Butyrate suppresses atherosclerotic inflammation by regulating macrophages and polarization via GPR43/HDAC-miRNAs axis in ApoE−/− mice

Abstract

Chronic low-grade inflammation is regarded to an important signature of atherosclerosis (AS). Macrophage (Mψ) and related polarization have been demonstrated to play a crucial role in the occurrence and development of AS inflammation. Butyrate, a bioactive molecule produced by the intestinal flora, has been increasingly demonstrated to exhibit a vital role for regulating the inflammation in chronic metabolic diseases. However, the effectiveness and multiple anti-inflammation mechanisms of butyrate on AS still need to be further understood. ApoE−/− mice fed with high-fat diet as AS model were administered with sodium butyrate (NaB) for 14 weeks of treatment. Our results showed that the atherosclerotic lesion in the AS group was dramatically reduced after NaB intervention. Moreover, deteriorated routine parameters of AS including body weights (BWs), low-density lipoprotein (LDL-C), triglyceride (TG), total cholesterol (TC) were significantly reversed by NaB administration. Abnormal elevated plasma and aorta pro-inflammatory indicators including interleukin (IL)-1β, IL-6, IL-17A, tumor necrosis factor (TNF)-α and lipopolysaccharide (LPS), as well as reduced anti-inflammatory IL-10 in plasma were respectively rectified after NaB administration. Consistently, accumulated Mψ and associated imbalance of polarization in the arota were attenuated with NaB treatment. Importantly, we demonstrated that the suppression of Mψ and associated polarization of NaB was dependent on binding G-protein coupled receptor (GPR) and inhibiting histone deacetylase HDAC3. Moreover, we found that intestinal butyrate-producing bacteria, anti-inflammatory bacteria and intestinal tight junction protein zonula occludens-1 (ZO)-1 may contribute to this effectiveness. Intriguingly, according to transcriptome sequencing of atherosclerotic aorta, 29 elevated and 24 reduced miRNAs were found after NaB treatment, especially miR-7a-5p, suggesting that non-coding RNA may possess a potential role in the protection of NaB against AS. Correlation analysis showed that there were close complicated interactions among gut microbiota, inflammation and differential miRNAs. Collectively, this study revealed that dietary NaB may ameliorate atherosclerotic inflammation by regulating Mψ polarization via GPR43/HDAC-miRNAs axis in ApoE−/− mice.

Non-coding RNAs are key players and promising therapeutic targets in atherosclerosis

“…Sodium butyrate, a product of intestinal flora, has a therapeutic effect on AS. A previous report revealed that sodium butyrate in an AS model increased the expression levels of 29 miRNAs, including miR-7a-5p, and reduced the expression of 24 (Ma et al, 2023). This finding suggests that sodium butyrate can regulate miRNA expression in AS.…”

Remodeling Intestinal Microbiota Alleviates Severe Combined Hyperlipidemia-Induced Nonalcoholic Steatohepatitis and Atherosclerosis in LDLR -/- Hamsters

“…Two independent groups reported that BA decreased plasma TC levels and increased HDL-C levels without affecting plasma TG levels in HFD-fed ApoE -/- mice [ 31 , 32 ]; however, Ma et al. [ 33 ] later showed that BA effectively lowered both TC and TG levels but did not increase HDL-C levels. Recently, using ApoE*3 Leiden.CETP mice, a mouse model generated to better mimic human, Liu and colleagues [ 34 ] found that BA had no effects on cholesterol metabolism and atherosclerosis, but the data of TG metabolism had not been reported in this human-like mouse model.…”

Potential Molecular Mechanisms of Alcohol Use Disorder with Non-Coding RNAs and Gut Microbiota for the Development of Superior Therapeutic Application

“…For example, microbial acetate and/or butyrate might alleviate obesity with the regulation of host miRNAs [57]. In addition, there were close intricate interactions between gut microbiota, inflammation, and differential miR-NAs, suggesting that ncRNAs may possess a potential role in the protection of the host against life-related diseases such as atherosclerosis [58]. Interestingly, it has been shown that circRNAs and the gut microbiome can interact to influence the growth of cancer cells [59].…”