Microbiota-derived butyrate dynamically regulates intestinal homeostasis through regulation of actin-associated protein synaptopodin

Abstract

<jats:p>The intestinal mucosa exists in dynamic balance with trillions of luminal microbes. Disruption of the intestinal epithelial barrier, commonly observed in mucosal inflammation and diseases such as inflammatory bowel diseases (IBDs), is often associated with dysbiosis, particularly decreases in species producing short-chain fatty acids (SCFAs), such as butyrate. It remains unclear to what extent microbiota-derived factors contribute to the overall maintenance of intestinal homeostasis. Initial studies revealed that butyrate selectively promotes epithelial barrier function and wound healing. We aimed to define the specific mechanism(s) through which butyrate contributes to these epithelial responses. Guided by an unbiased profiling approach, we identified the dominant regulation of the actin-binding protein synaptopodin (SYNPO). Extensions of this work revealed a role for SYNPO in intestinal epithelial barrier function and wound healing. SYNPO was localized to the intestinal epithelial tight junction and within F-actin stress fibers where it is critical for barrier integrity and cell motility. Butyrate, but not other SCFAs, induced SYNPO in epithelial cell lines and murine colonic enteroids through mechanisms possibly involving histone deacetylase inhibition. Moreover, depletion of the microbiota abrogated expression of SYNPO in the mouse colon, which was rescued with butyrate repletion. Studies in<jats:italic>Synpo</jats:italic>-deficient mice demonstrated exacerbated disease susceptibility and increased intestinal permeability in a dextran sulfate sodium colitis model. These findings establish a critical role for the microbiota and their products, specifically butyrate, in the regulated expression of SYNPO for intestinal homeostasis and reveal a direct mechanistic link between microbiota-derived butyrate and barrier restoration.</jats:p>

Effects of Xylo-Oligosaccharides on Growth and Gut Microbiota as Potential Replacements for Antibiotic in Weaning Piglets

“…Acetate can be oxidized in the tricarboxylic acid (TCA) cycle or is involved in de novo lipogenesis by conversion into to acetyl-CoA, while propionate is a well-known precursor for gluconeogenesis in the liver and is regarded as an inhibitor for lipogenesis (Den Besten et al, 2013a). Butyrate is the favored energy source for large intestinal cells and the majority of this SCFA is absorbed and utilized within the large intestine (Wang R. X. et al, 2020), while acetate and propionate enter hepatic circulation in significant quantities (Den Besten et al, 2013b). Except energy provision, butyrate probably plays beneficial effects on gut morphology, growth performance and anti-inflammatory under normal physiological conditions (Carney, 2015;Huang et al, 2017) through regulation of gene expression like proinflammatory cytokines nuclear factor kappa B (NF-κB) and interferon gamma (IFN-γ) inhibition and activation of SCFA-specific G protein-coupled receptors (Klampfer et al, 2003;Layden et al, 2013;Silva et al, 2018).…”

The gut microbiome in solid organ transplantation

“…They play an essential role in maintaining overall gut homeostasis as they strengthen the epithelial gut barrier, 43 modulate inflammation processes, 44 and prevent cancer cell proliferation. 45 In addition to local effects, SCFAs also have a systemic immune-inhibitory effect by inducing differentiation into T regs .…”

“…Further, dysbiosis is characterized by a notable decrease in short‐chain fatty acids (SCFAs), such as butyrate, propionate, and acetate, produced by bacterial fermentation. They play an essential role in maintaining overall gut homeostasis as they strengthen the epithelial gut barrier, 43 modulate inflammation processes, 44 and prevent cancer cell proliferation 45 . In addition to local effects, SCFAs also have a systemic immune‐inhibitory effect by inducing differentiation into T regs 30 .…”

Intestinal Inflammation as a Dysbiosis of Energy Procurement: New Insights into an Old Topic

“…This energetic supply provides critical support to the cytoskeleton and thus barrier, bestowing IECs an unsurpassed capacity to rapidly polarize and form strong AJCs. 111 A substantial contribution of butyrate to barrier function stems from ATP provision to the cytoskeleton, but also through upregulating the expression of actin-binding proteins like synaptopodin by HDAC inhibition and activation of other transcription factors like STAT3, SP1, and AMPK that induce genes encoding for TJ components. 106 , 111 , 112 …”

“… 107 Mitochondrial oxygen consumption-induced HIF stabilization increases glycolysis-driven ATP regeneration. 118 , 122–128 ATP regeneration 107 Induction of cytoskeletal binding proteins 111 Induction of TJ proteins 106 , 112 , 115 Induction of MUC2 128 , 129 Induction of creatine kinases 132 Hypoxanthine Associates with Barnesiella and Prevotella , 130 TBD* ATP and GTP generation. 43 , 44 Microbial substrate, 131 TBD* Cytoskeletal ATP 43 AJC formation and stability 43 Mucin generation and mucus barrier sterile integrity 44 Creatine Diet and Endogenous Biosynthesis Temporal and spatial ATP buffer.…”