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The gut microbiota-butyrate axis restores cardiomyocyte autophagy to alleviate Doxorubicin-induced cardiotoxicity

ABSTRACT:

Abstract

Background Doxorubicin (DOX), an anthracycline chemotherapeutic agent, is widely used for treating various malignancies. However, its clinical application is limited by dose-dependent cardiotoxicity (DOX-induced cardiotoxicity, DIC). Recent studies have shown that the gut microbiota and its metabolites may be involved in the occurrence and development of cardiovascular diseases through the 'gut-microbiota-heart axis'. Especially，doxorubicin may affect the structure and function of the gut microbiota due to its potential antimicrobial properties and its gut-damaging side effects, but the molecular mechanisms through which gut microbiota affects DIC remain poorly understood.

Results The results of 16S rRNA gene amplicon sequencing of fecal samples showed that the gut microbiota structure of the C57BL/6 DIC model mice changed. The depletion of gut microbiota by antibiotics partially improved DIC. Fecal microbiota transplantation (FMT) from DOX-treated donors impaired cardiac structure and function in recipient mice. Conversely, control-donor FMT significantly alleviated DOX-induced cardiac dysfunction, whether co-administered or given post-modeling. Mechanistically, we analyzed the metabolomics of fecal samples from mice after DOX administration and identified butyric acid (BA) as a key metabolite. Further experiments have shown that after BA treatment, the fatty acid oxidation levels impaired by DOX was restored meanwhile the glycolysis was inhibited. Besides, it was preliminarily confirmed that this metabolic alteration affects 4-hydroxynonenal (4HNE) and autophagy levels, which in turn affects DIC.

Conclusions The gut microbiota-butyrate axis restores fatty acid oxidation and normalizes glycolytic activity, further enhancing 4-HNE-mediated autophagy as a therapeutic strategy against DIC.

Keywords Doxorubicin, Gut microbiota, Cardiotoxicity, Butyric acid

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse phase, Liquid Chromatography MS - positive - reverse phase

PROVIDER: MTBLS12997 | MetaboLights | 2025-09-16

REPOSITORIES: MetaboLights

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			Action	DRS
	a_MTBLS12997_LC-MS_negative_reverse-phase_metabolite_profiling.txt	Txt
	a_MTBLS12997_LC-MS_positive_reverse-phase_metabolite_profiling.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS12997_LC-MS_negative_reverse-phase_metabolite_profiling_v2_maf.tsv	Tabular
	m_MTBLS12997_LC-MS_positive_reverse-phase_metabolite_profiling_v2_maf.tsv	Tabular

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Project description:Purpose: To determine whether previously observed behavioral differences in alcoholic human patients after fecal microbiota transplantation (FMT) could be transferred to mice. Methods: Fecal microbiota samples from a previously published phase 1, double-blind, randomized clinical trial of AUD-related cirrhosis patients were used to colonize germ-free mice. Fecal material was transferred to 10-15-week-old GF C57BL/6 male mice by daily gavage for 3 day. The mice were housed in sterile individually filtered cages for 15 days after which stool was collected and then they underwent the alcohol preference experiment using 2-bottle choice drinking (water and 20% ethanol v/v). Microbial DNA was isolated from stool samples by sequencing the V1 and V2 variable regions of the bacterial 16S rRNA gene were sequenced using Multitag fusion primers and sequenced on an Ion Torrent PGM next-generation sequencer. Intestinal mucosa, liver, and prefrontal cortex tissue was collected from mice at time of sacrifice. RNAseq was used to measure gene expression in pre-FMT and post-FMT samples. RNAseq data were aligned to the mouse genome (GRCm39) using STAR (version 2.7.9a) and counts were generated with HTSeq (version 0.13.5). Genes with very low counts across the study (defined as fewer than 10 counts in more than 2 samples) were eliminated before differential expression analysis. Low count genes were determined separately for each tissue type. The DESeq2 package for R was then used to measure differential expression between pre-FMT and post-FMT mice in the intestine, liver, and PFC. Benjamini and Hochberg False Discovery Rate (FDR) was used to correct for multiple testing with FDR ≤ 0.2 considered significant. Results: Mice colonized with post-FMT stool significantly reduced ethanol acceptance, intake and preference versus pre-FMT colonized mice. Microbial taxa that were higher in post-FMT humans were also associated with lower alcohol intake and preference in mice. RNAseq further showed that differential gene expression, post-FMT, occurred in the intestine rather than the liver and prefrontal cortex. Conclusions: FMT leads to significant change in gut microbiome population, which in turn alters gene expression in the intestine. FMT also significantly affects alcohol consumption. The microbiotal-intestinal interface may alter gut-liver-brain axis and reduce alcohol consumption in humans.

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The gut microbiota-butyrate axis restores cardiomyocyte autophagy to alleviate Doxorubicin-induced cardiotoxicity

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