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High-Fat Diet Determines the Composition of the Murine Gut Microbiome Independently of Obesity
Open accessAbstract
Background & aims The composition of the gut microbiome is affected by host phenotype, genotype, immune function, and diet. Here, we used the phenotype of RELMbeta knockout (KO) mice to assess the influence of these factors.Methods Both wild-type and RELMbeta KO mice were lean on a standard chow diet, but, upon switching to a high-fat diet, wild-type mice became obese, whereas RELMbeta KO mice remained comparatively lean. To investigate the influence of diet, genotype, and obesity on microbiome composition, we used deep sequencing to characterize 25,790 16S rDNA sequences from uncultured bacterial communities from both genotypes on both diets.Results We found large alterations associated with switching to the high-fat diet, including a decrease in Bacteroidetes and an increase in both Firmicutes and Proteobacteria. This was seen for both genotypes (ie, in the presence and absence of obesity), indicating that the high-fat diet itself, and not the obese state, mainly accounted for the observed changes in the gut microbiota. The RELMbeta genotype also modestly influenced microbiome composition independently of diet. Metagenomic analysis of 537,604 sequence reads documented extensive changes in gene content because of a high-fat diet, including an increase in transporters and 2-component sensor responders as well as a general decrease in metabolic genes. Unexpectedly, we found a substantial amount of murine DNA in our samples that increased in proportion on a high-fat diet.Conclusions These results demonstrate the importance of diet as a determinant of gut microbiome composition and suggest the need to control for dietary variation when evaluating the composition of the human gut microbiome.
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“administration of an HFD to healthy subjects caused a decrease in Bacteroidetes levels with an increase in both Firmicutes and Proteobacteria levels of gut microbiota (Hildebrandt et al., 2009;Zhang et al., 2012a).”
From The Microbiota-Gut-Brain Axis (2019) · cites this paper as Hildebrandt et al., 2009
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In the citing paper
“animal models fed an HFD demonstrated an alteration in their gut microbiota profile with a reduction in Bacteroidetes levels and an increase in both Proteobacteria and Firmicute levels (Hildebrandt et al., 2009).”
From The Microbiota-Gut-Brain Axis (2019) · cites this paper as Hildebrandt et al., 2009
In the citing paper
“Those with cystic fibrosis are recommended to consume a diet high in protein and fat (and therefore a comparative reduction in carbohydrates) which has been previously associated with an increase in Firmicutes to Bacteriodetes ratio in mice [96], though dietary data was not collected within the cystic fibrosis study [95].”
From Effect of Diet on the Gut Microbiota: Rethinking Intervention Duration (2019) · cites this paper as [96]
In the citing paper
“These changes were observed in mice resistant to weight gain, implying a direct effect of dietary lipids on the microbiota (26, 27).”
From The gut microbiota at the intersection of diet and human health (2018) · cites this paper as [26]
In the citing paper
“Experimental mice fed a high-fat diet (40 to 80% total caloric intake) exhibit decreases at the phyla-level in Bacteroidetes and increases in Firmicutes and Proteobacteria.”
From The gut microbiota at the intersection of diet and human health (2018) · cites this paper as [26]
In the citing paper
“a high-fat diet, independent of obesity, altered the composition of the intestinal microbiome (Hildebrandt, 2009).”
From Viral Infections, the Microbiome, and Probiotics (2021) · cites this paper as Hildebrandt, 2009
In the citing paper
“Similar to the Western diet, high-fat diets in animal studies reproducibly change gut microbial community structure, decreasing the overall microbiota diversity and beneficial bacteria (e.g., A. muciniphila, Bifidobacterium, Lactobacillus, and Lactococcus) and increasing the Firmicutes:Bacteroidetes ratio and the abundance of Enterobacteriales, Clostridium cluster XVIa, Mollicutes, and B. wadswort”
From Diet and the Microbiota–Gut–Brain Axis: Sowing the Seeds of Good Mental Health (2021) · cites this paper as [90]
In the citing paper
“To further isolate the solitary impact of sleep on the microbiota – separate from the previously documented impact of e.g. high-fat diet [32] – participants were provided with a non-sugar sweetened, low-fat diet throughout the three meals, the exception being the oral glucose tolerance (OGTT) test on day 2”
From Gut microbiota and glucometabolic alterations in response to recurrent partial sleep deprivation in normal-weight young individuals (2016) · cites this paper as [32]
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InfluentialXu, K., Guo, Y., Wang, Y., Ren, Y., Low, V., Cho, S., Ping, L., Peng, K., Li, X., Qiu, Y., et al. (2022) · Aging Cell · doi:10.1111/acel.13760 · Cited by 31
“When mice were switched to a fat- rich diet, the gut microbiota composition was altered within 24 h, driven by an increase in dietary fat content rather than the obese state (Hildebrandt et al., 2009).”
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Role of the microbiome in the normal and aberrant glycemic response
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“Similarly, in mice fed with HFD for 12 weeks, microbiota analysis has revealed increases in Proteobacteria (which includes Enterobacteriales) and Firmicutes phyla (which includes Clostridiales), but a concomitant reduction in the Bacteriodetes phylum was observed(17,69).”
InfluentialCarlos, D., Pérez, M. M., Leite, J. A., Rocha, F. A., Martins, L. M. S., Pereira, C. A., Fraga‐Silva, T. F. D. C., Pucci, T. A., Ramos, S. G., Câmara, N. O. S., et al. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.01265 · Cited by 35
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“Studies on intestinal dysbiosis associated to high-fat diets fed to mice have reported a decrease in Bacteroidetes and an increase in both Firmicutes and Proteobacteria (Hildebrandt et al. 2009; Myles et al. 2013).”
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“In obese rodents, diet components but not obese states are the dominant determinant of the gut microbial composition [10].”
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Zhou, J., Sun, S., Luan, S., Xiao, X., Yang, Y., Mao, C., Chen, L., Zeng, X., Zhang, Y., & Yuan, Y. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.717242 · Cited by 35
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“The intestinal wall is a physical barrier to protect from endotoxemia; however, after the consumption of high-fat (19) or high-fructose diet (20), reduced expression of epithelial tight junction proteins, which are involved in intestinal integrity, have been demonstrated alongside dysbiosis in the gut microbiota (21).”
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“A high-fat diet could promote changes in the gut microbiota composition, as described with the replacement of the Bacteroidetes enterotype by both Firmicutes and Proteobacteria (Hildebrandt et al., 2009).”
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Bacterial diversity in intestinal mucosa of mice fed with Dendrobium officinale and high-fat diet
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“Thus, the hypothesis that RELM-β drives susceptibility to colonic inflammation in the Muc2 model may depend on additional factors, including diet.(39) Mice fed a high-fat diet (lard as a saturated fat source) exhibit higher levels of RELM-β protein in the stool and have altered glucose intolerance and hyperlipidemia d…”
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Diets, Gut Microbiota and Metabolites
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Metadata
- Authors
- Hildebrandt, M. A., Hoffmann, C., Sherrill–Mix, S. A., Keilbaugh, S. A., Hamady, M., Chen, Y., Knight, R., Ahima, R. S., Bushman, F., & Wu, G. D.
- Affiliations
- University of Pennsylvania (US)
- University of Colorado Boulder (US)
- Corresponding author
- Bushman, Frederic
- Wu, Gary D.
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2009-11
- Volume
- 137
- Issue
- 5
- Pages
- 1716-1724.e2
- ISSN
- 0016-5085 (ISSN-L)
- PMC
- PMC2770164
- OpenAlex
- W2158630697
- Cited by
- 1,576
- References
- 43
- Citations by year
- 2026: 40 · 2025: 61 · 2024: 96 · 2023: 76 · 2022: 130 · 2021: 117 · 2020: 158 · 2019: 148 · 2018: 115 · 2017: 94 · 2016: 104 · 2015: 96 · 2014: 87 · 2013: 82 · 2012: 71
- FWCI
- 22.84
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Gastroenterology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- University of Pennsylvania
- National Institutes of Health
- National Human Genome Research Institute (R01HG004872, HG004872)
- National Institute of General Medical Sciences (T32GM065103)
- National Institute of Allergy and Infectious Diseases (R01AI039368, AI39368)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-50306, DK078669, P01DK078669, DK-019525, DK062348, R01DK062348, R56DK062348, P30DK019525, P30DK050306)
- National Center for Research Resources (S10RR024525)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Dentistry › Periodontics › Oral microbiology and periodontitis research
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- gut microbiota, high-fat diet, obesity, diet-induced obesity, Bacteroidetes, Firmicutes, Proteobacteria, gut microbiota composition, metagenomics, microbial gene content, 16S rRNA gene sequencing
- MeSH terms
- Animals, Diet, Dietary Fats, Female, Hormones, Ectopic, Intestines, Mice, Inbred C57BL, Obesity, RNA, Ribosomal, 16S, Mice, Knockout, Intercellular Signaling Peptides and Proteins, Mice, Metagenome
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