MODULATION OF INTESTINAL EPITHELIAL FUNCTION AND METABOLISM BY  DIETARY CANNABIDIOL

Alejandro Bravo Iniguez

Metabolic syndrome (MetS) represents a collection of metabolic irregularities associated with increased risk of noncommunicable diseases such as type 2 diabetes or certain cancers. Impaired gut health is a common feature of MetS and contributes to aberrant inflammation. While the etiology of MetS is complex and multifaceted, lifestyle changes such as adhering to healthier dietary patterns are an effective approach for improving both metabolic and gut health. Cannabidiol (CBD) is a nonpsychoactive constituent found in Cannabis sativa that has demonstrated various bioactive properties including anti-inflammatory effects. The goal of this dissertation was to evaluate the potential of CBD to safeguard intestinal and metabolic health against dysfunction and identify prospective molecular mechanisms orchestrating the observations. In the first study, human intestinal epithelial Caco-2 cells were cultured in the presence or absence of 10 µM CBD. Both CBD oil and pure CBD were used to analyze changes in mitochondrial and antioxidant signaling following exposure. CBD treatment increased levels of catalase, heme oxygenase-1 (HO-1), superoxide dismutase 1 (SOD1), and SOD2 while decreasing the formation reactive oxygen species (ROS). Upstream, CBD induced AMPK (AMP-activated protein kinase) and Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) signaling. In the second study, the mediary mechanisms behind CBD’s protective effects against hemin-driven impairment were explored. In wild-type Caco-2 cells, CBD cotreatment augmented induction of antioxidant defenses, reduced ROS production, and mitigated DNA damage resulting from exposure to hemin (10 µM). Alongside these changes, CBD recovered levels of phosphorylated AMPK. Chemical and pharmacological inhibition of AMPK kinase function blocked CBD-driven induction of catalase of catalase and SOD2 but not HO-1. Inhibition of AMPK kinase function also hampered the ability of CB treatment to suppress ROS production and DNA damage. In the third study, five-week-old male mice were fed a control or high-fat diet (45% calories from fat) with or without CBD oil (25 mg/kg body weight) for 2 months. Feeding the high-fat diet resulted in weight gain, increased baseline blood glucose levels, and adipocyte hypertrophy which were all ameliorated by CBD supplementation. Improvements to metabolic status by CBD were associated with improved levels of PGC1α and related markers of mitochondrial function in white adipose tissue (WAT). CBD supplementation also increased thermogenic signaling in WAT. The fourth study was a follow-up to the third, analyzing the colon tissue of the same mice. Compared to controls, mice fed a diet high in fat had potentiated canonical Wnt/β-catenin signaling associated with reduced crypt depth and staining for goblet-cell produced mucin. CBD treatment abrogated induction of Wnt/β-catenin signaling, promoted differentiation signaling, and increased levels of E-cadherin, an adherens junction and tumor suppressor protein.

MODULATION OF INTESTINAL EPITHELIAL FUNCTION AND METABOLISM BY DIETARY CANNABIDIOL

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