Chronic inflammatory diseases are often initiated and guided by the release of proinflammatory mediators. Rheumatoid arthritis (RA) is caused by an imbalance between the pro- and anti-inflammatory mediators in the joints, thereby favoring chronic inflammation and joint damage. Here, we investigate if short-term high-fiber dietary intervention shifts this towards anti-inflammatory mediators. Healthy controls (n = 10) and RA patients (n = 29) under routine care received daily high-fiber bars for 15 or 30 days, respectively. Stool and sera were analyzed for pro- and anti-inflammatory mediators. A high-fiber dietary intervention resulted in increased anti-inflammatory short-chain fatty acids (SCFA), decreased proarthritic cytokine concentrations, along with a durable shift in the Firmicutes-to-Bacteroidetes ratio. Together, these results further strengthen high-fiber dietary interventions as a practical approach complementing existing pharmacological therapies.

Objectives Metabolic changes are crucially involved in osteoclast development and may contribute to bone degradation in rheumatoid arthritis (RA). The enzyme aconitate decarboxylase 1 (Acod1) is known to link the cellular function of monocyte-derived macrophages to their metabolic status. As osteoclasts derive from the monocyte lineage, we hypothesised a role for Acod1 and its metabolite itaconate in osteoclast differentiation and arthritis-associated bone loss. Methods Itaconate levels were measured in human peripheral blood mononuclear cells (PBMCs) of patients with RA and healthy controls by mass spectrometry. Human and murine osteoclasts were treated with the itaconate derivative 4-octyl-itaconate (4-OI) in vitro. We examined the impact of Acod1-deficiency and 4-OI treatment on bone erosion in mice using K/BxN serum-induced arthritis and human TNF transgenic (hTNFtg) mice. SCENITH and extracellular flux analyses were used to evaluate the metabolic activity of osteoclasts and osteoclast progenitors. Acod1-dependent and itaconate-dependent changes in the osteoclast transcriptome were identified by RNA sequencing. CRISPR/Cas9 gene editing was used to investigate the role of hypoxia-inducible factor (Hif)-1α in Acod1-mediated regulation of osteoclast development. Results Itaconate levels in PBMCs from patients with RA were inversely correlated with disease activity. Acod1-deficient mice exhibited increased osteoclast numbers and bone erosion in experimental arthritis while 4-OI treatment alleviated inflammatory bone loss in vivo and inhibited human and murine osteoclast differentiation in vitro. Mechanistically, Acod1 suppressed osteoclast differentiation by inhibiting succinate dehydrogenase-dependent production of reactive oxygen species and Hif1α-mediated induction of aerobic glycolysis. Conclusion Acod1 and itaconate are crucial regulators of osteoclast differentiation and bone loss in inflammatory arthritis.

Corynebacterium ulcerans is an emerging pathogen, which is increasingly recognized as an etiological agent of diphtheria, but can also evoke ulcers of the skin and systemic infections in humans. Besides man, the bacteria can colonize a wide variety of different animals, including cattle and pet animals, which might serve as a reservoir for human infections. In this study, surface-located proteins and the exoproteome of two Corynebacterium ulcerans strains were analyzed, since these may have key roles in the interaction of the pathogen with host cells. Strain 809 was isolated from a fatal case of human respiratory tract infection, while strain BR-AD22 was isolated from a nasal swap of an asymptomatic dog. While a very similar pattern of virulence factors was observed in the culture supernatant and surface protein fractions of the two strains, proteome analyses revealed a higher stability of 809 cells compared to strain BR-AD22. During exponential growth, 17% of encoded proteins of strain 809 were detectable in the medium, while 38% of the predicted proteins encoded by the BR-AD22 chromosome were found. Furthermore, the data indicate differential expression of phospholipase D and a cell wall-associated hydrolase, since these were only detected in strain BR-AD22.

Chronic inflammatory diseases like rheumatoid arthritis (RA) have been described to cause CNS activation. Less is known about environmental factors that enable the CNS to suppress peripheral inflammation in RA. Here, we identified gut microbiota–derived histamine as such a factor. We showed that low levels of histamine activate the enteric nervous system, increase inhibitory neurotransmitter concentrations in the spinal cord, and restore homeostatic microglia, thereby reducing inflammation in the joints. We found that elective histamine 3 receptor (H3R) signaling in the intestine was critical for this effect, as systemic and intrathecal application did not show effects. Microglia depletion or pharmacological silencing of local nerve fibers impaired oral H3R agonist–induced pro-resolving effects on arthritis. Moreover, therapeutic supplementation of the short-chain fatty acid propionate revealed one way to expand local intestinal histamine concentrations in mice and humans. Thus, we define a gut/CNS/joint axis pathway where microbiota-derived histamine initiates the resolution of arthritis via the CNS.

The Dictyostelium discoideum NC4 genome harbors approximately 150 individual copies of a retrotransposable element called the Dictyostelium repetitive element (DRE). This element contains nonidenti...