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The Bacterial Fermentation Product Butyrate Influences Epithelial Signaling via Reactive Oxygen Species-Mediated Changes in Cullin-1 Neddylation¹

Amrita Kumar^*, Huixia Wu^*, Lauren S. Collier-Hyams^*, Young-Man Kwon^*, Jason M. Hanson and Andrew S. Neish^2,*

^* Department of Pathology and Laboratory Medicine, Epithelial Pathobiology Unit, Emory University School of Medicine, Atlanta, GA 30322; and Department of Pediatrics, Division of Pulmonary, Asthma, Cystic Fibrosis and Sleep, Emory University, School of Medicine, Atlanta, GA 30322

The human enteric flora plays a significant role in intestinal health and disease. Populations of enteric bacteria can inhibit the NF-B pathway by blockade of IB- ubiquitination, a process catalyzed by the E3-SCF^β-TrCP ubiquitin ligase. The activity of this ubiquitin ligase is regulated via covalent modification of the Cullin-1 subunit by the ubiquitin-like protein NEDD8. We previously reported that interaction of viable commensal bacteria with mammalian intestinal epithelial cells resulted in a rapid and reversible generation of reactive oxygen species (ROS) that modulated neddylation of Cullin-1 and resulted in suppressive effects on the NF-B pathway. Herein, we demonstrate that butyrate and other short chain fatty acids supplemented to model human intestinal epithelia in vitro and human tissue ex vivo results in loss of neddylated Cul-1 and show that physiological concentrations of butyrate modulate the ubiquitination and degradation of a target of the E3- SCF^β-TrCP ubiquitin ligase, the NF-B inhibitor IB-. Mechanistically, we show that physiological concentrations of butyrate induces reactive oxygen species that transiently alters the intracellular redox balance and results in inactivation of the NEDD8-conjugating enzyme Ubc12 in a manner similar to effects mediated by viable bacteria. Because the normal flora produces significant amounts of butyrate and other short chain fatty acids, these data provide a functional link between a natural product of the intestinal normal flora and important epithelial inflammatory and proliferative signaling pathways.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by National Institutes of Health Grants DK-71604 and AI-64462 (to A.S.N.).

² Address correspondence and reprint requests to Dr. Andrew S. Neish, Department of Pathology, Emory University School of Medicine, Room 105F, Whitehead Building, 615 Michael Street, Atlanta, GA, 30322. E-mail address: aneish{at}emory.edu

³ Abbreviations used in this paper: SCFA, short chain fatty acid; Cul-1, cullin-1; MAMP, microbial-associated molecular pattern; ROS, reactive oxygen species; NAC, N-acetyl cysteine; DPI, diphenyleneiodonium; DCF, 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate acetyl ester; DHE, dihydroethidium; MOI, multiplicity of infection; IAA, iodoacetamide; HMM, high molecular mass; E_h, redox potential; Trx, Thioredoxin.