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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
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“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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BackgroundResultAcharya, K. D., Noh, H. L., Graham, M. E., Suk, S., Friedline, R. H., Gomez, C. C., Parakoyi, A. E. R., Chen, J., Kim, J. K., & Tetel, M. J. (2021) · Metabolites · doi:10.3390/metabo11080499 · Cited by 22
“The gut microbiota influences host physiology through nutrient harvest, synthesis of vitamins, hormones, and neurotransmitters, and imprinting and strengthening of the immune system [20,21].”
BackgroundBile acid–gut microbiota crosstalk in irritable bowel syndrome
Gu, Y., Li, L., Yang, M., Liu, T., Song, X., Qin, X., Xu, X. J., Liu, J., Wang, B., & Cao, H. (2022) · Critical Reviews in Microbiology · doi:10.1080/1040841x.2022.2058353 · Cited by 26
“It has been extensively reported that a high-fat diet can induce alterations in the gut microbiota and bile acid pool, and cause bowel dysfunction and disrupt the gut barrier (Hildebrandt et al. 2009; Stenman et al. 2012; Stenman et al. 2013).”
BackgroundVitamin A, systemic T-cells, and the eye: Focus on degenerative retinal disease
Thirunavukarasu, A. J., Ross, A. C., & Gilbert, R. M. (2022) · Frontiers in Nutrition · doi:10.3389/fnut.2022.914457 · Cited by 27
Shu, C., Wu, S., Li, H., & Tian, J. (2023) · Nutrition Research · doi:10.1016/j.nutres.2023.04.002 · Cited by 24
The biomolecular gastrointestinal corona in oral drug delivery
Aljabbari, A., Kihara, S., Rades, T., & Boyd, B. J. (2023) · Journal of Controlled Release · doi:10.1016/j.jconrel.2023.09.049 · Cited by 26
Preparing the Bowel for Surgery: Learning from the Past and Planning for the Future
Alverdy, J. C., Hyman, N., Gilbert, J. A., Luo, J. N., & Krezalek, M. A. (2017) · Journal of the American College of Surgeons · doi:10.1016/j.jamcollsurg.2017.05.005 · Cited by 24
Pace, R. M., Prince, A., Ma, J., Belfort, B. D. W., Harvey, A. S., Hu, M., Baquero, K. C., Blundell, P., Takahashi, D. L., Dean, T. A., et al. (2018) · BMC Microbiology · doi:10.1186/s12866-018-1169-9 · Cited by 24
Variation in animal performance explained by the rumen microbiome or by diet composition1
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Impacts of fish oil on the gut microbiota of rats with alcoholic liver damage
Chen, Y.-L., Shirakawa, H., Lu, N.-S., Peng, H.-C., Xiao, Q., & Yang, S. (2020) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2020.108491 · Cited by 24
Self-citationThe frontier of health: Exploring therapeutic potentials of the microbiome
Abavisani, M., Foroushan, S. K., Kesharwani, P., & Sahebkar, A. (2025) · PharmaNutrition · doi:10.1016/j.phanu.2025.100435 · Cited by 23
Basic Definitions and Concepts: Organization of the Gut Microbiome
Quigley, E. M. M. (2017) · Gastroenterology Clinics of North America · doi:10.1016/j.gtc.2016.09.002 · Cited by 23
Yue, S., Wang, W.-X., Zhang, L., Liu, J., Feng, W., Gao, H., Tang, Y.-P., & Yan, D. (2021) · Chinese Journal of Integrative Medicine · doi:10.1007/s11655-021-3303-z · Cited by 22
A High-Fat Diet Induces Low-Grade Cochlear Inflammation in CD-1 Mice
Chan, J., Telang, R. S., Kociszewska, D., Thorne, P. R., & Vlajkovic, S. M. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23095179 · Cited by 23
“Interestingly, gut dysbiosis can occur in the absence of obesity [23].”
BackgroundThe association between vaginal microbiota disorders and early missed abortion: A prospective study
Sun, D., Zhao, X., Pan, Q., Li, F., Gao, B., Zhang, A., Huang, H., Xu, D., & Cheng, C. (2022) · Acta Obstetricia Et Gynecologica Scandinavica · doi:10.1111/aogs.14410 · Cited by 24
Bica, I.-C., Pietroșel, V.-A., Salmen, T., Diaconu, C.-T., Fierbinteanu-Braticevici, C. G., Stoica, R. A., Suceveanu, A., & Stoian, A. P. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24087184 · Cited by 26
“Furthermore, a high-fat diet led to a decrease in Bacteroidetes and an increase in Firmicutes and Proteobacteria, independent of the nutritional status, highlighting the importance of diet in gut microbiota changes [15].”
BackgroundDave, M., Johnson, L. A., Walk, S. T., Young, V. B., Stidham, R. W., Chaudhary, M. N., Funnell, J. A., & Higgins, P. (2011) · Gut · doi:10.1136/gut.2010.224337 · Cited by 24
Ju, H., Lee, Y. S., Ha, M. J., Cho, Y., Yi, H., Hwang, Y.-J., Hwang, G., & Shin, M. (2016) · Endocrine Journal · doi:10.1507/endocrj.ej15-0747 · Cited by 23
Zhao, J., Yu-yun, Z., & Zhu, W.-J. (2017) · General and Comparative Endocrinology · doi:10.1016/j.ygcen.2017.07.013 · Cited by 25
“As a result of energy surplus in cells, obesity may be induced by a high-fat diet, which has also been linked to obesity-related chronic inflammation (Hildebrandt et al., 2009).”
BackgroundSuwal, S., Wu, Q., Liu, W., Liu, Q., Sun, H., Ming, L., Gao, J., Zhang, B., Kou, Y., Liu, Z., et al. (2018) · Frontiers in Microbiology · doi:10.3389/fmicb.2018.02675 · Cited by 25
“Western diet, which is high in fat, can induce dysbiosis and is considered as a risk factor for the development of IBD (Hildebrandt et al., 2009; Chapman-Kiddell et al., 2010).”
BackgroundQian, L., Gao, R., Huang, J., & Qin, H. (2019) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2019.7801 · Cited by 25
Hou, D., Zhao, Q., Yousaf, L., Xue, Y., & Shen, Q. (2020) · European Journal of Nutrition · doi:10.1007/s00394-020-02395-x · Cited by 23
Langner, K., & Vervuert, I. (2019) · Tierärztliche Praxis Ausgabe G Großtiere / Nutztiere · doi:10.1055/a-0824-5210 · Cited by 35
Dietary Lipids, Gut Microbiota, and Their Metabolites: Insights from Recent Studies
Mohammadi, F., & Rudkowska, I. (2025) · Nutrients · doi:10.3390/nu17040639 · Cited by 22
“A study with mice on an HFD (45% of diet) with high LA showed an increase in the Clostridiaceae (Firmicutes) and Desulfovibrionaceae (Proteobacteria) families and a decrease in the Bacteroidaceae , Prevotel-laceae , and Rikenellaceae (Bacteroidetes) families [76].”
Hereu, M., Ramos‐Romero, S., Marín‐Valls, R., Amézqueta, S., Miralles‐Pérez, B., Romeu, M., Méndez, L., Medina, I., & Torres, J. L. (2019) · Nutrients · doi:10.3390/nu11112606 · Cited by 23
Bi, Q., Gu, W., Meng, F., Yang, X., Zeng, L., Liang, L., Yang, M., Zhang, T., & Yu, J. (2020) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2020.07.085 · Cited by 23
Omori, K., Miyakawa, H., Watanabe, A., Nakayama, Y., Lyu, Y., Ichikawa, N., Sasaki, H., & Shibata, S. (2021) · Nutrients · doi:10.3390/nu13010152 · Cited by 22
“Since HFD disturbs the intestinal environment [39], HFD was used in experiment two.”
MethodGut microbiota homeostasis restoration may become a novel therapy for breast cancer
Feng, Z., Xin, H.-Y., Zhang, Z., Liu, C., Yang, Z., You, H., & Xin, H.-W. (2021) · Investigational New Drugs · doi:10.1007/s10637-021-01063-z · Cited by 22
“A high-fat diet and obesity can affect gastrointestinal microorganisms and lead to increased estrogen levels; therefore, they may be a risk factor for BC [13, 15].”
BackgroundTargeting the Gut Microbiota for Remediating Obesity and Related Metabolic Disorders
Wang, B., Wang, L., Wang, H., Dai, H., Lu, X., Lee, Y. K., Gu, Z., Zhao, J., Zhang, H., Chen, W., et al. (2021) · Journal of Nutrition · doi:10.1093/jn/nxab103 · Cited by 26
Adithya, K. K., Rajeev, R., Selvin, J., & Kiran, G. S. (2021) · ACS Food Science & Technology · doi:10.1021/acsfoodscitech.0c00075 · Cited by 23
Aslam, H., Collier, F., Davis, J. A., Quinn, T. P., O’Hely, M., Pasco, J. A., Jacka, F. N., & Loughman, A. (2021) · Journal of Nutrition · doi:10.1093/jn/nxab252 · Cited by 20
Iwamoto, J., Honda, A., Miyazaki, T., Monma, T., Ueda, H., Morishita, Y., Yara, S., Hirayama, T. T., & Ikegami, T. (2021) · Hepatology Communications · doi:10.1002/hep4.1778 · Cited by 22
Gut microbiota is associated with dietary intake and metabolic markers in healthy individuals
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“A Western diet— characterized by high sugar and fat—is associated with chronic low-level systemic inflammation and reduced gut microbial diversity (21, 22); altered microbiota have been implicated in AD development (23, 24).”
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Exploring the Impact of the Gut Microbiome on Obesity and Weight Loss: A Review Article
Noor, J., Chaudhry, A., Batool, S. A., Noor, R., & Fatima, G. (2023) · Cureus · doi:10.7759/cureus.40948 · Cited by 28
“discovered that the microbiome was unrelated to the participants' ancestry [31].”
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Linking fat intake, the intestinal microbiome, and necrotizing enterocolitis in premature infants
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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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