Dietary modulation of the microbiome affects autoinflammatory disease

Abstract

The incidences of chronic inflammatory disorders have increased significantly over the past three decades1. Recent shifts in dietary consumption are believed to have contributed importantly to this surge, but how dietary consumption modulates inflammatory disease is poorly defined. Pstpip2cmo mice that express a homozygous L98P missense mutation in the Pombe Cdc15 homology (PCH) family proline-serine-threonine phosphatase interacting protein 2 (PSTPIP2) phosphatase spontaneously develop osteomyelitis that resembles chronic recurrent multifocal osteomyelitis (CRMO) in humans2-4. Recent reports demonstrated osteomyelitis to critically rely on IL-1β, 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 proIL-1β expression in distant neutrophils. Furthermore, proIL-1β expression was also decreased in antibiotics-treated Pstpip2cmo mice, and in wildtype mice that were kept under germfree conditions. We further demonstrated that combined deletion of caspases 1 and 8 was required for protection against IL-1β-dependent inflammatory bone disease, whereas deletion of each caspase alone, elastase or neutrophil proteinase-3 failed to prevent inflammatory disease. Collectively, this work reveals diet-associated changes in the intestinal microbiome as a critical factor regulating inflammasome- and caspase-8-mediated maturation of IL-1β and osteomyelitis in Pstpip2cmo mice.

IgD class switching is initiated by microbiota and limited to mucosa-associated lymphoid tissue in mice

“…Samples were sequenced on an Ion PGM System (Thermo Fisher Scientific) according to the manufacturer's instructions, and the results were analyzed with the Ion Reporter software Ion 16S Metagenomics Kit analyses module (Thermo Fisher Scientific). Relative proportions of microbial taxa for each sample and the signal-to-noise ratio were assembled as described previously after filtering out singletons (taxa found in only one sample) and low-coverage taxa (those with <20 total reads) (26). Ssignal-to-noise ratios are depicted in heat map plots generated with R software and principal component analyses generated with Ion Reporter software.…”

IL-1β and Caspase-1 Drive Autoinflammatory Disease Independently of IL-1α or Caspase-8 in a Mouse Model of Familial Mediterranean Fever

“…We previously showed that although IL-1a promotes disease in a mouse model of neutrophilic dermatosis, 10 IL-1b drives neutrophil-mediated disease in a mouse model of osteomyelitis. 16,21,22 Previous studies have shown contradictory roles for wildtype and mutant pyrin (harboring mutations associated with FMF) in IL-1b processing and inflammation. 1,4,23e27 Pyrin recently was identified as an inflammasome-forming sensor that responds to Rho inactivation induced by bacterial infections.…”

Impact of environmental factors on alloimmunity and transplant fate

“…Modifying the diet is another approach to altering the microbiota, though precise control will be difficult to achieve. Nevertheless, in mice with a genetic alteration that resulted in arthritis and spontaneous development of osteomyelitis that correlated with intestinal outgrowth of Prevotella, a diet rich in fat and cholesterol decreased levels of gut Prevotella, reduced systemic pro-IL-1β, and prevented bone erosion (163). This demonstrates that diet can have a dominant effect over genetic predisposition.…”