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Crosstalk between Gut Microbiota and Dietary Lipids Aggravates WAT Inflammation through TLR Signaling
Open accessAbstract
Dietary lipids may influence the abundance of circulating inflammatory microbial factors. Hence, inflammation in white adipose tissue (WAT) induced by dietary lipids may be partly dependent on their interaction with the gut microbiota. Here, we show that mice fed lard for 11 weeks have increased Toll-like receptor (TLR) activation and WAT inflammation and reduced insulin sensitivity compared with mice fed fish oil and that phenotypic differences between the dietary groups can be partly attributed to differences in microbiota composition. Trif(-/-) and Myd88(-/-) mice are protected against lard-induced WAT inflammation and impaired insulin sensitivity. Experiments in germ-free mice show that an interaction between gut microbiota and saturated lipids promotes WAT inflammation independent of adiposity. Finally, we demonstrate that the chemokine CCL2 contributes to microbiota-induced WAT inflammation in lard-fed mice. These results indicate that gut microbiota exacerbates metabolic inflammation through TLR signaling upon challenge with a diet rich in saturated lipids.
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In the citing paper
“Saturated and unsaturated fats have profoundly different effects on the gut microbiota, and the altered microbiota that results from feeding unsaturated fats can offer protection from lard-induced weight gain44.”
From Diet–microbiota interactions as moderators of human metabolism (2016) · cites this paper as [44]
In the citing paper
“germ-free mice that are fed a high-fat diet with less sucrose are only partly protected against obesity44”
From Diet–microbiota interactions as moderators of human metabolism (2016) · cites this paper as [44]
In the citing paper
“A switch to a diet rich in saturated fatty acids shifts the composition of the microbiota44.”
From Diet–microbiota interactions as moderators of human metabolism (2016) · cites this paper as [44]
In the citing paper
“Similarly, increased levels of Bilophila and a reduced abundance of Desulfovibrio were observed in mice that were fed lard compared with fish oil as a source of fat44.”
From Diet–microbiota interactions as moderators of human metabolism (2016) · cites this paper as [44]
In the citing paper
“Latest data implied that omega-3 PUFAs modulate the intestinal microbiota composition and help normalize it after disrupting environmental stress [166,168].”
From The Role of Microbiota-Gut-Brain Axis in Neuropsychiatric and Neurological Disorders (2021) · cites this paper as [168]
In the citing paper
“In a rodent study, animals fed lard showed increases in Bacteroides and displayed signs of metabolic dysfunction.”
From The athletic gut microbiota (2020) · cites this paper as [229]
In the citing paper
“In contrast, animals fed fish oil showed increased levels of lactic acid bacteria and were protected from metabolic dysfunction [229].”
From The athletic gut microbiota (2020) · cites this paper as [229]
In the citing paper
“The gut microbiota has been shown to differ between mice fed diets that are high or low in fat and between diets that contain equal amounts of fat but from different sources [10–13] (Fig. 1).”
From Dietary lipids, gut microbiota and lipid metabolism (2019) · cites this paper as [10]
In the citing paper
“In another study where mice fed a high-fat diet containing lard, rich in saturated fat, were compared to mice fed a isocaloric high-fat diet containing fish oil, rich in n-3 PUFA, it was found that phylogenetic diversity and abundance of the beneficial bacteria Akkermansia muciniphila, Lactobacillus and Bifidobacterium were lower in mice on a lard diet [10].”
From Dietary lipids, gut microbiota and lipid metabolism (2019) · cites this paper as [10]
In the citing paper
“Transplantation of cecum microbiota into germ-free (GF) mice showed that the diet-induced differences in host phenotype were partly caused by the gut microbiota.”
From Dietary lipids, gut microbiota and lipid metabolism (2019) · cites this paper as [10]
In the citing paper
“The lard diet also reduced insulin sensitivity and increased inflammation in white adipose tissue (WAT) through activation of Toll-like receptor 4 (TLR4) signaling.”
From Dietary lipids, gut microbiota and lipid metabolism (2019) · cites this paper as [10]
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Zhang, J.-G., Zhang, Y., Yang, G., Zhang, W.-W., Thakur, K., Ni, Z., & Wei, Z. (2024) · Food & Function · doi:10.1039/d4fo02123a · Cited by 9
The Yin-Yang Concept of Pediatric Obesity and Gut Microbiota
Meliţ, L. E., Mărginean, C. O., & Săsăran, M. O. (2022) · Biomedicines · doi:10.3390/biomedicines10030645 · Cited by 9
“Thus, increased consumption of fat is associated with a more severe degree of white adipose tissue inflammation and its related complications, while polyunsaturated fatty acid-based diets were found to counteract this inflammatory state in overweight and obesity, promoting a metabolically healthy phenotype [48,49].”
Bupi Yishen formula may prevent kidney fibrosis by modulating fatty acid metabolism in renal tubules
Liu, B., Jie, X., Deng, J., Zhang, S., Lu, F., Liu, X., & Zhang, D. (2023) · Phytomedicine · doi:10.1016/j.phymed.2023.154767 · Cited by 9
The FTO Gene, Browning of Adipose Tissue and Omega-3 Fatty Acids
Simopoulos, A. P. (2016) · Lifestyle Genomics · doi:10.1159/000448617 · Cited by 9
Rienzi, S. C. D., Johnson, E. L., Waters, J. L., Kennedy, E. A., Jacobson, J., Lawrence, P., Wang, D. H., Worgall, T. S., Brenna, J. T., & Ley, R. E. (2021) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2021.108808 · Cited by 9
Bariatric Surgery and Gut-Brain-Axis Driven Alterations in Cognition and Inflammation
Custers, E., Franco, A., & Kiliaan, A. J. (2023) · Journal of Inflammation Research · doi:10.2147/jir.s437156 · Cited by 9
“160,161 Probiotic administration has shown to reduce LPS inflammation and improve gut barrier function in vitro, 162 probably as a consequence of SCFA production, as they are derived from fiber fermentation.”
The association between macronutrients intake and myopia risk: a systematic review and meta-analysis
Massoudi, S., Azizi-Soleiman, F., Yazdi, M., Esfahani, M. M., Heidari‐Beni, M., & Kelishadi, R. (2024) · BMC Ophthalmology · doi:10.1186/s12886-024-03738-6 · Cited by 8
“In animal models, saturated fats could induce insulin resistance via promoting the proportion of endotoxin-containing bacteria in the gut and consequently increasing plasma endotoxin levels [28, 29].”
Obesity and Autoimmunity Epidemic: The Role of Immunometabolism
Colamatteo, A., Fusco, C., Matarese, A., & Matarese, G. (2025) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-111324-122456 · Cited by 10
Kilic, E., & Başaran, P. (2025) · Nutrients · doi:10.3390/nu17233787 · Cited by 11
Tumor Immunotherapy and Microbiome: From Bench‐to‐Bedside Applications
Lin, A., Xiong, M., Jiang, A., Chen, L., Huang, L., Li, K., Wong, H. Z. H., Zhang, J., Liu, Z., Cheng, Q., et al. (2026) · MedComm · doi:10.1002/mco2.70454 · Cited by 9
“Numerous studies confirm that activation of the NF-κ B signaling pathway induced by TLRs (especially TLR4) plays a crucial role in the development and progression of various malignancies, including CRC, pancreatic cancer, and HCC [110, 111].”
Chen, Y., Nakanishi, M., Bautista, E. J., Qendro, V., Sodergren, E. J., Rosenberg, D. W., & Weinstock, G. M. (2019) · Cancer Prevention Research · doi:10.1158/1940-6207.capr-19-0273 · Cited by 8
“Several studies have revealed that high animal protein and high saturated fat intake would result in disproportionately more propionate and acetate producing species, including Bacteroides and Enterobacteriales (43, 44).”
Okue, S., Ishikawa, E., Nakahara, R., Ito, T., Okura, T., Sakae, M., Miura, A., Ozaki‐Masuzawa, Y., Hosono, T., & Seki, T. (2021) · Bioscience Biotechnology and Biochemistry · doi:10.1093/bbb/zbaa038 · Cited by 8
Hamrick, C., & Chen, G. (2021) · Journal of Future Foods · doi:10.1016/j.jfutfo.2021.08.001 · Cited by 9
Keskitalo, A., Munukka, E., Aatsinki, A., Saleem, W., Kartiosuo, N., Lahti, L., Huovinen, P., Elo, L. L., Pietilä, S., Rovio, S., et al. (2022) · Nutrients · doi:10.3390/nu14132667 · Cited by 10
“Moreover, a diet high in SAFA appears to promote inflammation, partially due to interaction with gut microbes [15], while the ingestion of omega-3 polyunsaturated fatty acids (PUFA) apparently tends to increase the abundance of certain gut bacteria that are generally regarded as beneficial, such as Bifidobacterium spp.”
Kang, Y., Oba, P. M., Gaulke, C. A., Sánchez-Sánchez, L., & Swanson, K. S. (2023) · Journal of Nutrition · doi:10.1016/j.tjnut.2023.09.007 · Cited by 9
Immunomodulatory effect of marine lipids on food allergy
Abril, A. G., Carrera, M., & Pazos, M. (2023) · Frontiers in Nutrition · doi:10.3389/fnut.2023.1254681 · Cited by 9
Embelin modulates metabolic endotoxemia and associated obesity in high fat diet fed C57BL/6 mice
Bansal, P., Bhandari, U., Sharma, K., & Arya, P. (2020) · Human & Experimental Toxicology · doi:10.1177/0960327120934522 · Cited by 8
Unger, A. L., Eckstrom, K. M., Jetton, T. L., & Kraft, J. (2020) · PLoS ONE · doi:10.1371/journal.pone.0238893 · Cited by 9
Sánchez‐Trigueros, M. I., Méndez‐Cruz, F., Pineda‐Peña, E. A., Rivera‐Espinoza, Y., Castañeda‐Hernández, G., & Chávez‐Piña, A. E. (2020) · Drug Development Research · doi:10.1002/ddr.21772 · Cited by 8
“Similarly, Caesar et al., 2015 found that supplementation with omega-3 enriched fish oil enhanced beneficial populations of commensal bacteria such as Akkermansia, Lactobacillus, and Alphaproteobacteria (Caesar et al., 2015).”
Lang, J. M., Sedgeman, L. R., Cai, L., Layne, J. D., Wang, Z., Pan, C., Lee, R. G., Temel, R. E., & Lusis, A. J. (2021) · Frontiers in Medicine · doi:10.3389/fmed.2021.646710 · Cited by 8
“fish oil) (23), and quality (oxidized vs.”
de Souza, C. T. (2019) · HU Revista · doi:10.34019/1982-8047.2018.v44.16950 · Cited by 11
Colonic bacterial composition is sex-specific in aged CD-1 mice fed diets varying in fat quality
Unger, A. L., Eckstrom, K. M., Jetton, T. L., & Kraft, J. (2019) · PLoS ONE · doi:10.1371/journal.pone.0226635 · Cited by 9
“In this study, the dietary fat sources of interest (fish oil, dairy fat, or echium oil, respectively) were supplemented at 30% of total fat content, while other studies used 80–100% of an experimental fat source [21,22,28].”
InfluentialHaija, M. A. E., Ye, Y., Chu, Y., Herz, H., Linden, B., Shahi, S. K., Zarei, K., Mangalam, A. K., McElroy, S. J., & Mokadem, M. (2021) · Surgery for Obesity and Related Diseases · doi:10.1016/j.soard.2021.07.019 · Cited by 10
Pal, A., Al‐Shaer, A. E., Guesdon, W., Torres, M. J., Armstrong, M., Quinn, K. D., Davis, T., Reisdorph, N. A., Neufer, P. D., Spangenburg, E. E., et al. (2020) · Digital Commons - University of South Florida (University of South Florida) · Cited by 8
Diet, microbiome, and probiotics establish a crucial link in vaccine efficacy
Dutta, S., Chatterjee, N., Gallina, N. L. F., Kar, S., Koley, H., Nanda, P. K., Biswas, O., Das, A. K., Biswas, S., Bhunia, A. K., et al. (2025) · Critical Reviews in Microbiology · doi:10.1080/1040841x.2025.2480230 · Cited by 7
“On the other hand, fish oil (45% kcal, unsaturated fat) supplementation in mice diets significantly increased the levels of Lactobacillus , Bifidobacterium , and Akkermansia muciniphila (caesar et al. 2015).”
Dietary polyunsaturated fatty acids effect on cecal microbiome profile of maturing broiler chicken
Jadhav, V. V., Fasina, Y. O., & Harrison, S. H. (2025) · Poultry Science · doi:10.1016/j.psj.2025.105167 · Cited by 7
“These fats vary in their fatty acid composition and can influence the animal ’ s metabolic, inflammatory, and disease state via gut microbiome-mediated mechanisms (Caesar et al., 2015; Schoeler et al., 2023).”
Li, Z., & Liu, H. (2025) · Food Chemistry · doi:10.1016/j.foodchem.2025.144852 · Cited by 9
Nikolaidis, C. G., Gyriki, D., Stavropoulou, E., Karlafti, E., Didangelos, T., Tsigalou, C., & Thanopoulou, A. C. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1701504 · Cited by 8
We are what we eat: The role of lipids in metabolic diseases
Berná, G., López-Bermudo, L., Escudero‐López, B., & Martı́n, F. (2023) · Advances in food and nutrition research · doi:10.1016/bs.afnr.2022.11.004 · Cited by 8
Peng, D., Wang, Y., Yao, Y., Yang, Z., Wu, S., Zeng, K., Hu, X., & Zhao, Y. D. (2024) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-023-04904-y · Cited by 8
“[36] Data from experimental mouse models suggest that high dietary supplementation of n-3 PUFA or high levels of n-3 PUFA in tissues are linked to variations in intestinal microflora, which includes a significant increase in the abundance of bifidobacteria and lactobacilli [37, 38].”
Meng, X., Xv, C., Lv, J., Zhang, S., Ma, C., & Pang, X. (2024) · Microorganisms · doi:10.3390/microorganisms12050881 · Cited by 9
“Diets high in protein, fats, sugars, and saturated fats notably decrease Akk abundance in the gut [16–18], whereas ketogenic diets, foods rich in polyunsaturated fatty acids, and polyphenols promote its proliferation in the intestinal tract [19,20].”
Hilakivi-Clarke, L. A., Verma, V., McDermott, M., Koak, P., & Andrade, F. D. O. (2022) · Frontiers in Microbiomes · doi:10.3389/frmbi.2022.1049688 · Cited by 7
“Of individual foods, those high in omega-3 polyunsaturated fatty acids (PUFAs) in fish oil have been linked to increased alpha-diversity (Caesar et al., 2015).”
Llauradó-Calero, E., Climent, E., Chenoll, E., Ballester, M., Badiola, I., Lizardo, R., Torrallardona, D., Esteve-Garcia, E., & Tous, N. (2022) · Frontiers in Microbiology · doi:10.3389/fmicb.2022.982712 · Cited by 7
“muciniphila after fish oil supplementation (Caesar et al., 2015).”
Soy Lecithin in High‐Fat Diets Exerts Dual Effects on Adipose Tissue Versus Ileum
Buisson, C., Leuzy, V., Loizon, E., Meugnier, E., Monnoye, M., Philippe, C., Gérard, P., Michalski, M., & Laugerette, F. (2023) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.202200461 · Cited by 7
Metadata
- Authors
- Caesar, R., Tremaroli, V., Kovatcheva-Datchary, P., Cani, P. D., & Bäckhed, F.
- Affiliations
- University of Gothenburg (SE)
- Walloon Excellence in Lifesciences and Biotechnology (BE)
- University of Copenhagen (DK)
- Corresponding author
- Caesar, Robert
- Bäckhed, Fredrik
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2015-10
- Volume
- 22
- Issue
- 4
- Pages
- 658-668
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC4598654
- OpenAlex
- W2096736123
- Cited by
- 960
- References
- 51
- Citations by year
- 2026: 43 · 2025: 52 · 2024: 76 · 2023: 89 · 2022: 124 · 2021: 109 · 2020: 114 · 2019: 105 · 2018: 88 · 2017: 85 · 2016: 59 · 2015: 12
- FWCI
- 35.30
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by-nc-nd)
- Digital Access to Libraries (submittedVersion, other-oa)
- Funders
- Stiftelsen för Strategisk Forskning
- Fonds De La Recherche Scientifique - FNRS (WELBIO-CR-2012S-02R)
- Knut och Alice Wallenbergs Stiftelse
- Novo Nordisk
- Vetenskapsrådet
- Göteborgs Universitet
- Novo Nordisk Fonden (NNF13OC0008163)
- Walloon excellence in life sciences and biotechnology
- Wageningen University and Research
- Uppsala Multidisciplinary Center for Advanced Computational Science
- FP7 Food, Agriculture and Fisheries, Biotechnology
- 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
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- gut microbiota, dietary fat, white adipose tissue inflammation, Toll-like receptor signaling, lard, fish oil, saturated fatty acids, insulin sensitivity, metabolic inflammation, CCL2 chemokine, MyD88, TRIF, germ-free mice
- MeSH terms
- Gastrointestinal Microbiome, Animals, Bacteria, Body Weight, DNA, Bacterial, Fish Oils, Inflammation, Male, Mice, Inbred C57BL, Phylogeny, Signal Transduction, Mice, Knockout, Chemokine CCL2, Adaptor Proteins, Vesicular Transport, Gastrointestinal Tract, Toll-Like Receptors, Mice, Adipose Tissue, White, Myeloid Differentiation Factor 88, Diet, High-Fat
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