Germ-free C57BL/6J mice are resistant to high-fat-diet-induced insulin resistance and have altered cholesterol metabolism
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. GF mice 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 insulinemia, 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 hypercholesterolemia, 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.
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The gut microbiota affects lipid metabolism and lipid levels in blood and tissues in mice and humans.
“The gut microbiota has been shown to affect lipid metabolism and lipid levels in blood and tissues, both in mice and humans.”
From Dietary lipids, gut microbiota and lipid metabolism (2019) · cites this paper as [31]
Circulating triglycerides, HDL, and total cholesterol levels are increased by the gut microbiota in mice on a high-fat diet.
“In contrast, circulating triglycerides, HDL, and total cholesterol levels are increased by the gut microbiota in mice on a high-fat diet [31].”
From Dietary lipids, gut microbiota and lipid metabolism (2019) · cites this paper as [31]
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You Are What You Eat—The Relationship between Diet, Microbiota, and Metabolic Disorders—A Review
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“It has also been noted that germ-free mouse with the obesity-resistance phenotype fed a high-fat diet (HFD) consumes fewer calories and has increased excretion of lipids, while an HFD in mice with normal microbiota contributes to weight gain, obesity progression, worsening in insulin sensitivity and inflammatory chang…”
BackgroundPrecision Nutrition and the Microbiome, Part I: Current State of the Science
Mills, S., Stanton, C., Lane, J. A., Smith, G., & Ross, R. P. (2019) · Nutrients · doi:10.3390/nu11040923 · Cited by 406 · see citing works
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Gut microbiota Turicibacter strains differentially modify bile acids and host lipids
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The therapeutic potential of manipulating gut microbiota in obesity and type 2 diabetes mellitus
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BackgroundThe gut microbiome as therapeutic target
Cani, P. D., & Delzenne, N. M. (2011) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2011.01.012 · Cited by 349 · see citing works
“To date, unequivocal evidence for the role of the gut microbiota in energy homeostasis comes from studies performed in mice lacking gut microbiota (Backhed et al., 2004, 2007; Fleissner et al., 2010; Rabot et al., 2010).”
BackgroundThe Association between Early-Life Gut Microbiota and Long-Term Health and Diseases
Sarkar, A., Yoo, J. Y., Dutra, S. V. O., Morgan, K. H., & Groer, M. E. (2021) · Journal of Clinical Medicine · doi:10.3390/jcm10030459 · Cited by 346 · see citing works
“The function of gut microbiota in low-grade inflammation has also been supported by a germ-free mice study where inflammation did not develop in germ-free mice when a high-fat diet was provided [123].”
BackgroundProbiotics, prebiotics, synbiotics and insulin sensitivity
Kim, Y. A., Keogh, J. B., & Clifton, P. M. (2017) · Nutrition Research Reviews · doi:10.1017/s095442241700018x · Cited by 340 · see citing works
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“This metabolic phenotype is explained in part by the role of microbiota in nutrient uptake as GF mice show reduced food efficiency, and when fed a high fat diet, GF mice fail to extract lipid from the diet [24].”
BackgroundMicrobiota-liver axis in hepatic disease
Chassaing, B., Etienne‐Mesmin, L., & Gewirtz, A. T. (2013) · Hepatology · doi:10.1002/hep.26494 · Cited by 329 · see citing works
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Effects of Fecal Microbiota Transplantation With Oral Capsules in Obese Patients
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Liver diseases: epidemiology, causes, trends and predictions
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“365 This bene fi cial effect disappears following fecal microbiota transplantation (FMT) from MASLD mice to germ-free mice, resulting in increased liver triglyceride content and in fl ammation.”
The gut microbiota in obesity and weight management: microbes as friends or foe?
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The evolution of the use of faecal microbiota transplantation and emerging therapeutic indications.
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Gut Microbiota, Intestinal Permeability, Obesity‐Induced Inflammation, and Liver Injury
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Effects of the gut microbiota on obesity and glucose homeostasis
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The gut microbiota and metabolic disease: current understanding and future perspectives
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Non-Alcoholic Fatty Liver Disease: Metabolic, Genetic, Epigenetic and Environmental Risk Factors
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“In an interesting study, germ-free mice fed with a high-fat diet exhibited lower levels of liver lipids compared to conventionally housed mice [60].”
BackgroundThe microbiota–gut–brain axis in gastrointestinal disorders: stressed bugs, stressed brain or both?
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“Moreover, germ-free mice have an impaired capacity to harvest energy from the diet (Wostmann, 1981) and are protected against diet-induced obesity (Bäckhed et al. 2007; Rabot et al. 2010).”
BackgroundThe Intestinal Microbiota in Metabolic Disease
Woting, A., & Blaut, M. (2016) · Nutrients · doi:10.3390/nu8040202 · Cited by 284 · see citing works
“Indeed, experiments by Rabot et al. (2010) are in conflict with this explanation because they showed that the intestinal microbiota promotes lipid absorption: High-fat diet-fed conventional mice excreted 40% less lipids in their feces than high-fat diet-fed germfree mice [29], the opposite of what…”
BackgroundResultInfluentialHuman gut microbiota: the links with dementia development
Alkasir, R., Li, J., Li, X., Jin, M., & Zhu, B. (2016) · Protein & Cell · doi:10.1007/s13238-016-0338-6 · Cited by 283 · see citing works
Gut Microbiota Is a Key Modulator of Insulin Resistance in TLR 2 Knockout Mice
Caricilli, A. M., Picardi, P. K., de Abreu, L. L., Ueno, M., Prada, P. O., Ropelle, E. R., Hirabara, S. M., Castoldi, Â., Moraes‐Vieira, P. M., Câmara, N. O. S., et al. (2011) · PLoS Biology · doi:10.1371/journal.pbio.1001212 · Cited by 283 · see citing works
RetractedGut–liver axis, nutrition, and non-alcoholic fatty liver disease
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“Using germ free animal models, several research groups have demonstrated that mice lacking gut microbiota are resistant to diet-induced obesity, liver steatosis and insulin resistance [56, 57].”
BackgroundGeurts, L., Neyrinck, A. M., Delzenne, N. M., Knauf, C., & Cani, P. D. (2013) · Beneficial Microbes · doi:10.3920/bm2012.0065 · Cited by 279 · see citing works
“I P A dd re ss :1 30 .1 04 .1 94 .2 24 Beneficial Microbes 5(1) 5 and insulin resistance induced by a high-fat diet (Backhed et al., 2007; Ding et al., 2010; Rabot et al., 2010).”
BackgroundMicrobial modulation of insulin sensitivity
Khan, M. T., Nieuwdorp, M., & Bäckhed, F. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.07.006 · Cited by 260 · see citing works
Is the Gut Microbiota a New Factor Contributing to Obesity and Its Metabolic Disorders?
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“To further examine if glucose tolerance of mice is affected by the presence or absence of the gut microbiota, we fed both GF and Conv C57BL/6J mice with a high-fat diet, and our results showed that GF mice did not develop diet-induced obesity and glucose intolerance [36].”
BackgroundSelf-citationThe Role of Gut Microbiota on Insulin Resistance
Caricilli, A. M., & Saad, M. A. (2013) · Nutrients · doi:10.3390/nu5030829 · Cited by 273 · see citing works
“against related comorbidities [55,110] (Figure 2).”
Western diets, gut dysbiosis, and metabolic diseases: Are they linked?
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“For example, several groups have shown that germ-free mice fed a high-fat, high-sugar diet are resistance to diet-induced obesity (DIO).(5,8) Transplant of microbes induced by Western diets or obesity result in an increase in fat mass in germ-free mouse recipients.”
BackgroundThe Mouse Microbiome Is Required for Sex-Specific Diurnal Rhythms of Gene Expression and Metabolism
Weger, B. D., Gobet, C., Yeung, J., Martin, E., Jimenez, S., Betrisey, B., Foata, F., Berger, B., Balvay, A., Foussier, A., et al. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2018.09.023 · Cited by 269 · see citing works
“The male-biased concentration correlated with male-biased mRNA expression of the folate transporter SLC19A1 (RFC1) and the key enzyme for purine metabolism MTHFD2 (methylenetetrahydrofolate dehydrogenase and cyclohydrolase) (Ben-Sahra et al., 2016).”
BackgroundMethodInfluentialSelf-citationNon-alcoholic steatohepatitis: pathogenesis and novel therapeutic approaches
Schuppan, D., & Schattenberg, J. M. (2013) · Journal of Gastroenterology and Hepatology · doi:10.1111/jgh.12212 · Cited by 256 · see citing works
Is butyrate the link between diet, intestinal microbiota and obesity-related metabolic diseases?
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“Moreover, it has been suggested that germ-free animals are protected from pro-inflammatory consequences of a high-fat diet (113), supporting a key role for the intestinal microbiota in the metabolic response to the diet.”
BackgroundDoes lipopolysaccharide-mediated inflammation have a role in OA?
Huang, Z.-Y., & Kraus, V. (2015) · Nature Reviews Rheumatology · doi:10.1038/nrrheum.2015.158 · Cited by 259 · see citing works
The Alterations in and the Role of the Th17/Treg Balance in Metabolic Diseases
Zhang, S., Gang, X., Yang, S., Cui, M., Sun, L., Li, Z., & Wang, G. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.678355 · Cited by 263 · see citing works
Programming of Host Metabolism by the Gut Microbiota
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“AMPK (AMP-activated protein kinase) is an important energy sensor in all organisms from yeast to mammals and promotes energy-generating pathways, while shutting off anabolic pathways [ , , , , ,”
BackgroundResveratrol, Metabolic Syndrome, and Gut Microbiota
Chaplin, A. M. L., Carpéné, C., & Mercader, J. (2018) · Nutrients · doi:10.3390/nu10111651 · Cited by 248 · see citing works
“Since then, numerous studies have shown that the gut microbiota composition in obesity is different compared to lean subjects, characterized by increased levels of Firmicutes and less Bacteroidetes [177,178], increased capacity in energy harvesting from dietary polysaccharides [175,179], and is associated with increas…”
BackgroundNon-alcoholic fatty liver and the gut microbiota
Bashiardes, S., Shapiro, H., Rozin, S., Shibolet, O., & Elinav, E. (2016) · Molecular Metabolism · doi:10.1016/j.molmet.2016.06.003 · Cited by 241 · see citing works
“The prevalence of NAFLD is greatly increased in patients suffering from other pre-existing manifestations of the metabolic syndrome, such as obesity, type 2 diabetes, hyperlipidemia, and hypertension [1].”
BackgroundThe critical role of gut microbiota in obesity
Cheng, Z., Zhang, L., Yang, L., & Chu, H. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.1025706 · Cited by 233 · see citing works
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Oral–Gut Microbiome Axis in Gastrointestinal Disease and Cancer
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Fecal microbiota transplantation broadening its application beyond intestinal disorders
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MECHANISMS IN ENDOCRINOLOGY: Gut microbiota in patients with type 2 diabetes mellitus
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Impact of Gut Microbiota and Microbiota-Related Metabolites on Hyperlipidemia
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“When fed with high-fat, high-carbohydrate Western diet, GF mice have less hypercholesterolemia and more cholesterol excretion in the liver and feces (Rabot et al., 2010).”
BackgroundClostridium ramosum Promotes High-Fat Diet-Induced Obesity in Gnotobiotic Mouse Models
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“A study comparing conventional and germfree mice revealed that the intestinal microbiota increases intestinal absorption of lipids, resulting in better food efficiency and marked obesity (33).”
BackgroundFortification and Health: Challenges and Opportunities
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Lam, Y. Y., Ha, C. W. Y., Hoffmann, J. M. A., Oscarsson, J., Dinudom, A., Mather, T. J., Cook, D. I., Hunt, N. H., Caterson, I. D., Holmes, A. J., et al. (2015) · Obesity · doi:10.1002/oby.21122 · Cited by 223 · see citing works
“There is evidence for causal relationships between diet, gut dysfunction, and deleterious metabolic sequelae: high-fat diets induced inflammation and increased gut permeability (3,4); antibiotics normalized metabolic parameters in diet-induced obese mice (4); germ-free mice were protected against diet-induced obesity…”
BackgroundRecent advances in the development of farnesoid X receptor agonists.
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“Other factors are activation of toll-like receptor 4 (TLR4) by intestinal bacterial lipopolysaccharide (67-69) and other pro-inflammatory signals produced by dysbiosis (gut microbiota imbalance) (70-72).”
BackgroundThe Role of Gut Microbiota on Cholesterol Metabolism in Atherosclerosis
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The intestinal microbiota regulates host cholesterol homeostasis
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“mice [24] but discrepant with others [22].”
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Dietary fat and gut microbiota interactions determine diet-induced obesity in mice
Kübeck, R., Bonet-Ripoll, C., Hoffmann, C., Walker, A., Müller, V. M., Schüppel, V. L., Lagkouvardos, I., Scholz, B., Engel, K.-H., Daniel, H., et al. (2016) · Molecular Metabolism · doi:10.1016/j.molmet.2016.10.001 · Cited by 211 · see citing works
- 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 (Switzerland) (CH)
- Department of Bioanalytical Science, Nestlé Research Center, Lausanne, Switzerland
- Venue
- The FASEB Journal
- Publisher
- Wiley
- Published
- 2010-12
- Volume
- 24
- Issue
- 12
- Pages
- 4948-4959
- ISSN
- 0892-6638 (ISSN-L)
- 1530-6860
- 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
- 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 › Epidemiology › 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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