Host Genotype and Gut Microbiome Modulate Insulin Secretion and Diet-Induced Metabolic Phenotypes

Kreznar, Julia H.; Keller, Mark P.; Traeger, Lindsay L.; Rabaglia, Mary E.; Schueler, Kathryn L.; Stapleton, Donald S.; Wen, Zhang; Vivas, Eugenio I.; Yandell, Brian S.; Broman, Aimee Teo; Hagenbuch, Bruno; Attie, Alan D.; Rey, Federico E.

doi:10.1016/j.celrep.2017.01.062

Cited by 164 publications

(141 citation statements)

References 67 publications

Supporting

Mentioning

129

Contrasting

Order By: Relevance

“…These traits were particularly interesting because both have been shown to be influenced by host genetics by previous studies. Turicibacter has been identified as highly heritable in both mouse and human genetic studies (24,27,45,49), whereas multiple reports have found differences in CA levels as a function of host genotype (18,61). Furthermore, CA levels are influenced by both host genetics and microbial metabolism since it is synthesized by host liver enzymes from cholesterol and subsequently modified by gut microbes in the intestine.…”

Section: Resultsmentioning

confidence: 99%

Genetic determinants of gut microbiota composition and bile acid profiles in mice

Kemis

Linke

Barrett

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

26 The microbial communities that inhabit the distal gut of humans and other mammals exhibit large 27 inter-individual variation. While host genetics is a known factor that influences gut microbiota 28 composition, the mechanisms underlying this variation remain largely unknown. Bile acids (BAs) 29 are hormones that are produced by the host and chemically modified by gut bacteria. BAs serve as 30 environmental cues and nutrients to microbes, but they can also have antibacterial effects. We 31 hypothesized that host genetic variation in BA metabolism and homeostasis influence gut 32 microbiota composition. To address this, we used the Diversity Outbred (DO) stock, a population 33 of genetically distinct mice derived from eight founder strains. We characterized the fecal 34 microbiota composition and plasma and cecal BA profiles from 400 DO mice maintained on a 35 high-fat high-sucrose diet for ~22 weeks. Using quantitative trait locus (QTL) analysis, we 36 identified several genomic regions associated with variations in both bacterial and BA profiles.37 Notably, we found overlapping QTL for Turicibacter sp. and plasma cholic acid, which mapped 38 to a locus containing the gene for the ileal bile acid transporter, Slc10a2. Mediation analysis and 39 subsequent follow-up validation experiments suggest that differences in Slc10a2 gene expression 40 associated with the different strains influences levels of both traits and revealed novel interactions 41 between Turicibacter and BAs. This work illustrates how systems genetics can be utilized to 42 generate testable hypotheses and provide insight into host-microbe interactions. 44Author summary 45 Inter-individual variation in the composition of the intestinal microbiota can in part be attributed 46 to host genetics. However, the specific genes and genetic variants underlying differences in the 47 microbiota remain largely unknown. To address this, we profiled the fecal microbiota composition 3 48 of 400 genetically distinct mice, for which genotypic data is available. We identified many loci of 49 the mouse genome associated with changes in abundance of bacterial taxa. One of these loci is 50 also associated with changes in the abundance of plasma bile acidsmetabolites generated by the 51 host that influence both microbiota composition and host physiology. Follow up validation 52 experiments provide mechanistic insights linking host genetic differences, with changes in ileum 53 gene expression, bile acid-bacteria interactions and bile acid homeostasis. Together, this work 54 demonstrates how genetic approaches can be used to generate testable hypothesis to yield novel 55 insight into how host genetics shape gut microbiota composition. 56 57 Introduction 58The intestinal microbiota has profound effects on host physiology and health (1-3). The 59 composition of the gut microbiota is governed by a combination of environmental factors, 60 including diet, drugs, maternal seeding, cohabitation, and host genetics (4-7). Together, these 61 factors cause substantial inter-i...

show abstract

Section: Resultsmentioning

confidence: 99%

Genetic determinants of gut microbiota composition and bile acid profiles in mice

Kemis

Linke

Barrett

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…For example, two of the DO founder strains, NOD/ShiLtJ and NZO/HILtJ, are well known for their non-obese diabetic and obese body traits, respectively. Similarly, C57BL/6J and CAST/EiJ are known to be susceptible or resistant to diet-induced obesity, respectively 34 . Because each DO mouse contains genetic material from all of these strains in a unique and randomized pattern, the expectation is that an admixture of alleles results in a subset of individuals that exhibit extreme phenotypes of metabolic parameters.…”

Section: Discussionmentioning

confidence: 99%

NTP Research Report on Baseline Characteristics of Diversity Outbred (J:DO) Mice Relevant to Toxicology Studies

Harrill¹,

Borghoff²,

Zorrilla³

et al. 2018

View full text Add to dashboard Cite

“…An analysis of the metabolic phenotypes of eight genetically distinct inbred mouse strains in response to a HFD revealed several variations in their metabolic-related phenotypes and gut microbiota. 113 Clostridiaceae show the strongest positive correlation with plasma insulin levels and weight gain, whereas Bacteroidaceae are negatively associated with these parameters. In a follow-up microbiota transplant experiment, the composition of the murine gut microbiome was shown to be able to modify the host's susceptibility to diet-induced metabolic diseases, 113 a finding that is possibly related to an enhanced capacity to process dietary sugar and to produce hydrophobic bile acids.…”

Section: Metabolic Diseases and The Microbiomementioning

confidence: 96%

Exploring the microbiome in health and disease

Scotti

Boué

Sasso

et al. 2017

Toxicology Research and Application

View full text Add to dashboard Cite

The analysis of human microbiome is an exciting and rapidly expanding field of research. In the past decade, the biological relevance of the microbiome for human health has become evident. Microbiome comprises a complex collection of microorganisms, with their genes and metabolites, colonizing different body niches. It is now well known that the microbiome interacts with its host, assisting in the bioconversion of nutrients and detoxification, supporting immunity, protecting against pathogenic microbes, and maintaining health. Remarkable new findings showed that our microbiome not only primarily affects the health and function of the gastrointestinal tract but also has a strong influence on general body health through its close interaction with the nervous system and the lung. Therefore, a perfect and sensitive balanced interaction of microbes with the host is required for a healthy body. In fact, growing evidence suggests that the dynamics and function of the indigenous microbiota can be influenced by many factors, including genetics, diet, age, and toxicological agents like cigarette smoke, environmental contaminants, and drugs. The disruption of this balance, that is called dysbiosis, is associated with a plethora of diseases, including metabolic diseases, inflammatory bowel disease, chronic obstructive pulmonary disease, periodontitis, skin diseases, and neurological disorders. The importance of the host microbiome for the human health has also led to the emergence of novel therapeutic approaches focused on the intentional manipulation of the microbiota, either by restoring missing functions or eliminating harmful roles. In the present review, we outline recent studies devoted to elucidate not only the role of microbiome in health conditions and the possible link with various types of diseases but also the influence of various toxicological factors on the microbial composition and function.

show abstract

Host Genotype and Gut Microbiome Modulate Insulin Secretion and Diet-Induced Metabolic Phenotypes

Cited by 164 publications

References 67 publications

Genetic determinants of gut microbiota composition and bile acid profiles in mice

Genetic determinants of gut microbiota composition and bile acid profiles in mice

NTP Research Report on Baseline Characteristics of Diversity Outbred (J:DO) Mice Relevant to Toxicology Studies

Exploring the microbiome in health and disease

Contact Info

Product

Resources

About