Lactobacillus plantarum FRT4 alleviated obesity by modulating gut microbiota and liver metabolome in high-fat diet-induced obese mice

  • Hongying Cai Institute of Feed Research, Chinese Academy of Agricultural Sciences, Beijing; National Engineering Research Center of Biological Feed, Beijing; School of Life Sciences, Qilu Normal University, Jinan, P. R. China
  • Zhiguo Wen Institute of Feed Research, Chinese Academy of Agricultural Sciences, Beijing, China
  • Lulu Zhao Institute of Feed Research, Chinese Academy of Agricultural Sciences, Beijing, China
  • Dali Yu Institute of Feed Research, Chinese Academy of Agricultural Sciences, Beijing, China
  • Kun Meng Institute of Feed Research, Chinese Academy of Agricultural Sciences, Beijing, China
  • Peilong Yang Institute of Feed Research, Chinese Academy of Agricultural Sciences, Beijing; National Engineering Research Center of Biological Feed, Beijing, China
Keywords: Lactobacillus plantarum FRT4; obesity; liver metabolomics; glycerophospholipid metabolism; gut microbiota


Background: Obesity has become a global epidemic recognized by the World Health Organization. Probiotics supplementation has been shown to contribute to improve lipid metabolism. However, mechanisms of action of probiotics against obesity are still not clear. Lactobacillus plantarum FRT4, a probiotic previously isolated from a kind of local yogurt, had good acid and bile salt tolerance and lowered cholesterol in vitro.

Objective: This study aimed to evaluate the effect of L. plantarum FRT4 on serum and liver lipid profile, liver metabolomics, and gut microbiota in mice fed with a high-fat diet (HFD).

Design: Mice were fed with either normal diet or HFD for 16 weeks and administered 0.2 mL of 1 × 109 or 1 × 1010 CFU/mL dosage of L. plantarum FRT4 during the last 8 weeks of the diet. Cecal contents were analyzed by 16S rRNA sequencing. Hepatic gene expression and metabolites were detected by real-time quantitative polymerase chain reaction (PCR) and metabolomics, respectively.

Results: L. plantarum FRT4 intervention significantly reduced the HFD-induced body weight gain, liver weight, fat weight, serum cholesterol, triglyceride, and alanine aminotransferase (ALT) levels in the liver (P < 0.05). Liver metabolomics demonstrated that the HFD increased choline, glycerophosphocholine, and phosphorylcholine involved in the glycerophospholipid metabolism pathway. All these changes were reversed by FRT4 treatment, bringing the levels close to those in the control group. Further mechanisms showed that FRT4 favorably regulated gut barrier function and pro-inflammatory biomediators. Furthermore, FRT4 intervention altered the gut microbiota profiles and increased microbial diversity. The relative abundances of BacteroidesParabateroidesAnaerotruncusAlistipesIntestinimonasButyicicoccus, and Butyricimonas were significantly upregulated. Finally, Spearman’s correlation analysis revealed that several specific genera were strongly correlated with glycerophospholipid metabolites (P < 0.05).

Conclusions: These findings suggested that L. plantarum FRT4 had beneficial effects against obesity in HFD-induced obese mice and can be used as a potential functional food for the prevention of obesity.


Download data is not yet available.


  1. Hotamisligil GS. Inflammation, metaflammation and immunometabolic disorders. Nature 2017; 542(7640): 177–5. doi: 10.1038/nature21363

  2. Iannelli A, Treacy P, Sebastianelli L, Schiavo, L, Martini, F. Perioperative complications of sleeve gastrectomy: review of the literature. J Minim Access Surg 2019; 15(1): 1–7. doi: 10.4103/jmas.JMAS_271_17

  3. Bäckhed F, Ding H, Wang T, Hooper LV, Gou YK, Nagy A, et al. The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci U S A 2004; 101(44): 15718–23. doi: 10.1073/pnas.0407076101

  4. Tremaroli V, Bäckhed F. Functional interactions between the gut microbiota and host metabolism. Nature 2012; 489(7415): 242–9. doi: 10.1038/nature11552

  5. Leung C, Rivera L, Furness JB, Angus PW. The role of the gut microbiota in NAFLD. Nat Rev Gastro Hepat 2016; 13(7): 412–25. doi: 10.1038/nrgastro.2016.85

  6. Murphy EF, Cotter PD, Hogan A, O’Sullivan O, Joyce A, Fouhy F, et al. Divergent metabolic outcomes arising from targeted manipulation of the gut microbiota in diet-induced obesity. Gut 2013; 62(2): 220–6. doi: 10.1136/gutjnl-2011-300705

  7. Abenavoli L, Scarpellini E, Colica C, Boccuto L, Salehi B, Sharifi-Rad J, et al. Gut microbiota and obesity: a role for probiotics. Nutrients 2019; 11(11): 2690. doi: 10.3390/nu11112690

  8. Seddik HA, Bendali F, Gancel F, Fliss I, Spano G, Drider D. Lactobacillus plantarum and its probiotic and food potentialities. Probiotics Antimicrob Proteins 2017; 9(2): 111–22. doi: 10.1007/s12602-017-9264-z

  9. Zheng Z, Cao F, Wang W, Yu J, Chen C, Chen B, et al. Probiotic characteristics of Lactobacillus plantarum E680 and its effect on Hypercholesterolemic mice. BMC Microbiol 2020; 20(1): 239. doi: 10.1186/s12866-020-01922-4

  10. Han KJ, Lee J, Lee N, Paik H. Antioxidant and anti-inflammatory effect of probiotic Lactobacillus plantarum KU15149 derived from Korean homemade diced-radish kimchi. J Microbiol Biotechnol 2020; 30(4): 591–8. doi: 10.4014/jmb.2002.02052

  11. Lee E, Jung SR, Lee SY, Lee NK, Paik HD, Lim SI. Lactobacillus plantarum strain Ln4 attenuates diet-induced obesity, insulin resistance, and changes in hepatic mRNA levels associated with glucose and lipid metabolism. Nutrients 2018; 10(5): 643. doi: 10.3390/nu10050643

  12. Long X, Zeng X, Tan X, Yi R, Pan Y, Zhou X, et al. Lactobacillus plantarum KFY04 prevents obesity in mice through the PPAR pathway and alleviates oxidative damage and inflammation. Food Funct 2020; 11(6): 5460–72. doi: 10.1039/d0fo00519c

  13. Cai H, Wen Z, Li X, Meng K, Yang P. Lactobacillus plantarum FRT10 alleviated high-fat diet–induced obesity in mice through regulating the PPARα signal pathway and gut microbiota. Appl. Microbiol. Biotechnol 2020; 104(13): 5959–72. doi: 10.1007/s00253-020-10620-0

  14. Li X, Xiao Y, Song Li, Huang Y, Chu Q, Zhu S, et al. Effect of Lactobacillus plantarum HT121 on serum lipid profile, gut microbiota, and liver transcriptome and metabolomics in a high-cholesterol diet–induced hypercholesterolemia rat model. Nutrition 2020; 79–80: 110966. doi: 10.1016/j.nut.2020.110966

  15. Chen M, Guo W, Li Q, Xu J, Cao Y, Liu B, et al. The protective mechanism of Lactobacillus plantarum FZU3013 against non-alcoholic fatty liver associated with hyperlipidemia in mice fed a high-fat diet. Food Funct 2020; 11(4): 3316–31. doi: 10.1039/c9fo03003d

  16. Gan Y, Tang M, Tan F, Zhou X, Fan L, Xie Y, et al. Anti-obesity effect of Lactobacillus plantarum CQPC01 by modulating lipid metabolism in high-fat diet-induced C57BL/6 mice. J Food Biochem 2020; 44(12): e13491. doi: 10.1111/jfbc.13491

  17. Liu Y, Gao Y, Ma F, Sun M, Mu G, Tuo Y. The ameliorative effect of Lactobacillus plantarum Y44 oral administration on inflammation and lipid metabolism in obese mice fed with a high fat diet. Food Funct 2020; 11(6): 5024–39. doi: 10.1039/d0fo00439a

  18. Yin X, Peng J, Zhao L, Yu Y, Zhang X, Liu P, et al. Structural changes of gut microbiota in a rat non-alcoholic fatty liver disease model treated with a Chinese herbal formula. Syst Appl Microbiol 2013; 36(3): 188–96. doi: 10.1016/j.syapm.2012.12.009

  19. Edgar RC. UPARSE: highly accurate OTU sequences from microbial amplicon reads. Nat Methods 2013; 10(10): 996–8. doi: 10.1038/nmeth.2604

  20. Caporaso JG, Kuczynski J, Stombaugh J, Bittinger K, Bushman FD, Costello EK, et al. QIIME allows analysis of high-throughput community sequencing data. Nat Methods 2010; 7(5): 335–6. doi: 10.1038/nmeth.f.303

  21. Wang H, Liu Z, Wang S, Cui D, Zhang X, Liu Y, et al. UHPLC-Q-TOF/MS based plasma metabolomics reveals the metabolic perturbations by manganese exposure in rat models. Metallomics 2017; 9(2): 192–203. doi: 10.1039/c7mt00007c

  22. Schindhelm RK, Diamant M, Dekker JM, Tushuizen ME, Teerlink T, Heine RJ, Alanine aminotransferase as a marker of non-alcoholic fatty liver disease in relation to type 2 diabetes mellitus and cardiovascular disease. Diabetes Metab Res Rev 2006; 22(6): 437–43. doi: 10.1002/dmrr.666

  23. Zeisel SH. Choline: an important nutrient in brain development, liver function and carcinogenesis. J Am Coll Nutr 1992; 11(5): 473–81. doi: 10.1080/07315724.1992.10718251

  24. Zeisel SH, Blusztajn JK. Choline and human nutrition. Annu Rev Nutr 1994; 14: 269–96. doi: 10.1146/

  25. Dumas ME, Barton RH, Toye A, Cloarec O, Blancher C, Rothwell A, et al. Metabolic profiling reveals a contribution of gut microbiota to fatty liver phenotype in insulin-resistant mice. Proc Natl Acad Sci U S A 2006; 103(33): 12511–6. doi: 10.1073/pnas.0601056103

  26. Koeth RA, Wang Z, Levison, BS, Buffa JA, Org E, Sheehy BT, et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med 2013; 19(5): 576–85. doi: 10.1038/nm.3145

  27. Imajo K, Fujita K, Yoneda M, Shinohara Y, Suzuki K, Mawatari H. Plasma free choline is a novel non-invasive biomarker for early-stage non-alcoholic steatohepatitis: a multi-center validation study. Hepatol Res 2012; 42(8): 757–66. doi: 10.1111/j.1872-034X.2012.00976.x

  28. Aragonès G, González-García S, Aguilar C, Richart C, Auguet T. Gut microbiota-derived mediators as potential markers in nonalcoholic fatty liver disease. Biomed Res Int 2019; 2019: 8507583. doi: 10.1155/2019/8507583

  29. Mazidi M, Katsiki N, Mikhailidis DP, Banach, M. Adiposity may moderate the link between choline intake and non-alcoholic fatty disease. J Am Coll Nutr 2019; 38(7): 633–9. doi: 10.1080/07315724.2018.1507011

  30. Jialal I, Kaur H, Devaraj S. Toll-like receptor status in obesity and metabolic syndrome: a translational perspective. J Clin Endocrinol Metab 2014; 99(1): 39–48. doi: 10.1210/jc.2013-3092

  31. Tenorio-Jiménez C, Martínez-Ramírez MJ, Castillo-Codes ID, Arraiza-Irigoyen C, Tercero-Lozano M, Camacho J, et al. Lactobacillus reuteri V3401 reduces inflammatory biomarkers and modifies the gastrointestinal microbiome in adults with metabolic syndrome: the PROSIR study. Nutrients 2019; 11(8): 1761. doi: 10.3390/nu11081761

  32. Gan Y, Tong J, Zhou X, Long X, Pan Y, Liu W. Hepatoprotective effect of Lactobacillus plantarum HFY09 on ethanol-induced liver injury in mice. Front Nutr 2021; 8: 684588. doi: 10.3389/fnut.2021.684588

  33. Kim HJ, Kim JH, Noh S, Hur HJ, Sung MJ, Hwang JT, et al. Metabolomic analysis of livers and serum from high-fat diet induced obese mice. J Proteome Res 2011; 10(2): 722–31. doi: 10.1021/pr100892r

  34. Martinic A, Barouei J, Bendiks Z, Mishchuk D, Heeney DD, Martin R, et al. Supplementation of Lactobacillus plantarum improves markers of metabolic dysfunction induced by a high fat diet. J Proteome Res 2018; 17(8): 2790–802. doi: 10.1021/acs.jproteome.8b00282

  35. Fernández-Murray JP, McMaster CR. Glycerophosphocholine catabolism as a new route for choline formation for phosphatidylcholine synthesis by the Kennedy pathway. J Biol Chem 2005; 280(46): 38290–6. doi: 10.1074/jbc.M507700200

  36. Romano KA, Martinez-Del CA, Kasahara K, Chittim CL, Vivas EI, Amador-Noguez D, et al. Metabolic, epigenetic, and transgenerational effects of gut bacterial choline consumption. Cell Host Microbe 2017; 22(3): 279–90. doi: 10.1016/j.chom.2017.07.021

  37. Chu H, Duan Y, Yang L, Schnabl B. Small metabolites, possible big changes: a microbiota-centered view of non-alcoholic fatty liver disease. Gut 2019; 68(2): 359–70. doi: 10.1136/gutjnl-2018-316307

  38. Obeid R, Awwad HM, Rabagny Y, Graeber S, Herrmann W, Geisel J. Plasma trimethylamine N-oxide concentration is associated with choline, phospholipids, and methylmetabolism. Am J Clin Nutr 2016; 103(3): 703–11. doi: 10.3945/ajcn.115.121269

  39. Furet JP, Kong LC, Tap J, Poitou C, Basdevant A, Bouillot, JL, et al. Differential adaptation of human gut microbiota to bariatric surgery-induced weight loss: links with metabolic and low-grade inflammation markers. Diabetes 2010; 59(12): 3049–57. doi: 10.2337/db10-0253

  40. Thingholm LB, Rühlemann MC, Koch M, Fuqua B, Laucke G, Boehm R, et al. Obese individuals with and without type2 diabetes show different gut microbial functional capacity and composition. Cell Host Microbe 2019; 26(2): 252–64. doi: 10.1016/j.chom.2019.07.004

  41. Martin-Gallausiaux, C, Marinelli L, Blottière HM, Larraufie P, Lapaque N. SCFA: mechanisms and functional importance in the gut. Proc Nutr Soc 2021; 80(1): 37–49. doi: 10.1017/S0029665120006916

  42. Blaak EE, Canfora EE, Theis S, Frost G, Groen AK, Mithieux G, et al. Short chain fatty acids in human gut and metabolic health. Benef Microbes 2020; 11(5): 411–55. doi: 10.3920/BM2020.0057

  43. Kong C, Gao R, Yan X, Huang L, Qin H. Probiotics improve gut microbiota dysbiosis in obese mice fed a high-fat or high-sucrose diet. Nutrition 2019; 60: 175–84. doi: 10.1016/j.nut.2018.10.002

  44. Kim J, Lee H, An J, Song Y, Lee CK, Kim K, et al. Alterations in gut microbiota by statin therapy and possible intermediate effects on hyperglycemia and hyperlipidemia. Front Microbiol 2019; 10: 1947. doi: 10.3389/fmicb.2019.01947

  45. Schwiertz A, Taras D, Schäfer K, Beijer S, Bos NA, Donus C, et al. Microbiota and SCFA in lean and over-weight healthy subjects. Obesity 2010; 18(1): 190–5. doi: 10.1038/oby.2009.167

  46. Claesson MJ, O’Sullivan O, Wang Q, Nikkilä J, Marchesi JR, Smidt H, et al. Comparative analysis of pyrosequencing and a phylogenetic microarray for exploring microbial community structures in the human distal intestine. PLoS One 2009; 4(8): e6669. doi: 10.1371/journal.pone.0006669

  47. Chen M, Hui S, Lang H, Zhou M, Zhang Y, Kang C, et al. SIRT3 deficiency promotes high-fat diet-induced nonalcoholic fatty liver disease in correlation with impaired intestinal permeability through gut microbial dysbiosis. Mol Nutr Food Res 2019; 63(4): e1800612. doi: 10.1002/mnfr.201800612

  48. Tang W, Yao X, Xia F, Yang M, Chen Z, Zhou B, et al. Modulation of the gut microbiota in rats by Hugan Qingzhi tablets during the treatment of high-fat-diet-induced nonalcoholic fatty liver disease. Oxid Med Cell Longev 2018; 2018: 7261619. doi: 10.1155/2018/7261619

  49. Leiva-Gea I, Sánchez-Alcoholado L, Martín-Tejedor B, Castellano-Castillo D, Moreno-Indias I, Urda-Cardona A, et al. Gut microbiota differs in composition and functionality between children with type 1 diabetes and mody2 and healthy control subjects: a case-control study. Diabetes Care 2018; 41(11): 2385–95. doi: 10.2337/dc18-0253

  50. Sarma SM, Khare P, Jagtap S, Singh DP, Baboota RK, Podili K, et al. Kodo millet whole grain and bran treatment prevents high-fat diet induced derangements in a lipid profile, inflammatory status and gut bacteria in mice. Food Funct 2017; 8(3): 1174–83. doi: 10.1039/c6fo01467d

  51. Chen YM, Liu Y, Zhou RF, Chen XL, Wang C, Tan XY, et al. Associations of gut-flora-dependent metabolite trimethylamine-N-oxide, betaine and choline with non-alcoholic fatty liver disease in adults. Sci Rep 2016; 6: 19076. doi: 10.1038/srep19076

How to Cite
Cai H., Wen Z., Zhao L., Yu D., Meng K., & Yang P. (2022). <em>Lactobacillus plantarum</em&gt; FRT4 alleviated obesity by modulating gut microbiota and liver metabolome in high-fat diet-induced obese mice. Food & Nutrition Research, 66.
Original Articles