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Dietary modulation of the microbiome affects autoinflammatory disease

(2014) NATURE. 516(7530). p.246-249
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Abstract
The incidences of chronic inflammatory disorders have increased considerably over the past three decades(1). Recent shifts in dietary consumption may have contributed importantly to this surge, but how dietary consumption modulates inflammatory disease is poorly defined. Pstpip2(cmo) mice, which express a homozygous Leu98Pro missense mutation in the Pombe Cdc15 homology family protein PSTPIP2 (proline-serine-threonine phosphatase interacting protein 2), spontaneously develop osteomyelitis that resembles chronic recurrent multifocal osteomyelitis in humans(2-4). Recent reports demonstrated a crucial role for interleukin-1 beta (IL-1 beta) in osteomyelitis, but deletion of the inflammasome components caspase-1 and NLRP3 failed to rescue Pstpip2(cmo) mice from inflammatory bone disease(5,6). Thus, the upstream mechanisms controlling IL-1 beta production in Pstpip2(cmo) mice remain to be identified. In addition, the environmental factors driving IL-1 beta-dependent inflammatory bone erosion are unknown. Here we show that the intestinal microbiota of diseased Pstpip2(cmo) mice was characterized by an outgrowth of Prevotella. Notably, Pstpip2(cmo) mice that were fed a diet rich in fat and cholesterol maintained a normal body weight, but were markedly protected against inflammatory bone disease and bone erosion. Diet-induced protection against osteomyelitis was accompanied by marked reductions in intestinal Prevotella levels and significantly reduced pro-IL-1 beta expression in distant neutrophils. Furthermore, pro-IL-1 beta expression was also decreased in Pstpip2(cmo) mice treated with antibiotics, and in wild-type mice that were kept under germ-free conditions. We further demonstrate that combined deletion of caspases 1 and 8 was required for protection against IL-1 beta-dependent inflammatory bone disease, whereas the deletion of either caspase alone or of elastase or neutrophil proteinase 3 failed to prevent inflammatory disease. Collectively, this work reveals diet-associated changes in the intestinal microbiome as a crucial factor regulating inflammasome- and caspase-8-mediated maturation of IL-1 beta and osteomyelitis in Pstpip2cmo mice.
Keywords
HOMEOSTASIS, ACTIVATION, PROTEINASE-3, OSTEOMYELITIS, INTERLEUKIN-1-BETA, CELL, IL-1-BETA PRODUCTION, CASPASE-8, INFLAMMASOME, MICE

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Chicago
Lukens, John R, Prajwal Gurung, Peter Vogel, Gordon R Johnson, Robert A Carter, Daniel J McGoldrick, Srinivasa Rao Bandi, et al. 2014. “Dietary Modulation of the Microbiome Affects Autoinflammatory Disease.” Nature 516 (7530): 246–249.
APA
Lukens, J. R., Gurung, P., Vogel, P., Johnson, G. R., Carter, R. A., McGoldrick, D. J., Bandi, S. R., et al. (2014). Dietary modulation of the microbiome affects autoinflammatory disease. NATURE, 516(7530), 246–249.
Vancouver
1.
Lukens JR, Gurung P, Vogel P, Johnson GR, Carter RA, McGoldrick DJ, et al. Dietary modulation of the microbiome affects autoinflammatory disease. NATURE. 2014;516(7530):246–9.
MLA
Lukens, John R, Prajwal Gurung, Peter Vogel, et al. “Dietary Modulation of the Microbiome Affects Autoinflammatory Disease.” NATURE 516.7530 (2014): 246–249. Print.
@article{5808541,
  abstract     = {The incidences of chronic inflammatory disorders have increased considerably over the past three decades(1). Recent shifts in dietary consumption may have contributed importantly to this surge, but how dietary consumption modulates inflammatory disease is poorly defined. Pstpip2(cmo) mice, which express a homozygous Leu98Pro missense mutation in the Pombe Cdc15 homology family protein PSTPIP2 (proline-serine-threonine phosphatase interacting protein 2), spontaneously develop osteomyelitis that resembles chronic recurrent multifocal osteomyelitis in humans(2-4). Recent reports demonstrated a crucial role for interleukin-1 beta (IL-1 beta) in osteomyelitis, but deletion of the inflammasome components caspase-1 and NLRP3 failed to rescue Pstpip2(cmo) mice from inflammatory bone disease(5,6). Thus, the upstream mechanisms controlling IL-1 beta production in Pstpip2(cmo) mice remain to be identified. In addition, the environmental factors driving IL-1 beta-dependent inflammatory bone erosion are unknown. Here we show that the intestinal microbiota of diseased Pstpip2(cmo) mice was characterized by an outgrowth of Prevotella. Notably, Pstpip2(cmo) mice that were fed a diet rich in fat and cholesterol maintained a normal body weight, but were markedly protected against inflammatory bone disease and bone erosion. Diet-induced protection against osteomyelitis was accompanied by marked reductions in intestinal Prevotella levels and significantly reduced pro-IL-1 beta expression in distant neutrophils. Furthermore, pro-IL-1 beta expression was also decreased in Pstpip2(cmo) mice treated with antibiotics, and in wild-type mice that were kept under germ-free conditions. We further demonstrate that combined deletion of caspases 1 and 8 was required for protection against IL-1 beta-dependent inflammatory bone disease, whereas the deletion of either caspase alone or of elastase or neutrophil proteinase 3 failed to prevent inflammatory disease. Collectively, this work reveals diet-associated changes in the intestinal microbiome as a crucial factor regulating inflammasome- and caspase-8-mediated maturation of IL-1 beta and osteomyelitis in Pstpip2cmo mice.},
  author       = {Lukens, John R and Gurung, Prajwal and Vogel, Peter and Johnson, Gordon R and Carter, Robert A and McGoldrick, Daniel J and Bandi, Srinivasa Rao and Calabrese, Christopher R and Vande Walle, Lieselotte and Lamkanfi, Mohamed and Kanneganti, Thirumala-Devi},
  issn         = {0028-0836},
  journal      = {NATURE},
  keywords     = {HOMEOSTASIS,ACTIVATION,PROTEINASE-3,OSTEOMYELITIS,INTERLEUKIN-1-BETA,CELL,IL-1-BETA PRODUCTION,CASPASE-8,INFLAMMASOME,MICE},
  language     = {eng},
  number       = {7530},
  pages        = {246--249},
  title        = {Dietary modulation of the microbiome affects autoinflammatory disease},
  url          = {http://dx.doi.org/10.1038/nature13788},
  volume       = {516},
  year         = {2014},
}

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