Dietary modulation of the microbiome affects autoinflammatory disease

Autor: Thirumala-Devi Kanneganti, Gordon R. Johnson, Peter Vogel, Srinivasa Rao Bandi, John R. Lukens, Daniel J. McGoldrick, Prajwal Gurung, Christopher Calabrese, Robert A. Carter, Lieselotte Vande Walle, Mohamed Lamkanfi
Rok vydání: 2014
Předmět:
Zdroj: Nature
ISSN: 1476-4687
Popis: Pstpip2-mutant mice fed a high-fat diet are protected against inflammatory bone disease and bone erosion; this protection is associated with reductions in intestinal Prevotella levels and pro-IL-1β expression, and is dependent on the deletion of both caspases 1 and 8. It has been suggested that recent increases in the prevalence of autoinflammatory diseases may be due in part to dietary change, but the possible mechanisms involved remain poorly defined. This study shows that mice with a Pstpip2cmo mutant gene, a model for osteomyelitis, are fully protected against inflammatory bone disease and bone erosion when fed a diet rich in fat and cholesterol. Protection correlates with a shift in the intestinal microbiota, including marked reductions in Prevotella levels, and significantly reduced pro-interleukin-1β levels in circulating immune cells. The incidences of chronic inflammatory disorders have increased considerably over the past three decades1. Recent shifts in dietary consumption may have contributed importantly to this surge, but how dietary consumption modulates inflammatory disease is poorly defined. Pstpip2cmo 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 humans2,3,4. Recent reports demonstrated a crucial role for interleukin-1β (IL-1β) in osteomyelitis, but deletion of the inflammasome components caspase-1 and NLRP3 failed to rescue Pstpip2cmo mice from inflammatory bone disease5,6. Thus, the upstream mechanisms controlling IL-1β production in Pstpip2cmo mice remain to be identified. In addition, the environmental factors driving IL-1β-dependent inflammatory bone erosion are unknown. Here we show that the intestinal microbiota of diseased Pstpip2cmo mice was characterized by an outgrowth of Prevotella. Notably, Pstpip2cmo 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-1β expression in distant neutrophils. Furthermore, pro-IL-1β expression was also decreased in Pstpip2cmo 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-1β-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-1β and osteomyelitis in Pstpip2cmo mice.
Databáze: OpenAIRE