A high fermentable fiber Western diet reduces indole levels

Priyadarshini, M.; Jorgensen, J.; Stauffer, S. R. C.; Issa, L.; Pandya, N.; Nnyamah, C.; Xu, K.; Boyett, J. E.; Kular, P.; Mhatre, A.; Brahambhatt, V. H.; Gilbert, J. A.; Khan, M. W.; Wicksteed, B.; Dai, Y.; Layden, B. T.

doi:10.64898/2026.01.27.702025

bioRxiv · 10.64898/2026.01.27.702025

A high fermentable fiber Western diet reduces indole levels

Priyadarshini, M.·Jorgensen, J.·Stauffer, S. R. C.·Issa, L.·Pandya, N.·Nnyamah, C.·Xu, K.·Boyett, J. E.·Kular, P.·Mhatre, A.·Brahambhatt, V. H.·Gilbert, J. A.·Khan, M. W.·Wicksteed, B.·Dai, Y.·Layden, B. T.

View original source ↗Export metadata ↓

Abstract

Changes in gut microbiota composition due to diet impact health. Fiber-rich diets promote beneficial microbiota and reduce the risk of metabolic diseases, while low-fiber, calorie-dense diets are linked to dysbiosis and increased disease risk. This study examines the effects of a Western diet (WD) and explores dietary fiber supplements as potential modifiers of those effects. 10-week-old C57Bl/6J male mice were fed control (low-fat) or WD (high-fat, high-sucrose) containing 0% fermentable fiber (FF) or WD supplemented with 20% FF (fructooligosaccharides, FOS; guar gum, GG, or pectin, Pec). After 19 weeks, analysis of the cecal metagenome using whole-genome shotgun sequencing, metabolome by untargeted and targeted LC-MS/MS, and tissue RNA and protein expression by RT-PCR and immunoblotting was undertaken. WD-FF reduced metabolic derangements from WD while also improving GM diversity and altering cecal metabolites, particularly tryptophan metabolism. A profound increase in cecal indole levels (targeted metabolomics) was noted in WD vs WD-FF groups. As the primary indole-oxidizing enzyme, CYP2E1 generates indoxyl sulfate, which contributes to oxidative stress and a leaky gut. Mice on WD displayed higher expression of Cyp2e1 mRNA in the gut. In the liver, the levels of both CYP2E1 protein and mRNA were higher in the WD group compared to the WD-FOS group, with protein levels also higher than in the WD-Pec group and mRNA levels higher than in the WD-GG group. mRNA expression of markers of oxidative stress, inflammation, and leaky barrier was significantly higher in the liver and intestine of the WD vs the WD-FF groups. FFs reduced high plasma indoxyl sulfate levels (except in WD-GG), and boosted short-chain fatty acids and indole acetic acid. Our data suggest that WD disrupts GM tryptophan metabolism, possibly by altering the balance between indole-producing and utilizing gut bacteria. Dietary fiber supplementation exerts protective effects, in part, by mitigating this imbalance.

Explore related subjects

physiology Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Priyadarshini, M., Jorgensen, J., Stauffer, S. R. C., Issa, L., Pandya, N., Nnyamah, C., Xu, K., Boyett, J. E., Kular, P., Mhatre, A., Brahambhatt, V. H., Gilbert, J. A., Khan, M. W., Wicksteed, B., Dai, Y., Layden, B. T.. 2026-01-30. A high fermentable fiber Western diet reduces indole levels. https://doi.org/10.64898/2026.01.27.702025

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Rad and Phospholamban are Key Drivers of the Ventricular Adrenergic Response and Stress-Induced Arrhythmia

The adrenergic response is a fundamental mechanism that regulates heart rate (chronotropy), cardiac contractility (inotropy) and relaxation (lusitropy). Adrenergic stress is also a recognized trigger of arrhythmia in disease. Yet, our understanding of the underlying molecular basis remains incomplete. Protein kinase A (PKA) and the calcium/calmodulin-dependent kinase II (CaMKII) phosphorylate multiple targets proposed to participate in the adrenergic response, including the GTP-binding protein Rad, phospholamban (PLB) and ryanodine receptor 2 (RyR2). Here we demonstrate that phosphorylation of both Rad and PLB is necessary for inotropy and lusitropy. We show that changes in cardiac contractility and relaxation are primarily dependent on intracellular calcium handling. Finally, we report that Rad and PLB control stress-induced arrhythmogenesis, despite the phosphorylation of other pro-arrhythmic targets. We have identified the essential molecular components of the adrenergic response, resolving a long-standing debate in cardiac excitation-contraction coupling and refining current models of sympathetic regulation in health and disease.

physiology↗

bioRxiv2026

MCT6 is an intestinal Lac-Phe exporter required for metformin-associated weight loss

Metabolites are increasingly recognized as circulating molecules that regulate physiology, yet the mechanisms that couple intracellular production to organism-wide action remain poorly defined. Using the anorexigenic metabolite Lac-Phe as a tractable system, we identify the orphan transporter MCT6 (SLC16A5) as a physiologic intestinal Lac-Phe exporter. This mechanism controls the extent to which intracellularly synthesized Lac-Phe acquires systemic activity. MCT6 transports Lac-Phe, mediates its cellular efflux, and is required for maintaining its blood levels in mice following strong glycolytic stimuli. Both global and intestinal epithelial-specific deletion of MCT6 confers resistance to metformin-associated weight loss on a high-fat diet. Bypassing the transport defect with exogenous Lac-Phe normalizes the body weight phenotype of MCT6-KO mice. Together, these data connect MCT6 to metformin pharmacology and intestinal lactate metabolism, and more generally underscore the importance of transporter-mediated release in the conversion of an intracellular metabolic state into a circulating metabolite effector.

physiology↗

bioRxiv2026

DEPP1 connects nutrient and oxygen availability to maintenance of muscle mass

Nutrients and oxygen are sensed within the muscle to control growth and disruption of either signal is sufficient to lead to muscle atrophy. While nutrient limitation is sensed via a conserved transcriptional atrophy program (commonly referred to as atrogenes) dictated via the Forkhead box O (FoxO) transcription factors, how low oxygen promotes muscle loss remains unknown. Accordingly, the downstream mechanisms that initiate muscle loss when oxygen and nutrients are limiting are only partly understood. Here, we find Hypoxia Inducible Factor (HIF), the master regulator of our adaptation to low oxygen, is necessary and sufficient to mediate muscle loss under hypoxia in mice. RNA sequencing in skeletal muscle isolated from starved or hypoxic mice identifies Decidual Protein Induced by Progesterone 1 (Depp1), which is induced in skeletal muscle when nutrients or oxygen is limiting via FoxO1 and HIF activation, respectively. Whole body Depp1 loss in mice reduces muscle loss under fasting and hypoxia and skeletal muscle Depp1 overexpression is sufficient to mediate muscle atrophy. Mechanistically, Depp1 localizes to the mitochondria and is necessary to control autophagy activation and mitochondrial degradation in skeletal muscle. Taken together, our studies nominate Depp1 as a new atrogene necessary for muscle loss under multiple atrophy scenarios involving FoxO and HIF.

physiology↗