Metabolic diseases are major public health issues worldwide and are responsible for disproportionately higher healthcare costs and increased complications of many diseases including SARS-CoV-2 infection. The Western Diet (WD) specifically is believed to be a major contributor to the global metabolic disease epidemic. In contrast, the Mediterranean diet (MeD), Ketogenic diet (KD), and Japanese diet (JD) are often considered beneficial for metabolic health. Yet, there is a growing appreciation that the effect of diet on metabolic health varies depending on several factors including host genetics. Additionally, poor metabolic health has also been attributed to altered gut microbial composition and/or function. To understand the complex relationship between host genetics, gut microbiota, and dietary patterns, we treated four widely used metabolically diverse inbred mouse strains (A/J, C57BL/6J, FVB/NJ, and NOD/ShiLtJ) with four human-relevant diets (MeD, JD, KD, WD), and a control mouse chow from 6 weeks to 30 weeks of age. We found that diet-induced alteration of gut microbiota (α-diversity, β-diversity, and abundance of several bacteria including Bifidobacterium, Ruminococcus, Turicibacter, Faecalibaculum, and Akkermansia) is significantly modified by host genetics. In addition, depending on the gut microbiota, the same diet could have different metabolic health effects. Our study also revealed that C57BL/6J mice are more susceptible to altered gut microbiota compared to other strains in this study indicating that host genetics is an important modulator of the diet-microbiota-metabolic health axis. Overall, our study demonstrated complex interactions between host genetics, gut microbiota, and diet on metabolic health; indicating the need to consider both host genetics and the gut microbiota in the development of new and more effective precision nutrition strategies to improve metabolic health.

Background/objectives There is a growing appreciation for individual responses to diet. In a previous study, mouse strain-specific responses to American and ketogenic diets were observed. In this study, we searched for genetic variants underlying differences in the responses to American and ketogenic diets between C57BL/6J (B6) and FVB/NJ (FVB) mouse strains. Results Genetic mapping of fat and lean mass gain revealed QTLs on Chromosome (Chr) 1 at 191.6 Mb (Fmgq1) (P < 0.001, CI = 180.2–194.4 Mb), Chr5 at 73.7 Mb (Fmgq2, Lmgq1) (P < 0.001, CI = 66.1–76.6 Mb), and Chr7 at 40.5 Mb (Fmgq3) (P < 0.01, CI = 36.6–44.5 Mb). Analysis of serum HDL cholesterol concentration identified a significant (P < 0.001, CI = 160.6–176.1 Mb) QTL on Chr1 at 168.6 Mb (Hdlq1). Causal network inference suggests that HDL cholesterol and fat mass gain are both linked to Fmgq1. Conclusions Strong sex effects were identified at both Fmgq2 and Lmgq1, which are also diet-dependent. Interestingly, Fmgq2 and Fmgq3 affect fat gain directly, while Fmgq1 influences fat gain directly and via an intermediate change in serum cholesterol. These results demonstrate how precision nutrition will be advanced through the integration of genetic variation and sex in physiological responses to diets varied in carbohydrate composition.

ERBB3 has gained attention as a potential therapeutic target to treat colorectal and other types of cancers. To confirm a previous study showing intestinal polyps are dependent upon ERBB3, we generated an intestinal epithelia-specific ERBB3 deletion in C57BL/6-ApcMin/+ mice. Contrary to the previous report showing a significant reduction in intestinal polyps with ablation of ERBB3 on a B6;129 mixed genetic background, we observed a significant increase in polyp number with ablation of ERBB3 on C57BL/6J compared to control littermates. We confirmed the genetic background dependency of ERBB3 by also analyzing polyp development on B6129 hybrid and B6;129 advanced intercross mixed genetic backgrounds, which showed that ERBB3 deficiency only reduced polyp number on the mixed background as previously reported. Increased polyp number with ablation of ERBB3 was also observed in C57BL/6J mice treated with azoxymethane showing the effect is model independent. Polyps forming in absence of ERBB3 were generally smaller than those forming in control mice, albeit the effect was greatest in genetic backgrounds with reduced polyp numbers. The mechanism for differential polyp number in the absence of ERBB3 was through altered proliferation. Backgrounds with increased polyp number with loss of ERBB3 showed an increase in cell proliferation even in non-tumor epithelia, while backgrounds showing reduced polyp number with loss of ERBB3 showed reduced cellular proliferation. Increase polyp number caused by loss of ERBB3 was mediated by increased epidermal growth factor receptor (EGFR) expression, which was confirmed by deletion of Egfr. Taken together, this study raises substantial implications on the use of ERBB3 inhibitors against colorectal cancer. The prediction is that some patients may have increased progression with ERBB3 inhibitor therapy, which is consistent with observations reported for ERBB3 inhibitor clinical trials.

Background The gut microbiota is modulated by a combination of diet, host genetics, and sex effects. The magnitude of these effects and interactions among them is important to understanding inter-individual variability in gut microbiota. In a previous study, mouse strain-specific responses to American and ketogenic diets were observed along with several QTL for metabolic traits. In the current study, we searched for genetic variants underlying differences in the gut microbiota in response to American and ketogenic diets, which are high in fat and vary in carbohydrate composition, between C57BL/6J (B6) and FVB/NJ (FVB) mouse strains. Results Genetic mapping of microbial features revealed 18 loci under the QTL model (i.e., marginal effects that are not specific to diet or sex), 12 loci under the QTL by diet model, and 1 locus under the QTL by sex model. Multiple metabolic and microbial features map to the distal part of Chr 1 and Chr 16 along with eigenvectors extracted from principal coordinate analysis of measures of β-diversity. Bilophila, Ruminiclostridium 9, and Rikenella (Chr 1) were identified as sex and diet independent QTL candidate keystone organisms and Rikenelleceae RC9 Gut Group (Chr 16) was identified as a diet-specific, candidate keystone organism in confirmatory factor analyses of traits mapping to these regions. For many microbial features, irrespective of which QTL model was used, diet or the interaction between diet and a genotype were the strongest predictors of the abundance of each microbial trait. Sex, while important to the analyses, was not as strong of a predictor for microbial abundances. Conclusions These results demonstrate that sex, diet, and genetic background have different magnitudes of effects on inter-individual differences in gut microbiota. Therefore, Precision Nutrition through the integration of genetic variation, microbiota, and sex affecting microbiota variation will be important to predict response to diets varying in carbohydrate composition.

Diet-related metabolic syndrome is the largest contributor to adverse health in the United States. However, the study of gene-environment interactions and their epigenomic and transcriptomic integration is complicated by the lack of environmental and genetic control in humans that is possible in mouse models. Here we exposed three mouse strains, C57BL/6J (BL6), A/J, and NOD/ShiLtJ (NOD), to a high-fat high-carbohydrate diet, leading to varying degrees of metabolic syndrome. We then performed transcriptomic and genomic DNA methylation analyses and found overlapping but also highly divergent changes in gene expression and methylation upstream of the discordant metabolic phenotypes. Strain-specific pathway analysis of dietary effects reveals a dysregulation of cholesterol biosynthesis common to all three strains but distinct regulatory networks driving this dysregulation. This suggests a strategy for strain-specific targeted pharmacologic intervention of these upstream regulators informed by transcriptional regulation. As a pilot study, we administered the drug GW4064 to target one of these genotype-dependent networks, the Farnesoid X receptor pathway, and found that GW4064 exerts genotype-specific protection against dietary effects in BL6, as predicted by our transcriptomic analysis, as well as increased inflammatory-related gene expression changes in NOD. This pilot study demonstrates the potential efficacy of precision therapeutics for genotype-informed dietary metabolic intervention, and a mouse platform for guiding this approach.

Objectives In previous studies into effects of carbohydrate restriction, we demonstrated differential responses to American and ketogenic diets in C57BL/6J (B6) and FVB/NJ (FVB) mice during lifetime feeding trials. These preliminary data suggested that both sex and genetic background regulated response to carbohydrate restriction. More recently, we have examined the utility of the ketogenic diet as a dietary intervention in obese B6 and FVB mice. Methods Four-to six-week-old B6 and FVB mice were exposed to an American (35% of energy from fat, 50% from carbohydrates) diet for 3 months. After 3 months on the American diet, half of the animals were reversed to a ketogenic dietary intervention for the remainder of the 6-month feeding trial while the other half were left on the American diet. Results B6 females that received the ketogenic diet as a dietary intervention after 3 months of exposure to the American diet gained less fat mass than B6 females that remained on the American diet for the duration of the feeding trial (B6 female American: 15.94g, +/− 5.00g; B6 female Reversal: 9.67g, +/− 3.98g; p = 0.007, 95% CI: 1.91–10.63g). In contrast, B6 males exposed to the dietary intervention gained more fat mass than B6 males that remained on the American diet for the duration of the feeding trial (B6 male American: 19.69g, +/− 1.42g; B6 male Reversal: 23.86g, +/− 1.28g; P &lt; 0.001, 95% CI: −5.43 – (−2.89) g). As expected, no effect was seen in either FVB males or females. The amount of fat mass gained on the American diet prior to the introduction of the dietary intervention was highly correlated to the amount of fat mass gained at the end of the feeding trial for all strain and diet combinations (r = 0.878, p &lt; 0.001, 95% CI: 0.81- 0.92). Conclusions The strong relationship observed between the amount of fat mass gained prior to the introduction of the dietary intervention and the amount of fat mass gained at the end of the feeding trial suggests that there are mechanisms contributing to obesity that are not attenuated by simple dietary intervention, even within genetic backgrounds predicted to respond to carbohydrate restriction. Further studies are under way to investigate temporally controlled windows of opportunity for intervention as well as the effects of surgical removal of accumulated lipid on the plasticity of the obese phenotype. Funding Sources National Institutes of Health.

Objectives Carbohydrate restriction is a widely used dietary intervention to treat chronic diseases like metabolic syndrome. The ketogenic diet represents a severe type of carbohydrate restriction and is being rapidly adopted by metabolically healthy individuals. Recently, different responses to American (35% of energy from fat, 50% from carbohydrate) and ketogenic (80% of energy from fat, and 0% from carbohydrate) were observed between C57BL/6 J and FVB/NJ mice suggesting that genetic background effects response and non-response to carbohydrate restriction. Methods To further investigate the apparent response and non-response to carbohydrate restriction, we generated a C57BL/6 J x FVB/NJ intercross (F2) population (250 females and 264 males) to identify quantitative trait loci (QTL) involved in response to these two high fat diets. All animals were genotyped on the Mouse Universal Genotyping Array. Results Genetic analyses for fat gain during 3 months on diet revealed a diet and sex dependent (pdiet: Chr5 = 0.0013, psex: Chr5 = 0.0087) QTL on Chromosome (Chr) 5 at 73.7 Mb that results in a male-specific response to the ketogenic diet. There is an additional QTL on distal Chr1 at 191.6 Mb for fat mass gain in both males and females, on on both diets that overlaps with a QTL for serum HDL cholesterol concentration after 3 months on diet at 168.6 Mb. Conclusions This distal locus on Chr1 has previously been associated with Apoa2 and serum HDL cholesterol concentration in these strains. Additional candidate genes in these regions include Hsd11b1 and Srd5a3 and are associated with steroid hormone biosynthesis. These candidates are of primary interest given the relationship between cholesterol and synthesis of steroid hormones. These results demonstrate that the response to American and ketogenic diets is strain and sex specific. Our ongoing efforts to validate the regulatory role of these loci in response to carbohydrate restriction will be used to assess the utility of the relevant genotypes and analytes as biomarkers for response to carbohydrate restriction. Funding Sources National Institutes of Health.

The International Society of Nutrigenetics and Nutrigenomics (ISNN) held its 11th annual Congress in Los Angeles, California, between September 16 and 19, 2017. In addition to 2 keynote lectures, 4 plenary sessions included presentations by internationally renowned speakers on cutting-edge areas of research and new discoveries in genetics/genomics, the microbiome, and nutrition. Scientific topics included multi-omics approaches; diet and the microbiome; cancer, longevity, and metabolism; moving the field forward; and translational/educational aspects and the future of medicine. There was also an accepted oral abstracts session designed specifically to provide young investigators and trainees with the opportunity to present their work, as well as a session focused on industry-academic partnerships, which included a roundtable discussion afterwards. Overall, the 11th ISNN Congress was an exciting and intellectually stimulating meeting focused on understanding the impact of biological interactions between genes and nutrients on health and disease. These efforts continued the decade-long tradition of the annual ISNN Congress to provide an interdisciplinary platform for scientists from various disciplines to discuss research ideas and advance the fields of nutrigenetics and nutrigenomics.