What is the clinical evidence from this study?

Study design: Cross-Sectional. Population: Atrial fibrillation (n=48). Intervention: Atrial fibrillation vs. Healthy controls. Primary outcome: Fecal SCFA levels (μg/g) (p=0.045).

What does this research mean for the field?

Fecal short-chain fatty acid levels are significantly reduced in patients with atrial fibrillation, and these commensal microbe-derived SCFAs protect against AF development by deactivating the NLRP3 inflammasome via GPR43 signaling. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

January 1, 2022Open Access

Commensal microbe-derived SCFA alleviates atrial fibrillation via GPR43/NLRP3 signaling

Key Result

Fecal short-chain fatty acid levels were significantly reduced in patients with atrial fibrillation (3060.67 μg/g) compared to matched healthy controls (3559.68 μg/g).

Study Design

Type

Cross-Sectional (n=48)

Multicenter

Structured PICO

Does SCFA derived from dietary fiber fermentation alleviate atrial fibrillation development and atrial remodeling?

Population

48 human subjects (24 AF patients, 24 matched healthy controls) for cross-sectional metabolomics; 6-8 week old wild-type male C57BL/6 mice; murine atrial-derived HL-1 cardiomyocytes.

Intervention

High-fiber diet (5% cellulose + 5% inulin) or low-fiber diet supplemented with SCFA (sodium propionate 25 mM, sodium butyrate 40 mM, sodium acetate 67.5 mM in sterile water) for 4 weeks in mice; SCFA pre-treatment in HL-1 cells.

Comparator

Normal-fiber diet (5% cellulose) or low-fiber diet (1% cellulose) in mice; LPS/nigericin stimulation without SCFA pre-treatment in HL-1 cells.

Outcome

Fecal SCFA levels in human cohort; AF inducibility by transesophageal burst pacing and atrial remodeling (P wave duration, LA diameter, fibrosis, NLRP3 inflammasome activation) in mice.surrogate

Commensal microbe-derived short-chain fatty acids from dietary fiber fermentation protect against atrial fibrillation by attenuating NLRP3 inflammasome activation via GPR43 signaling.

Main Result

Absolute Event Rate: 3060.67% vs 3559.68%

p-value: p=0.045

Limitations

Small sample size of the cross-sectional study
Potential mechanism underlying low-fiber diet and activated NLRP3 is yet to be deduced
Further experiments on atrial refractoriness and patch clamp-based ion channel study are needed
Non-targeted metabolomic analysis is needed to explore other metabolites

Abstract

Rationale: Dysbiotic gut microbiota (GM) and NLRP3 inflammasome are proarrhythmic factors in atrial fibrillation (AF). Herein, whether short-chain fatty acid (SCFA) produced from GM fermentation of dietary fiber serving as invisible mediators is yet unclear. Thus, the current study aimed to determine whether SCFA alleviated from NLRP3 signaling-mediated atrial remodeling protects AF development. Methods: First, a cross-sectional study based on the GC-MS metabolomics was performed to explore the association between fecal SCFA levels and AF traits in a cohort consisted of 48 individuals. Then, a well-established mice model fed diet deficient or enriched in dietary fiber was established to elucidate the pathophysiological role of SCFA involved in AF susceptibility, atrial remodeling, and G-protein-coupled receptor 43 (GPR43)/NLRP3 signaling. Finally, the effects of SCFA were verified on HL-1 cells. Results: Fecal SCFA levels were remarkably reduced in AF patients with a declining trend from paroxysmal to persistent AF. Prolonged P wave duration based on surface ECG and increased left atrial diameter gained from echocardiography was identified in low-fiber diet mice but lost in SCFA-supplemented group. Lack of dietary fiber enhanced susceptibility to AF under burst pacing, whereas SCFA might exert a protective effect. The supplementation of SCFA prevented dietary fiber deficiency-upregulated phosphorylation of calmodulin-dependent protein kinase II and ryanodine receptor 2, the disarray fibrosis, collagen expression, and NLRP3 inflammasome activation in atrial tissue. Finally, the AF protective roles of SCFA were identified through GPR43 mediated deactivation of NLRP3 by GPR43 knockdown in HL-1 cells. Conclusions: SCFA derived from dietary fiber fermentation by gut commensals alleviates AF development via GPR43/NLRP3 signaling.

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