Cited by 611Gut microbiota and healthAdipokines, Inflammation, and Metabolic DiseasesDiet, Metabolism, and Disease

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Germ‐free C57BL/6J mice are resistant to high‐fat‐diet‐induced insulin resistance and have altered cholesterol metabolism

Rabot, Sylvie, Membrez, Mathieu, Bruneau, Aurélia, Gérard, Philippe, Harach, Taoufiq, Moser, Mireille, Raymond, Frederic, Mansourian, Robert, Chou, Chieh J.·2010·The FASEB Journal

DOI 10.1096/fj.10.164921

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Abstract

Recent studies showed that germ‐free (GF) mice are resistant to obesity when consuming a high‐fat, high‐carbohydrate Western diet. However, it remains unclear what mechanisms are involved in the antiobesity phenotype and whether GF mice develop insulin resistance and dyslipidemia with high‐fat (HF) feeding. In the present study, we compared the metabolic consequences of HF feeding on GF and conventional (conv) C57BL/6J mice. GFmice consumed fewer calories, excreted more fecal lipids, and weighed significantly less than conv mice. GF/HF animals also showed enhanced insulin sensitivity with improved glucose tolerance, reduced fasting and nonfasting insuline‐mia, and increased phospho‐Akt (Ser‐473) in adipose tissue. In association with enhanced insulin sensitivity, GF/HF mice had reduced plasma TNF‐α and total serum amyloid A concentrations. Reduced hypercholes‐terolemia, a moderate accretion of hepatic cholesterol, and an increase in fecal cholesterol excretion suggest an altered cholesterol metabolism in GF/HF mice. Pronounced nucleus SREBP2 proteins and up‐regulation of cholesterol biosynthesis genes indicate that enhanced cholesterol biosynthesis contributed to the cholesterol homeostasis in GF/HF mice. Our results demonstrate that fewer calorie consumption and increased lipid excretion contributed to the obesity‐resistant phenotype of GF/HF mice and reveal that insulin sensitivity and cholesterol metabolism are metabolic targets influenced by the gut microbiota.— Rabot, S., Membrez, M., Bruneau, A., Gerard, P., Harach, T., Moser, M., Raymond, F., Mansourian, R., Chou. C. J. Germ‐free C57BL/6J mice are resistant to high‐fat‐diet‐induced insulin resistance and have altered cholesterol metabolism. FASEB J. 24, 4948–4959 (2010). www.fasebj.org

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Background
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Background
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Background
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BackgroundInfluential
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Background
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Background
Ground flaxseed reverses protection of a reduced-fat diet against Citrobacter rodentium-induced colitis
Määttänen, P., Lurz, E., Botts, S. R., Wu, R., Yeung, C. W., Li, B., Abiff, S. K., Johnson‐Henry, K. C., Lepp, D., Power, K. A., et al. (2018) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00101.2018 · Cited by 27
“Furthermore, previous studies demonstrate that mice fed an HF diets exhibit reduced inflammation either with antibiotic treatment or under germ-free conditions (7, 41).”
Background
Abnormal Intestinal Microbiome in Medical Disorders and Potential Reversibility by Fecal Microbiota Transplantation
DuPont, H. L., Jiang, Z., Dupont, A. W., & Utay, N. S. (2020) · Digestive Diseases and Sciences · doi:10.1007/s10620-020-06102-y · Cited by 30
Effects of Low-Carbohydrate Diet and Exercise Training on Gut Microbiota
Sun, S., Lei, O. K., Nie, J., Shi, Q., Xu, Y., & Kong, Z. (2022) · Frontiers in Nutrition · doi:10.3389/fnut.2022.884550 · Cited by 27
Buyang Huanwu decoction affects gut microbiota and lipid metabolism in a ZDF rat model of co-morbid type 2 diabetes mellitus and obesity: An integrated metabolomics analysis
Liu, M., Zhao, Q., Liu, J., Huang, A., & Xia, X. (2022) · Frontiers in Chemistry · doi:10.3389/fchem.2022.1036380 · Cited by 27
“Other studies have also reported that germ-free mice transplanted with gut microbiota from normal, obese, and lean mice eventually exhibited no significant changes in body weight, obesity, and wasting, respectively (Rabot et al., 2010).”
Background
Gut Microbiota and Energy Expenditure in Health and Obesity
Bakker, G. J., Zhao, J., Herrema, H., & Nieuwdorp, M. (2015) · Journal of Clinical Gastroenterology · doi:10.1097/mcg.0000000000000363 · Cited by 26
Depletion of the gut microbiota differentially affects the impact of whey protein on high‐fat diet‐induced obesity and intestinal permeability
Boscaini, S., Cabrera‐Rubio, R., Golubeva, A. V., Nychyk, O., Fülling, C., Speakman, J. R., Cotter, P. D., Cryan, J. F., & Nilaweera, K. N. (2021) · Physiological Reports · doi:10.14814/phy2.14867 · Cited by 29
“Similarly, germ free mice were resistant to HFD- induced metabolic dysfunction such as insulin resistance, inflammation, glucose tolerance and hypercholesterolemia (Rabot et al., 2010).”
Background
Fecal Microbiota Transplantation as a Tool for Therapeutic Modulation of Non-gastrointestinal Disorders
Lipták, R., Gromová, B., & Gardlík, R. (2021) · Frontiers in Medicine · doi:10.3389/fmed.2021.665520 · Cited by 26
The role of faecal microbiota transplantation in chronic noncommunicable disorders
Mullish, B. H., Tohumcu, E., Porcari, S., Fiorani, M., Tommaso, N. D., Gasbarrini, A., Cammarota, G., Ponziani, F. R., & Ianiro, G. (2023) · Journal of Autoimmunity · doi:10.1016/j.jaut.2023.103034 · Cited by 25
The microbiota revolution: Excitement and caution
Rescigno, M. (2017) · European Journal of Immunology · doi:10.1002/eji.201646576 · Cited by 27
Prenylation of viral proteins by enzymes of the host: Virus‐driven rationale for therapy with statins and FT/GGT1 inhibitors
Marakasova, E. S., Eisenhaber, B., Maurer‐Stroh, S., Eisenhaber, F., & Baranova, A. V. (2017) · BioEssays · doi:10.1002/bies.201700014 · Cited by 25
“Moreover, we speculate that domesticated andwild swine demonstrate differential susceptibility to ASF due to the variance in intrinsic activity of HMG-CoA reductase, which is known to be induced by obesity-promoting diet [57, 58], and therefore, in relative availability of prenylationprecursors.”
Background
Regulation of body fat mass by the gut microbiota: Possible mediation by the brain
Schéle, E., Grahnemo, L., Anesten, F., Hallén, A., Bäckhed, F., & Jansson, J. (2015) · Peptides · doi:10.1016/j.peptides.2015.03.027 · Cited by 25
Association of Gut Hormones and Microbiota with Vascular Dysfunction in Obesity
Rovella, V., Rodia, G., Daniele, F. D., Cardillo, C., Campia, U., Noce, A., Candi, E., Della‐Morte, D., & Tesauro, M. (2021) · Nutrients · doi:10.3390/nu13020613 · Cited by 24
“Interestingly, germ free mice appear to be resistant to diet-induced obesity (High Fat Diet) and to have low levels of inflammatory cytokines (TNF alfa) and improved insulin sensitivity [207].”
Background
Microbiome-liver crosstalk: A multihit therapeutic target for liver disease
Kirundi, J., Moghadamrad, S., & Urbaniak, C. (2023) · World Journal of Gastroenterology · doi:10.3748/wjg.v29.i11.1651 · Cited by 24
“Rabot et al [52] also showed that germ-free mice fed a high-fat diet were more resistant to hepatic steatosis than colonized controls.”
Tomato Pectin Ameliorated Hepatic Steatosis in High-Fat-Diet Mice by Modulating Gut Microbiota and Bile Acid Metabolism
Wang, P., Sun, J., Zhao, W., Wang, D., Ma, Y., Zhao, Y., Wang, Y., & Zhao, X. (2024) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.4c01598 · Cited by 25
Pinto beans modulate the gut microbiome, augment MHC II protein, and antimicrobial peptide gene expression in mice fed a normal or western-style diet
Ojo, B. A., Lu, P., Alake, S. E., Keirns, B. H., Anderson, K. L., Gallucci, G., Hart, M. D., El-Rassi, G. D., Ritchey, J. W., Chowanadisai, W., et al. (2020) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2020.108543 · Cited by 22
Fecal Microbiota Transplantation Shows Marked Shifts in the Multi-Omic Profiles of Porcine Post-weaning Diarrhea
Su, Y., Li, X., Li, D., & Sun, J. (2021) · Frontiers in Microbiology · doi:10.3389/fmicb.2021.619460 · Cited by 25
“…among the groups were mainly in lipids and lipid-like molecules, which can be explained by the role of bacteria as regulators for the digestion, absorption, storage, and secretion of dietary lipids in the intestinal tract (Rabot et al., 2010; Sommer and Bäckhed, 2016; Martinez-Guryn et al., 2018).”
Background
Role of gut microbe-derived metabolites in cardiometabolic diseases: Systems based approach
Cao, Y., Aquino-Martínez, R., Hutchison, E. R., Allayee, H., Lusis, A. J., & Rey, F. E. (2022) · Molecular Metabolism · doi:10.1016/j.molmet.2022.101557 · Cited by 26
“For example, germ-free mice exhibit altered cholesterol metabolism, and studies have shown that gut microbiota influences cholesterol metabolism [6], in part through regulating cholesterol biosynthesis in the liver [124].”
Background
The Influence of Gut Microbial Metabolism on the Development and Progression of Non-alcoholic Fatty Liver Disease
Jia, W. P., & Rajani, C. (2018) · Advances in experimental medicine and biology · doi:10.1007/978-981-10-8684-7_8 · Cited by 23
Monitoring type 2 diabetes from volatile faecal metabolome in Cushing’s syndrome and single Afmid mouse models via a longitudinal study
Lourenco, C. M., Kelly, D. J., Cantillon, J., Cauchi, M., Yon, M. A., Bentley, L., Cox, R., & Turner, C. (2019) · Scientific Reports · doi:10.1038/s41598-019-55339-9 · Cited by 24
NOD1 deficiency promotes an imbalance of thyroid hormones and microbiota homeostasis in mice fed high fat diet
González-Ramos, S., Paz-García, M., Fernández-García, V., Portune, K. J., Acosta-Medina, E. F., Sanz, Y., Castrillo, A., Martín‐Sanz, P., Obregón, M.-J., & Boscá, L. (2020) · Scientific Reports · doi:10.1038/s41598-020-69295-2 · Cited by 24
Gut–Liver Axis in Nonalcoholic Fatty Liver Disease: the Impact of the Metagenome, End Products, and the Epithelial and Vascular Barriers
Gil‐Gómez, A., Brescia, P., Rescigno, M., & Romero‐Gómez, M. (2021) · Seminars in Liver Disease · doi:10.1055/s-0041-1723752 · Cited by 24
Beeinflussung der equinen Mikrobiota durch Fütterung und Probiotika: aktueller Stand der Forschung und rechtliche Grundlagen
Langner, K., & Vervuert, I. (2019) · Tierärztliche Praxis Ausgabe G Großtiere / Nutztiere · doi:10.1055/a-0824-5210 · Cited by 35
Multi-organ Coordination of Lipoprotein Secretion by Hormones, Nutrients and Neural Networks
Stahel, P., Xiao, C., Nahmias, A., Tian, L., & Lewis, G. F. (2021) · Endocrine Reviews · doi:10.1210/endrev/bnab008 · Cited by 24
Three of a Kind: Control of the Expression of Liver-Expressed Antimicrobial Peptide 2 (LEAP2) by the Endocannabinoidome and the Gut Microbiome
Shen, M., Manca, C., Suriano, F., Nallabelli, N., Pechereau, F., Allam‐Ndoul, B., Iannotti, F. A., Flamand, N., Veilleux, A., Cani, P. D., et al. (2021) · Molecules · doi:10.3390/molecules27010001 · Cited by 21
“The results observed in these and DIO mice may suggest that Leap2 expression in the small intestine, and the ileum, in particular, maybe due to glucose intolerance rather than obesity per se, since this dysmetabolic feature was common to both genetically obese mice and HFHS mice when they showed increase Leap2 mRNA le…”
BackgroundInfluential
Comparison between Egg Intake versus Choline Supplementation on Gut Microbiota and Plasma Carotenoids in Subjects with Metabolic Syndrome
Thomas, M. S., DiBella, M., Blesso, C. N., Malysheva, O., Caudill, M. A., Sholola, M. J., Cooperstone, J. L., & Fernández, M. L. (2022) · Nutrients · doi:10.3390/nu14061179 · Cited by 22
Escherichia coli NF73‐1 disrupts the gut–vascular barrier and aggravates high‐fat diet‐induced fatty liver disease via inhibiting Wnt/β‐catenin signalling pathway
Ke, Z., Huang, Y., Xu, J., Liu, Y., Zhang, Y., Wang, Y., Zhang, Y. Y., & Liu, Y. (2024) · Liver International · doi:10.1111/liv.15823 · Cited by 23
Role of the Intestine and Its Gut Microbiota in Metabolic Syndrome and Obesity
Busch, C. B. E., Bergman, J. J. G. H. M., Nieuwdorp, M., & van Baar, A. C. G. (2024) · The American Journal of Gastroenterology · doi:10.14309/ajg.0000000000002730 · Cited by 29
“In germ-free mice, adiposity was associated with improved insulin sensitivity, indicating that the gut microbiota directly contributes to altered glucose metabolism (23).”
Background
Habitual Diets Rich in Dark-Green Vegetables Are Associated with an Increased Response to ω-3 Fatty Acid Supplementation in Americans of African Ancestry
O’Sullivan, A. M., Armstrong, P., Schuster, G. U., Pedersen, T. L., Allayee, H., Stephensen, C. B., & Newman, J. W. I. (2013) · Journal of Nutrition · doi:10.3945/jn.113.181875 · Cited by 22
Gut Microbiome and Obesity. How to Prove Causality?
Gérard, P. (2017) · Annals of the American Thoracic Society · doi:10.1513/annalsats.201702-117aw · Cited by 22
Self-citation
Correlation between Jejunal Microbial Diversity and Muscle Fatty Acids Deposition in Broilers Reared at Different Ambient Temperatures
Li, X., Cao, Z., Yang, Y., Chen, L., Liu, J., Lin, Q., Qiao, Y., Zhao, Z., An, Q., Zhang, C., et al. (2019) · Scientific Reports · doi:10.1038/s41598-019-47323-0 · Cited by 22
Role of Gastrointestinal Microbiota on Kidney Injury and the Obese Condition
Wanchai, K., Pongchaidecha, A., Chatsudthipong, V., Chattipakorn, S. C., Chattipakorn, N., & Lungkaphin, A. (2016) · The American Journal of the Medical Sciences · doi:10.1016/j.amjms.2016.11.019 · Cited by 22
“To date, it has been reported that changes in microbiota composition of the GI tract are involved in the development of obesity and associated conditions such as insulin resistance [29, 30].”
Background
An anti-atherosclerotic signaling cascade involving intestinal microbiota, microRNA-10b, and ABCA1/ABCG1 mediated reverse cholesterol transport
Hazen, S., & Smith, J. D. (2012) · Circulation Research · doi:10.1161/circresaha.112.277277 · Cited by 18
Gut microbiota and metabolic disease: from pathogenesis to new therapeutic strategies
Kang, Y., Zhang, X., Cai, Y., Su, J., & Kong, X. (2016) · Reviews in Medical Microbiology · doi:10.1097/mrm.0000000000000085 · Cited by 20
Message in a Biota: Gut Microbes Signal to the Circadian Clock
Marcinkevicius, E., & Shirasu‐Hiza, M. (2015) · Cell Host & Microbe · doi:10.1016/j.chom.2015.04.013 · Cited by 21
Flaxseed- and Buckwheat-Supplemented Diets Altered Enterobacteriaceae Diversity and Prevalence in the Cecum and Feces of Obese Mice
Pulkrabek, M., Rhee, Y. S., Gibbs, P. S., & Hall, C. (2017) · Journal of Dietary Supplements · doi:10.1080/19390211.2017.1305477 · Cited by 21
“This animal model is prone to obesity development after feeding a high-fat diet (Wang & Liao, 2012; Rabot et al., 2010).”
Background
Understanding mouse bile acid formation: Is it time to unwind why mice and rats make unique bile acids?
Rudling, M. (2016) · Journal of Lipid Research · doi:10.1194/jlr.c072876 · Cited by 21
“Germ-free mice have been shown to have an improved resistance to high-fat feeding (11).”
Background
Effect of Sheng‐Jiang Powder on Gut Microbiota in High‐Fat Diet‐Induced NAFLD
Li, J., Hu, Q., Dai, X.-Y., Zhu, L., Miao, Y., Kang, H., Zhao, X., Yao, J., Long, D., Tang, W., et al. (2020) · Evidence-based Complementary and Alternative Medicine · doi:10.1155/2020/6697638 · Cited by 21
Altered intestinal epithelial nutrient transport: an underappreciated factor in obesity modulated by diet and microbiota
Sundaram, S., & Borthakur, A. (2021) · Biochemical Journal · doi:10.1042/bcj20200902 · Cited by 21
Effect of Microbial Status on Hepatic Odd-Chain Fatty Acids Is Diet-Dependent
Weitkunat, K., Bishop, C. A., Wittmüss, M., Machate, T., Schifelbein, T., Schulze, M. B., & Klaus, S. (2021) · Nutrients · doi:10.3390/nu13051546 · Cited by 20
“These data are in line with those form a study comparing germ-free and conventional mice, which showed that a complex composition of gut bacteria in mice increased the intestinal absorption of lipids, resulting in marked obesity [41].”
Result
Hepatoprotection of Probiotics Against Non-Alcoholic Fatty Liver Disease in vivo: A Systematic Review
Sabirin, F., Lim, S. M., Neoh, C. F., & Ramasamy, K. (2022) · Frontiers in Nutrition · doi:10.3389/fnut.2022.844374 · Cited by 21
Diarrhea induced by insufficient fat absorption in weaned piglets: Causes and nutrition regulation
Li, Y., Shi, P., Kang, Y., Lin, Q., Wang, M., Hou, Z., Tang, W., & Diao, H. (2023) · Animal nutrition · doi:10.1016/j.aninu.2023.12.004 · Cited by 20
Feeling the Burn: Intestinal Epithelial Cells Modify Their Lipid Metabolism in Response to Bacterial Fermentation Products
Wen, J., & Rawls, J. F. (2020) · Cell Host & Microbe · doi:10.1016/j.chom.2020.02.009 · Cited by 20
FATORES ASSOCIADOS À OBESIDADE: UMA BREVE REVISÃO NARRATIVA
do Nascimento, O. V., do Nascimento, W. M., Melo, C. D. S., & Lima, É. S. (2022) · RECISATEC - REVISTA CIENTÍFICA SAÚDE E TECNOLOGIA · doi:10.53612/recisatec.v2i5.108 · Cited by 24
Therapeutic Strategies to Modulate Gut Microbial Health: Approaches for Chronic Metabolic Disorder Management
Rondanelli, M., Borromeo, S., Cavioni, A., Gasparri, C., Gattone, I., Genovese, E., Lazzarotti, A., Minonne, L., Moroni, A., Patelli, Z., et al. (2025) · Metabolites · doi:10.3390/metabo15020127 · Cited by 27

Authors: Rabot, S., Membrez, M., Bruneau, A., Gérard, P., Harach, T., Moser, M., Raymond, F., Mansourian, R., & Chou, C. J.
Affiliations: Microbiologie de l’alimentation au service de la santé (FR)
Department of Nutrition and Health Nestlé Research Center Lausanne Switzerland
Nestlé (Switzerland) (CH)
Department of Bioanalytical Science Nestlé Research Center Lausanne Switzerland
ORCID: Rabot, Sylvie
Membrez, Mathieu
Bruneau, Aurélia
Gérard, Philippe
Moser, Mireille
Chou, Chieh J.
Venue: The FASEB Journal
Publisher: Wiley
Published: 2010-08-19
Volume: 24
Issue: 12
Pages: 4948-4959
ISSN: 0892-6638 (ISSN-L)
1530-6860
DOI: 10.1096/fj.10.164921
OpenAlex: W2088697466
Cited by: 610
References: 41
Citations by year: 2026: 9 · 2025: 19 · 2024: 34 · 2023: 43 · 2022: 50 · 2021: 64 · 2020: 75 · 2019: 49 · 2018: 42 · 2017: 40 · 2016: 39 · 2015: 44 · 2014: 24 · 2013: 33 · 2012: 22
FWCI: 10.17
Type: journal article
Language: en
Open access: closed
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: The FASEB Journal (publishedVersion)
PubMed (publishedVersion)
HAL (submittedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diet, Metabolism, and Disease
Keywords: germ-free mice, gut microbiota, high-fat diet, insulin resistance, cholesterol metabolism, hypercholesterolemia, obesity resistance, glucose tolerance, TNF-α, serum amyloid A, SREBP2, cholesterol biosynthesis, liver cholesterol, fecal cholesterol excretion, C57BL/6J mice
MeSH terms: Animals, Body Weight, Cholesterol, Dietary Fats, Germ-Free Life, Glucose Tolerance Test, Glycogen, Insulin Resistance, Lipids, Liver, Male, Mice, Inbred C57BL, Obesity, Blotting, Western, Polymerase Chain Reaction, Oligonucleotide Array Sequence Analysis, Mice

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Germ‐free C57BL/6J mice are resistant to high‐fat‐diet‐induced insulin resistance and have altered cholesterol metabolism

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