Intestinal stem cell-derived enteroids from morbidly obese patients preserve obesity-related phenotypes: Elevated glucose absorption and gluconeogenesis.

OBJECTIVE: The mechanisms behind the efficacy of bariatric surgery (BS) for treating obesity and type 2 diabetes, particularly with respect to the influence of the small bowel, remain poorly understood. In vitro and animal models are suboptimal with respect to their ability to replicate the human intestinal epithelium under conditions induced by obesity. Human enteroids have the potential to accelerate the development of less invasive anti-obesity therapeutics if they can recapitulate the pathophysiology of obesity. Our aim was to determine whether adult stem cell-derived enteroids preserve obesity-characteristic patient-specific abnormalities in carbohydrate absorption and metabolism. METHODS: We established 24 enteroid lines representing 19 lean, overweight, or morbidly obese patients, including post-BS cases. Dietary glucose absorption and gluconeogenesis in enteroids were measured. The expression of carbohydrate transporters and gluconeogenic enzymes was assessed and a pharmacological approach was used to dissect the specific contribution of each transporter or enzyme to carbohydrate absorption and metabolism, respectively. RESULTS: Four phenotypes representing the relationship between patients' BMI and intestinal dietary sugar absorption were found, suggesting that human enteroids retain obese patient phenotype heterogeneity. Intestinal glucose absorption and gluconeogenesis were significantly elevated in enteroids from a cohort of obese patients. Elevated glucose absorption was associated with increased expression of SGLT1 and GLUT2, whereas elevated gluconeogenesis was related to increased expression of GLUT5, PEPCK1, and G6Pase. CONCLUSIONS: Obesity phenotypes preserved in human enteroids provide a mechanistic link to aberrant dietary carbohydrate absorption and metabolism. Enteroids can be used as a preclinical platform to understand the pathophysiology of obesity, study the heterogeneity of obesity mechanisms, and identify novel therapeutics.

ss3sim: an R package for fisheries Stock Assessment simulation with stock synthesis.

Simulation testing is an important approach to evaluating fishery stock assessment methods. In the last decade, the fisheries stock assessment modeling framework Stock Synthesis (SS3) has become widely used around the world. However, there lacks a generalized and scriptable framework for SS3 simulation testing. Here, we introduce ss3sim, an R package that facilitates reproducible, flexible, and rapid end-to-end simulation testing with SS3. ss3sim requires an existing SS3 model configuration along with plain-text control files describing alternative population dynamics, fishery properties, sampling scenarios, and assessment approaches. ss3sim then generates an underlying 'truth' from a specified operating model, samples from that truth, modifies and runs an estimation model, and synthesizes the results. The simulations can be run in parallel, reducing runtime, and the source code is free to be modified under an open-source MIT license. ss3sim is designed to explore structural differences between the underlying truth and assumptions of an estimation model, or between multiple estimation model configurations. For example, ss3sim can be used to answer questions about model misspecification, retrospective patterns, and the relative importance of different types of fisheries data. We demonstrate the software with an example, discuss how ss3sim complements other simulation software, and outline specific research questions that ss3sim could address.