Gut microbiota-dependent IDO1 promotes angiotensin Ⅱ-induced cardiomyopathy via non-enzymatic activation of ANGPTL4

Q: What is the clinical evidence from this study?

Population: Angiotensin II-induced cardiomyopathy. Intervention: Epacadostat (IDO1 inhibitor) or Butyrate supplementation vs. Angiotensin II (0.5 mg/kg every other day for 2 months in vivo; 100 nM for 48 hours in vitro) or vehicle control. Primary outcome: Angiotensin II-induced cardiac oxidative stress, remodeling, and systolic dysfunction (ejection fraction and fractional shortening).

Q: What does this research mean for the field?

Gut microbiota-derived butyrate and IDO1 inhibition attenuate angiotensin II-induced cardiac dysfunction and oxidative stress by suppressing the non-enzymatic STAT1/IDO1/ANGPTL4/gp91phox pathway. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.ESTABLISHES_NEW_DIRECTION.

Wei Liu; Ke Xu; Yuan Tian; Rui Sun; Meiqi Wang; Mengrou Geng; Chao Dong; Tong Zhou; Xin Mei Jiang; Ying Xin

doi:10.1038/s41419-026-09358-w

October 25, 2026Cell Death and DiseaseOpen Access

Gut microbiota-dependent IDO1 promotes angiotensin Ⅱ-induced cardiomyopathy via non-enzymatic activation of ANGPTL4

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Key result

Butyrate and IDO1 inhibition attenuate angiotensin II-induced cardiac dysfunction and oxidative stress in mice.

Why the study?

Angiotensin II-mediated oxidative stress is a key pathological driver of cardiomyopathy, yet the gut microbiota-dependent regulatory network underlying this process remained unclear.

Does pharmacological inhibition of IDO1 or butyrate supplementation attenuate angiotensin II-induced cardiac oxidative stress, remodeling, and dysfunction in preclinical models of cardiomyopathy?

Key Points

To investigate the gut microbiota-dependent signaling mechanisms through which IDO1 mediates angiotensin II-induced oxidative stress and cardiomyopathy.
Administered a sub-pressor dose of Ang II (0.5 mg/kg every other day for 2 months) with or without the IDO1 inhibitor epacadostat (30 mg/kg every other day for 6 months) to C57BL/6 J mice.
Evaluated cardiac geometry and function by echocardiography, histology, and assays for oxidative stress and apoptosis markers (gp91 phox, 4-HNE, MDA, and cleaved Caspase3).
Investigated non-enzymatic IDO1 signaling, Notch1/HES1 repression, and ANGPTL4 promoter binding using enzymatic-mutant IDO1 (H346A), ChIP, and AC16 cardiomyocyte models.
Ang II activated STAT1 phosphorylation at Tyr701 to upregulate IDO1, driving left ventricular dilation, hypertrophy, systolic dysfunction, and oxidative damage, all of which were attenuated by epacadostat.
IDO1 promoted ANGPTL4 expression independently of its catalytic activity; Y111 phosphorylation of IDO1 recruited SHP2 to suppress Notch1/HES1 signaling and relieve HES1-mediated transcriptional repression on the ANGPTL4 promoter.
Ang II depleted gut microbiota-derived butyrate, which normally suppresses IDO1 by enhancing H3K9 acetylation-mediated AHR/SOCS3 activation and promoting IDO1 ubiquitin-proteasomal degradation.

Structured PICO

Does pharmacological inhibition of IDO1 or butyrate supplementation attenuate angiotensin II-induced cardiac oxidative stress, remodeling, and dysfunction in preclinical models of cardiomyopathy?

P

Population

Preclinical C57BL/6J mouse models of angiotensin II-induced cardiomyopathy, AC16 cardiomyocytes, and myocardial tissue samples from 7 cardiomyopathy patients and 3 normotensive controls.

I

Intervention

Epacadostat (30 mg/kg every other day for 6 months in vivo; 4 μM for 48 h in vitro), exogenous butyrate supplementation (1 mM for 48 h in vitro and in vivo), fludarabine (20 μM for 48 h), valproic acid (4 mM for 48 h), SHP099 (5 μM for 48 h), and AAV9-mediated cardiac-specific IDO1 overexpression (cTNT-Ido1).

C

Comparator

Untreated control or angiotensin II-infused mice/stimulated AC16 cardiomyocytes without pharmacological inhibition or butyrate supplementation; empty vector or wild-type IDO1 controls.

O

Outcome

Cardiac function and remodeling assessed by echocardiography (ejection fraction [EF], fractional shortening [FS], left ventricular internal diameter [LVID], left ventricular end-diastolic posterior wall thickness [LVPWd]), histology (heart weight to tibia length ratio, cardiomyocyte cross-sectional area, collagen accumulation/fibrosis), and myocardial oxidative stress and apoptosis markers (gp91 phox, 4-HNE, MDA, ROS, cleaved Caspase3).surrogate

This preclinical study identifies a gut-heart signaling circuit in which gut microbiota-derived butyrate suppresses STAT1-driven IDO1 expression and its non-enzymatic activation of the ANGPTL4/gp91 phox axis, positioning butyrate and IDO1 as potential therapeutic targets for angiotensin II-induced cardiomyopathy.

Limitations

Did not directly investigate the mechanism by which Ang II promotes IDO1 phosphorylation at Y111
Not designed to systematically compare Ang II dose and duration effects on gut microbial community structure and Firmicutes/Bacteroides ratio
Did not perform fecal microbiota transplantation (FMT) to establish causality between overall gut microbiota dysbiosis and Ang II-induced cardiac injury or to exclude contributions from other microbial metabolites
Limited sample size in gut microbiota alpha-diversity analysis

Implication

Should not yet change practice; hypothesis-generating for butyrate/IDO1 modulation in angiotensin II cardiomyopathy from mouse data.

Abstract

Angiotensin II (Ang II)-mediated oxidative stress is the key pathological driver of cardiomyopathy, yet the gut microbiota-dependent regulatory network underlying this process remains unclear. Administration of a sub-pressor dose of Ang II to C57BL/6 J mice induced cardiac oxidative stress and dysfunction via signal transducer and activator of transcription 1 (STAT1)-triggered upregulation of indoleamine 2,3-dioxygenase 1 (IDO1), which promoted angiopoietin like protein 4 (ANGPTL4) and gp91 phox-driven oxidative damage; IDO1 pharmacological reduction partially reversed these effects. Mechanistically, IDO1 induced ANGPTL4 by relieving Notch1/HES1 transcriptional repression, independently of its catalytic activity: Y111 phosphorylation of IDO1 recruited SHP2 to suppress Notch1/HES1 signaling, revealing a previously unrecognized, non-enzymatic function. Concurrently, Ang Ⅱ depleted gut microbiota-derived butyrate, contributing to cardiomyopathy through the same STAT1/IDO1 axis, while cardiac-specific overexpression of Ido1 attenuated butyrate’s protective effect. Furthermore, butyrate also suppressed IDO1 by enhancing H3K9 acetylation-mediated AHR/SOCS3 activation and promoting IDO1 ubiquitin-proteasomal degradation. These findings identify a gut-heart signaling circuit in which gut microbiota-derived butyrate modulates IDO1 expression and its non-enzymatic pro-oxidative function, positioning the butyrate/IDO1/ANGPTL4 axis as a potential therapeutic target for oxidative stress and Ang II-associated cardiomyopathy.

Discussion

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Cite This Study

Liu et al. (2026) studied Angiotensin II-induced cardiomyopathy. Epacadostat (IDO1 inhibitor) or Butyrate supplementation vs. Angiotensin II (0.5 mg/kg every other day for 2 months in vivo; 100 nM for 48 hours in vitro) or vehicle control was evaluated on Angiotensin II-induced cardiac oxidative stress, remodeling, and systolic dysfunction (ejection fraction and fractional shortening). Butyrate supplementation and IDO1 inhibition with epacadostat attenuated angiotensin II-induced cardiac dysfunction and oxidative stress by suppressing the STAT1/IDO1/ANGPTL4/gp91phox axis in mice.

synapsesocial.com/papers/6adf55a4953ea0d7a3d1d83a https://doi.org/10.1038/s41419-026-09358-w

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Gut microbiota-dependent IDO1 promotes angiotensin Ⅱ-induced cardiomyopathy via non-enzymatic activation of ANGPTL4

Key Points

Structured PICO

Limitations

Implication

Abstract

Discussion

Cite This Study

Gut microbiota-dependent IDO1 promotes angiotensin Ⅱ-induced cardiomyopathy via non-enzymatic activation of ANGPTL4

Key Points

Structured PICO

Limitations

Implication

Abstract

Discussion

Cite This Study

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