medicines Article Gut Microbiota Regulates the Interaction between Diet and Genetics to Influence Glucose Tolerance † Jeralyn J. Franson ‡ , Julianne H. Grose * ,‡ , Kaitlyn W. Larson and Laura C. Bridgewater *   Citation: Franson, J.J.; Grose, J.H.; Larson, K.W.; Bridgewater, L.C. Gut Microbiota Regulates the Interaction between Diet and Genetics to Influence Glucose Tolerance. Medicines 2021, 8, 34. https:// doi.org/10.3390/medicines8070034 Academic Editor: Abhishek Singh Received: 13 May 2021 Accepted: 24 June 2021 Published: 1 July 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Department of Microbiology and Molecular Biology, Brigham Young University, Provo, UT 84602, USA; jer.franson@gmail.com (J.J.F.); kaitlynwilliams20@gmail.com (K.W.L.) * Correspondence: julianne_grose@byu.edu (J.H.G.); laura_bridgewater@byu.edu (L.C.B.) † Franson, J.J.; Grose, J.H.; Larson, K.W.; Bridgewater, L.C. Gut Microbiota Regulates the Interplay Between Diet and Genetics to Influence Glucose Tolerance. In Proceedings of 1st International Electronic Conference on Nutrients—Nutritional and Microbiota Effects on Chronic Disease, 2–15 November 2020; Available online: https://iecn2020.sciforum.net/. ‡ These authors contributed equally to this work. Abstract: Background: Metabolic phenotypes are the result of an intricate interplay between mul- tiple factors, including diet, genotype, and the gut microbiome. Per–Arnt–Sim (PAS) kinase is a nutrient-sensing serine/threonine kinase, whose absence (PASK −/− ) protects against triglyceride ac- cumulation, insulin resistance, and weight gain on a high-fat diet; conditions that are associated with dysbiosis of the gut microbiome. Methods: Herein, we report the metabolic effects of the interplay of diet (high fat high sugar, HFHS), genotype (PASK −/− ), and microbiome (16S sequencing). Results: Microbiome analysis identified a diet-induced, genotype-independent forked shift, with two discrete clusters of HFHS mice having increased beta and decreased alpha diversity. A “lower” cluster contained elevated levels of Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria and Defferibacteres, and was associated with increased weight gain, glucose intolerance, triglyceride accumulation, and decreased claudin-1 expression. Genotypic effects were observed within the clusters, lower cluster PASK −/− mice displayed increased weight gain and decreased triglyceride accumulation, whereas upper PASK −/− were resistant to decreased claudin-1. Conclusions: These results confirm previous reports that PAS kinase deficiency can protect mice against the deleterious effects of diet, and they suggest that microbiome imbalances can override protection. In addition, these results support a healthy diet for beneficial microbiome maintenance and suggest microbial culprits associated with metabolic disease. Keywords: gut microbiome; diet; insulin resistance; glucose tolerance; obesity; triglyceride; high fat; high sugar; leaky gut; PAS kinase; claudin-1 1. Introduction In healthy individuals, increased blood glucose levels trigger beta cells in the pancreas to produce insulin. Extracellular insulin can subsequently bind to insulin receptors on cellu- lar membranes [1], allowing for increased glucose uptake by the cell, through translocating glucose transporters to the cellular membrane and stimulating glycogen synthesis [2]. A decrease in the cell’s sensitivity to insulin is known as insulin resistance, which can lead to hyperglycemia, hepatic lipid synthesis, and adiposity [3]. The severity of insulin resistance is used to classify individuals as either prediabetic or type 2 diabetic, with prediabetes affecting 33.9% and diabetes affecting 10.5% of adults in the United States (US) [4]. Of adults diagnosed with diabetes, 87.5% are overweight or obese [5], with obesity alone affecting 39.8% of all US adults. Thus, understanding the pathways contributing to these interrelated diseases is essential to the development of proper treatments, as well as pre- ventative strategies. Studies of insulin resistance and obesity have led to the identification of multiple contributing factors, including diet, microbiome, and genetics. Medicines 2021, 8, 34. https://doi.org/10.3390/medicines8070034 https://www.mdpi.com/journal/medicines