Vorinostat and other inhibitors of different histone deacetylase (HDAC) enzymes are currently being sought to modulate a variety of human conditions, including chronic inflammatory diseases. Some HDAC inhibitors are anti-inflammatory in rodent models of arthritis and colitis, usually at cytotoxic doses that may cause side effects. Here, we investigate the dose-dependent pro-and anti-inflammatory efficacy of two known inhibitors of multiple HDACs, vorinostat and BML281, in human macrophages and in a rat model of collagen-induced arthritis by monitoring effects on disease progression, histopathology, and immunohistochemistry. Both HDAC inhibitors differentially modulated lipopolysaccharide (LPS)-induced cytokine release from human macrophages, suppressing release of some inflammatory mediators (IL12p40, IL6) at low concentrations (,3 mM) but amplifying production of others (TNF, IL1b) at higher concentration (.3 mΜ). This trend translated in vivo to rat arthritis, with anti-inflammatory activity inversely correlating with dose. Both compounds were efficacious only at a low dose (1 mg×kg 21 ×day 21 s.c.), whereas a higher dose (5 mg×kg 2 1 ×day 2 1 s.c.) showed no positive effects on reducing pathology, even showing signs of exacerbating disease. These striking effects suggest a smaller therapeutic window than previously reported for HDAC inhibition in experimental arthritis. The findings support new investigations into repurposing HDAC inhibitors for anti-inflammatory therapeutic applications. However, HDAC inhibitors should be reinvestigated at lower, rather than higher, doses for enhanced efficacy in chronic diseases that require long-term treatment, with careful management of efficacy and long-term safety.

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LINKED CONTENT This article is linked to Ronkainen et al paper. To view this article, visit https://doi.org/10.1111/apt.15308

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BackgroundFunctional dyspepsia is characterised by chronic symptoms of post-prandial distress or epigastric pain not associated with defined structural pathology. Increased peripheral gut-homing T cells have been previously identified in patients. To date, it is unknown if these T cells were antigen-experienced, or if a specific phenotype was associated with FD.ObjectiveThis study aimed to characterise T cell populations in the blood and duodenal mucosa of FD patients that may be implicated in disease pathophysiology.MethodsWe identified duodenal T cell populations from 23 controls and 49 Rome III FD patients by flow cytometry using a surface marker antibody panel. We also analysed T cell populations in peripheral blood from 37 controls and 61 patients. Where available, we examined the number of duodenal eosinophils in patients and controls.ResultsThere was a shift in the duodenal T helper cell balance in FD patients compared to controls. For example, patients had increased duodenal mucosal Th2 populations in the effector (13.03 ± 16.11, 19.84 ± 15.51, p=0.038), central memory (23.75 ± 18.97, 37.52 ± 17.51, p=0.007) and effector memory (9.80±10.50 vs 20.53±14.15, p=0.001) populations. Th17 populations were also increased in the effector (31.74±24.73 vs 45.57±23.75, p=0.03) and effector memory (11.95±8.42 vs 18.44±15.63, p=0.027) subsets. Peripheral T cell populations were unchanged between FD and control.ConclusionOur findings identify an association between lymphocyte populations and FD, specifically a Th2 and Th17 signature in the duodenal mucosa. The presence of effector and memory cells suggest that the microinflammation in FD is antigen driven.

Background/AimsSystemic sclerosis (SSc) often is complicated by small intestinal bacterial overgrowth (SIBO). A systematic review and meta-analysis thus examined the prevalence of SIBO in SSc (SSc-subtypes), identify risk factors for SIBO in SSc and the effects of concomitant SIBO on gastrointestinal symptoms in SSc. MethodsWe searched electronic databases until January-2022 for studies providing prevalence rates of SIBO in SSc. The prevalence rates, odds ratio (OR) and 95% confidence intervals (CI) of SIBO in SSc and controls were calculated. ResultsThe final dataset comprised 28 studies with 1112 SSc-patients and 335 controls. SIBO prevalence in SSc-patients was 39.9% (95% CI, 33.1-47.1; P = 0.006), with considerable heterogeneity, (I 2 = 76.00%, P < 0.001). As compared to controls, there was a 10-fold increased SIBO prevalence in SSc-patients (OR, 9.6; 95% CI, 5.6-16.5; P < 0.001). The prevalence of SIBO was not different in limited cutaneous SSc as compared to diffuse cutaneous SSc (OR, 1.01; 95% CI, 0.46-2.20; P = 0.978). Diarrhea (OR, 5.9; 95% CI, 2.9-16.0; P = 0.001) and the association between SIBO in SSc and proton pump inhibitor use (OR, 2.3; 95% CI, 0.8-6.4; P = 0.105) failed statistical significance. Rifaximin was significantly more effective as compared to rotating antibiotic in eradicating SIBO in SSc-patients (77.8% [95% CI, 64.4-87.9]) vs 44.8% [95% CI, 31.7-58.4]; P < 0.05). ConclusionsThere is a 10-fold increased prevalence of SIBO in SSc, with similar SIBO prevalence rates in SSc-subtypes. Antimicrobial therapy of SIBO-positive SSc-patients with diarrhea should be considered. However, the results must be interpreted with caution due to substantial unexplained heterogeneity in the prevalence studies, and the low sensitivity and specificity of the diagnostic tests suggesting that the reliability of the evidence may be low.

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