leads to tissue-specific modifications in the proportion of BA, thereby amplifying BA signaling in intestine, liver, and white adipose tissue (WAT). Activation of BA-regulated pathways ultimately reinforces the intestinal protection against bacterial infection and pathological secretion of fluids and electrolytes, attenuates inflammation in colon and WAT, alters protein and lipid metabolism in liver, and increases the circulating levels of the hormone FGF19. Conceivably, these alterations could spare nutrients for growth and improve the metabolic efficiency of AMA-treated animals. This work provides evidence that BA act as signaling molecules that mediate host physiological, metabolic, and immune responses to the AMA-induced alterations in gut microbial metabolism, eventually permitting the growth-promoting action of AMA. Consequently, BA emerge as a promising target for developing efficacious alternatives to AMA.
Highlights
For more than 50 years, low doses of antibiotics either alone or in combination with pharmacological levels of heavy metals have been widely used in swine production to accelerate growth[1,2]
Using an experimental approach that closely resembles intensive systems of pig production, we show that combinations of antimicrobial agents (AMA) with different bacterial spectrum at doses commonly used for stimulating growth and preventing post-weaning enteritis converge in promoting body weight (BW) gain and altering the metabolism of bile acids (BA) by gut microbiota as well as the profile and signaling of BA in intestinal mucosa, liver, and white adipose tissue (WAT)
This work provides evidence that BA serve a mechanistic role in the growth-permitting action of AMA by acting as signaling molecules that mediate host physiological, metabolic, and immune-inflammatory responses to the AMA-induced alterations in gut microbial metabolism
Summary
For more than 50 years, low doses of antibiotics either alone or in combination with pharmacological levels of heavy metals (i.e., zinc and copper) have been widely used in swine production to accelerate growth[1,2]. Disruption of mouse microbiota by antibiotics altered synthesis and enterohepatic cycling of primary (produced by the liver) and secondary (produced by bacteria) BA and affected BA signature and FXR signaling in a tissue-specific manner[22,23] Both increased BSH activity due to expression of cloned BSH in the gut[24] and decreased BSH activity due to suppression of intestinal Lactobacilli[25] were associated with weight gain in rodents. A second study was conducted to confirm and expand findings from the first study To this end, a combination of zinc oxide, chlortetracycline, and tiamulin (ZCT) (Supplementary Table S2) was used to cover a different bacterial spectrum than ZAC and BA instructive functions were mainly examined in tissues outside the enterohepatic system. This work identifies BA as integrators and modulators of the host physiological, metabolic, and immune-inflammatory responses to the AMA-mediated alterations in gut microbial metabolism, which makes them a promising target for the development of efficacious alternatives to AMA
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