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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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“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]
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“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]
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“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]
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“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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“High fat feeding increases Proteobacteria and may help in maximizing nutrient extraction from these types of foods (Hildebrandt et al., 2009).”
BackgroundMicrobiota prevents cholesterol loss from the body by regulating host gene expression in mice
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Alzheimer’s disease and gut microbiota: does trimethylamine N-oxide (TMAO) play a role?
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“Changes in intestinal flora occurred in ob/ob mice, with the up-regulation of Firmicutes and down-regulation of Bacteroidetes (62, 78).”
BackgroundModulatory Effect of Gut Microbiota on the Gut-Brain, Gut-Bone Axes, and the Impact of Cannabinoids
Ibrahim, I., Soumyakrishnan, S., Ayariga, J. A., Xu, J., Robertson, B. K., SREEPRIYA, M., & Ajayi, O. S. (2022) · Metabolites · doi:10.3390/metabo12121247 · Cited by 57
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“Later in life, the microbiota can change due to external factors, such as food (4–6) or pathogens (7, 8).”
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“Value is the mean ± SEM (n = 4) cells, and the proportion of Firmicutesto Bacteroidetes in many obese patients is much higher than that of the normal group (Hildebrandt et al., 2009).”
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Taking a metagenomic view of human nutrition
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Trans Fatty Acid Intake Induces Intestinal Inflammation and Impaired Glucose Tolerance
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“(9) also reported that trans fatty acid-rich diet caused a decrease in the relative abundance of the phylum Bacteroidetes, along with an increase in the phylum Proteobacteria and the family Desulfovibrionaceae, which are gram-negative sulfate-reducing bacteria found to be significantly abundant in obese and metabolica…”
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Does the Gut Microbiota Contribute to Obesity? Going beyond the Gut Feeling
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“[112] who observed that the normal configuration of the microbiota in Resistin-like molecule-beta (RELM-β) knockout mice also changed after a high-fat diet, however, the mice were resistant to a diet-induced obesity.”
BackgroundMicrobial regulation of allergic responses to food
Feehley, T., Stefka, A. T., Cao, S. Z., & Nagler‐Anderson, C. (2012) · Seminars in Immunopathology · doi:10.1007/s00281-012-0337-5 · Cited by 50
“Other work demonstrated that the phylum-level shifts in microbial composition noted when mice were switched to a high-fat diet were independent of obesity, suggesting that it was not the obese state, but the high-fat diet itself, that drove the changes observed [87].”
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Background
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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