Yonsei Med J.  2017 Nov;58(6):1083-1091. 10.3349/ymj.2017.58.6.1083.

Alterations in Gut Microbiota and Immunity by Dietary Fat

• Yang BG
• Hur KY
• Lee MS

• KMID: 2418889
• DOI: http://doi.org/10.3349/ymj.2017.58.6.1083

Abstract

Gut microbiota play critical physiological roles in energy extraction from the intestine and in the control of systemic immunity, as well as local intestinal immunity. Disturbance of gut microbiota leads to the development of several diseases, such as colitis, inflammatory bowel diseases, metabolic disorders, cancer, etc. From a metabolic point of view, the gut is a large metabolic organ and one of the first to come into contact with dietary fats. Interestingly, excessive dietary fat has been incriminated as a primary culprit of metabolic syndrome and obesity. After intake of high-fat diet or Western diet, extensive changes in gut microbiota have been observed, which may be an underlying cause of alterations in whole body metabolism and nutrient homeostasis. Here, we summarize recent data on changes in the gut microbiota and immunity associated with dietary fat, as well as their relationships with the pathogenesis of metabolic syndrome. These findings may provide insight into the understanding of the complex pathophysiology related to the development of metabolic diseases and offer an opportunity to develop novel candidates for therapeutic agents.

Keyword

Gut microbiota; gut immunity; obesity; diabetes

MeSH Terms

*Diet, High-Fat
Dietary Fats
*Gastrointestinal Microbiome
Humans
Inflammatory Bowel Diseases
Intestines
*Metabolic Syndrome
Obesity/*physiopathology
Dietary Fats

Figure

• 

  Fig. 1 Regulation of host metabolism and immunity by gut microbiota. Under a fiber-rich diet, gut microbiota metabolize undigested dietary fiber into SCFAs (acetate, propionate, and butyrate), affecting host metabolism and immunity. Microbial metabolites from this process improve host metabolism. In particular, the secretion of peptide hormones, such as PYY and GLP-1, is promoted by microbial metabolites: PYY decreases appetite and GLP-1 lowers blood glucose level via promotion of insulin secretion. Among SCFAs, butyrate and propionate activate intestinal gluconeogenesis and improve systemic glucose profiles. Meanwhile, acetate promotes secretion of ghrelin, a hunger hormone, and increases food intake, consequently causing hyperphagia and obesity. Nevertheless, acetate has anti-inflammatory function like butyrate. Butyrate enhances gut barrier function of intestinal epithelial cells and increases regulatory T (Treg) cells. In addition, gut microbiota suppress expression of fasting-induced adipose factor (Fiaf), an inhibitor of LPL, promoting fat storage in adipocytes. Under fiber-deficient diet, mucus-degrading bacteria expand and impair the integrity of the mucus layer. Thereby, endotoxemia-induced metabolic inflammation ensues. SCFAs, short-chain fatty acids; PYY, peptide YY; GLP-1, glucagon-like peptide-1; LPL, lipoprotein lipase.

• 

  Fig. 2 Changes in the intestinal immunity by HFD. HFD changes intestinal immunity, as well as gut microbiota composition. HFD, in particular, increases the frequency of Th1 cells among the CD4 T cells and decreases those of Th17 and Treg cells. HFD increases the frequency of a CX3CR1+CD11chigh macrophage (MΦ) subset, preferentially inducing Th1 cells, and decreases that of a CX3CR1+CD11clow MΦ subset, preferentially inducing Th17 cells without affecting that of CD103+ DCs. Changes in the proportions of two MΦ subsets lead to the changes in Th1 and Th17 cells after HFD feeding. Intriguingly, intestinal Th17 cells play an important role in improving metabolic diseases through IL-17 and IL-22. IL-22 is produced also by ILC3 and functions to improve metabolic profiles. Proportions of ILC3 are decreased by HFD. IL-17, mainly produced by Th17 cells, reverses decreased granules and antimicrobial peptide production of Paneth cells, leading to expansion of microbiota associated with lean phenotype. In addition, IL-17 enhances barrier function of intestinal epithelial cell by increasing expression of tight junction molecules. HFD, high-fat diet; DCs, dendritic cells; IL, interleukin, ILC3, group 3 innate lymphoid cells.

Reference

1. Beltrán-Sánchez H, Harhay MO, Harhay MM, McElligott S. Prevalence and trends of metabolic syndrome in the adult U.S. population, 1999-2010. J Am Coll Cardiol. 2013; 62:697–703.

2. Hotamisligil GS. Inflammation and metabolic disorders. Nature. 2006; 444:860–867.

3. Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D, et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes. 2007; 56:1761–1772.

4. Hill DA, Artis D. Intestinal bacteria and the regulation of immune cell homeostasis. Intestinal bacteria and the regulation of immune cell homeostasis. Annu Rev Immunol. 2010; 28:623–667.

5. Qin J, Li R, Raes J, Arumugam M, Burgdorf KS, Manichanh C, Nielsen T, et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature. 2010; 464:59–65.

6. Nøhr MK, Pedersen MH, Gille A, Egerod KL, Engelstoft MS, Husted AS, et al. GPR41/FFAR3 and GPR43/FFAR2 as cosensors for short-chain fatty acids in enteroendocrine cells vs FFAR3 in enteric neurons and FFAR2 in enteric leukocytes. Endocrinology. 2013; 154:3552–3564.

7. De Vadder F, Kovatcheva-Datchary P, Goncalves D, Vinera J, Zitoun C, Duchampt A, et al. Microbiota-generated metabolites promote metabolic benefits via gut-brain neural circuits. Cell. 2014; 156:84–96.

8. Delaere F, Duchampt A, Mounien L, Seyer P, Duraffourd C, Zitoun C, et al. The role of sodium-coupled glucose co-transporter 3 in the satiety effect of portal glucose sensing. Mol Metab. 2012; 2:47–53.

9. Plöger S, Stumpff F, Penner GB, Schulzke JD, Gäbel G, Martens H, et al. Microbial butyrate and its role for barrier function in the gastrointestinal tract. Ann N Y Acad Sci. 2012; 1258:52–59.

10. Alenghat T, Osborne LC, Saenz SA, Kobuley D, Ziegler CG, Mullican SE, et al. Histone deacetylase 3 coordinates commensal-bacteria-dependent intestinal homeostasis. Nature. 2013; 504:153–157.

11. Sealy L, Chalkley R. The effect of sodium butyrate on histone modification. Cell. 1978; 14:115–121.

12. Arpaia N, Campbell C, Fan X, Dikiy S, van der Veeken J, deRoos P, et al. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature. 2013; 504:451–455.

13. Maslowski KM, Vieira AT, Ng A, Kranich J, Sierro F, Yu D, et al. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature. 2009; 461:1282–1286.

14. Perry RJ, Peng L, Barry NA, Cline GW, Zhang D, Cardone RL. Acetate mediates a microbiome-brain-β-cell axis to promote metabolic syndrome. Nature. 2016; 534:213–217.

15. Cani PD, Lecourt E, Dewulf EM, Sohet FM, Pachikian BD, Naslain D, et al. Gut microbiota fermentation of prebiotics increases satietogenic and incretin gut peptide production with consequences for appetite sensation and glucose response after a meal. Am J Clin Nutr. 2009; 90:1236–1243.

16. Bäckhed F, Ding H, Wang T, Hooper LV, Koh GY, Nagy A, et al. The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci U S A. 2004; 101:15718–15723.

17. Bäckhed F, Manchester JK, Semenkovich CF, Gordon JI. Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proc Natl Acad Sci U S A. 2007; 104:979–984.

18. Turnbaugh PJ, Bäckhed F, Fulton L, Gordon JI. Diet-induced obesity is linked to marked but reversible alterations in the mouse distal gut microbiome. Cell Host Microbe. 2008; 3:213–223.

19. Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature. 2006; 444:1027–1031.

20. Woo PC, Ng KH, Lau SK, Yip KT, Fung AM, Leung KW, et al. Usefulness of the MicroSeq 500 16S ribosomal DNA-based bacterial identification system for identification of clinically significant bacterial isolates with ambiguous biochemical profiles. J Clin Microbiol. 2003; 41:1996–2001.

21. Ley RE, Bäckhed F, Turnbaugh P, Lozupone CA, Knight RD, Gordon JI. Obesity alters gut microbial ecology. Proc Natl Acad Sci U S A. 2005; 102:11070–11075.

22. Krajmalnik-Brown R, Ilhan ZE, Kang DW, DiBaise JK. Effects of gut microbes on nutrient absorption and energy regulation. Nutr Clin Pract. 2012; 27:201–214.

23. Liu R, Hong J, Xu X, Feng Q, Zhang D, Gu Y, et al. Gut microbiome and serum metabolome alterations in obesity and after weight-loss intervention. Nat Med. 2017; 23:859–868.

24. Cani PD, Bibiloni R, Knauf C, Waget A, Neyrinck AM, Delzenne NM, et al. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes. 2008; 57:1470–1481.

25. Karlsson FH, Tremaroli V, Nookaew I, Bergström G, Behre CJ, Fagerberg B, et al. Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature. 2013; 498:99–103.

26. Qin J, Li Y, Cai Z, Li S, Zhu J, Zhang F, et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature. 2012; 490:55–60.

27. Quévrain E, Maubert MA, Michon C, Chain F, Marquant R, Tailhades J, et al. Identification of an anti-inflammatory protein from Faecalibacterium prausnitzii, a commensal bacterium deficient in Crohn's disease. Gut. 2016; 65:415–425.

28. Choi Y, Kwon Y, Kim DK, Jeon J, Jang SC, Wang T, et al. Gut microbe-derived extracellular vesicles induce insulin resistance, thereby impairing glucose metabolism in skeletal muscle. Sci Rep. 2015; 5:15878.

29. Kovatcheva-Datchary P, Nilsson A, Akrami R, Lee YS, De Vadder F, Arora T, et al. Dietary fiber-induced improvement in glucose metabolism is associated with increased abundance of prevotella. Cell Metab. 2015; 22:971–982.

30. Wu GD, Chen J, Hoffmann C, Bittinger K, Chen YY, Keilbaugh SA, et al. Linking long-term dietary patterns with gut microbial enterotypes. Science. 2011; 334:105–108.

31. Karlsson CL, Onnerfält J, Xu J, Molin G, Ahrné S, Thorngren-Jerneck K. The microbiota of the gut in preschool children with normal and excessive body weight. Obesity (Silver Spring). 2012; 20:2257–2261.

32. Santacruz A, Collado MC, García-Valdés L, Segura MT, Martín-Lagos JA, Anjos T, et al. Gut microbiota composition is associated with body weight, weight gain and biochemical parameters in pregnant women. Br J Nutr. 2010; 104:83–92.

33. Caesar R, Tremaroli V, Kovatcheva-Datchary P, Cani PD, Bäckhed F. Crosstalk between Gut Microbiota and Dietary Lipids Aggravates WAT Inflammation through TLR Signaling. Cell Metab. 2015; 22:658–668.

34. Schneeberger M, Everard A, Gómez-Valadés AG, Matamoros S, Ramírez S, Delzenne NM, et al. Akkermansia muciniphila inversely correlates with the onset of inflammation, altered adipose tissue metabolism and metabolic disorders during obesity in mice. Sci Rep. 2015; 5:16643.

35. Devkota S, Wang Y, Musch MW, Leone V, Fehlner-Peach H, Nadimpalli A, et al. Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in Il10^-/- mice. Nature. 2012; 487:104–108.

36. Collado MC, Derrien M, Isolauri E, de Vos WM, Salminen S. Intestinal integrity and Akkermansia muciniphila, a mucin-degrading member of the intestinal microbiota present in infants, adults, and the elderly. Appl Environ Microbiol. 2007; 73:7767–7770.

37. Everard A, Belzer C, Geurts L, Ouwerkerk JP, Druart C, Bindels LB, et al. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc Natl Acad Sci U S A. 2013; 110:9066–9071.

38. Shin NR, Lee JC, Lee HY, Kim MS, Whon TW, Lee MS, et al. An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice. Gut. 2014; 63:727–735.

39. Chevalier C, Stojanović O, Colin DJ, Suarez-Zamorano N, Tarallo V, Veyrat-Durebex C, et al. Gut microbiota orchestrates energy homeostasis during cold. Cell. 2015; 163:1360–1374.

40. Dao MC, Everard A, Aron-Wisnewsky J, Sokolovska N, Prifti E, Verger EO, et al. Akkermansia muciniphila and improved metabolic health during a dietary intervention in obesity: relationship with gut microbiome richness and ecology. Gut. 2016; 65:426–436.

41. Liou AP, Paziuk M, Luevano JM Jr, Machineni S, Turnbaugh PJ, Kaplan LM. Conserved shifts in the gut microbiota due to gastric bypass reduce host weight and adiposity. Sci Transl Med. 2013; 5:178ra41.

42. Li J, Lin S, Vanhoutte PM, Woo CW, Xu A. Akkermansia muciniphila protects against atherosclerosis by preventing metabolic endotoxemia-induced inflammation in Apoe^-/- mice. Circulation. 2016; 133:2434–2446.

43. Lee H, Ko G. Effect of metformin on metabolic improvement and gut microbiota. Appl Environ Microbiol. 2014; 80:5935–5943.

44. Cabreiro F, Au C, Leung KY, Vergara-Irigaray N, Cochemé HM, Noori T, et al. Metformin retards aging in C. elegans by altering microbial folate and methionine metabolism. Cell. 2013; 153:228–239.

45. de la Cuesta-Zuluaga J, Mueller NT, Corrales-Agudelo V, Velásquez-Mejía EP, Carmona JA, Abad JM, et al. Metformin is associated with higher relative abundance of mucin-degrading Akkermansia muciniphila and several short-chain fatty acid-producing microbiota in the gut. Diabetes Care. 2017; 40:54–62.

46. Wu H, Esteve E, Tremaroli V, Khan MT, Caesar R, Mannerås-Holm L, et al. Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug. Nat Med. 2017; 23:850–858.

47. Plovier H, Everard A, Druart C, Depommier C, Van Hul M, Geurts L, et al. A purified membrane protein from Akkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and diabetic mice. Nat Med. 2017; 23:107–113.

48. Suzuki T, Hara H. Dietary fat and bile juice, but not obesity, are responsible for the increase in small intestinal permeability induced through the suppression of tight junction protein expression in LETO and OLETF rats. Nutr Metab (Lond). 2010; 7:19.

49. Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS. TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest. 2006; 116:3015–3025.

50. Vandanmagsar B, Youm YH, Ravussin A, Galgani JE, Stadler K, Mynatt RL, et al. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat Med. 2011; 17:179–188.

51. Wen H, Gris D, Lei Y, Jha S, Zhang L, Huang MT, et al. Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nat Immunol. 2011; 12:408–415.

52. Cario E, Rosenberg IM, Brandwein SL, Beck PL, Reinecker HC, Podolsky DK. Lipopolysaccharide activates distinct signaling pathways in intestinal epithelial cell lines expressing Toll-like receptors. J Immunol. 2000; 164:966–972.

53. Chung H, Vilaysane A, Lau A, Stahl M, Morampudi V, Bondzi-Simpson A, et al. NLRP3 regulates a non-canonical platform for caspase-8 activation during epithelial cell apoptosis. Cell Death Differ. 2016; 23:1331–1346.

54. Everard A, Geurts L, Caesar R, Van Hul M, Matamoros S, Duparc T, et al. Intestinal epithelial MyD88 is a sensor switching host metabolism towards obesity according to nutritional status. Nat Commun. 2014; 5:5648.

55. Vijay-Kumar M, Aitken JD, Carvalho FA, Cullender TC, Mwangi S, Srinivasan S, et al. Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5. Science. 2010; 328:228–231.

56. Chassaing B, Ley RE, Gewirtz AT. Intestinal epithelial cell toll-like receptor 5 regulates the intestinal microbiota to prevent low-grade inflammation and metabolic syndrome in mice. Gastroenterology. 2014; 147:1363–1377.

57. Singh V, Chassaing B, Zhang L, San Yeoh B, Xiao X, Kumar M, et al. Microbiota-dependent hepatic lipogenesis mediated by stearoyl CoA desaturase 1 (SCD1) promotes metabolic syndrome in TLR5-deficient mice. Cell Metab. 2015; 22:983–996.

58. Brestoff JR, Kim BS, Saenz SA, Stine RR, Monticelli LA, Sonnenberg GF, et al. Group 2 innate lymphoid cells promote beiging of white adipose tissue and limit obesity. Nature. 2015; 519:242–246.

59. Lee MW, Odegaard JI, Mukundan L, Qiu Y, Molofsky AB, Nussbaum JC, et al. Activated type 2 innate lymphoid cells regulate beige fat biogenesis. Cell. 2015; 160:74–87.

60. Luck H, Tsai S, Chung J, Clemente-Casares X, Ghazarian M, Revelo XS, et al. Regulation of obesity-related insulin resistance with gut anti-inflammatory agents. Cell Metab. 2015; 21:527–542.

61. Wang X, Ota N, Manzanillo P, Kates L, Zavala-Solorio J, Eidenschenk C, et al. Interleukin-22 alleviates metabolic disorders and restores mucosal immunity in diabetes. Nature. 2014; 514:237–241.

62. Gross M, Salame TM, Jung S. Guardians of the gut-murine intestinal macrophages and dendritic cells. Front Immunol. 2015; 6:254.

63. Garidou L, Pomié C, Klopp P, Waget A, Charpentier J, Aloulou M, et al. The gut microbiota regulates intestinal CD4 T cells expressing RORγt and controls metabolic disease. Cell Metab. 2015; 22:100–112.

64. Hong CP, Park A, Yang BG, Yun CH, Kwak MJ, Lee GW, et al. Gut-specific delivery of T-helper 17 cells reduces obesity and insulin resistance in mice. Gastroenterology. 2017; 152:1998–2010.

65. Monteiro-Sepulveda M, Touch S, Mendes-Sá C, André S, Poitou C, Allatif O, et al. Jejunal T cell inflammation in human obesity correlates with decreased enterocyte insulin signaling. Cell Metab. 2015; 22:113–124.

66. Gaublomme JT, Yosef N, Lee Y, Gertner RS, Yang LV, Wu C, et al. Single-cell genomics unveils critical regulators of Th17 cell pathogenicity. Cell. 2015; 163:1400–1412.

67. Lee Y, Awasthi A, Yosef N, Quintana FJ, Xiao S, Peters A, et al. Induction and molecular signature of pathogenic TH17 cells. Nat Immunol. 2012; 13:991–999.

68. Wagner N, Löhler J, Kunkel EJ, Ley K, Leung E, Krissansen G, et al. Critical role for beta7 integrins in formation of the gut-associated lymphoid tissue. Nature. 1996; 382:366–370.

69. Williams MB, Butcher EC. Homing of naive and memory T lymphocyte subsets to Peyer's patches, lymph nodes, and spleen. J Immunol. 1997; 159:1746–1752.

70. Kinugasa T, Sakaguchi T, Gu X, Reinecker HC. Claudins regulate the intestinal barrier in response to immune mediators. Gastroenterology. 2000; 118:1001–1011.

71. Cani PD, Neyrinck AM, Fava F, Knauf C, Burcelin RG, Tuohy KM, et al. Selective increases of bifidobacteria in gut microflora improve high-fat-diet-induced diabetes in mice through a mechanism associated with endotoxaemia. Diabetologia. 2007; 50:2374–2383.

72. Desai MS, Seekatz AM, Koropatkin NM, Kamada N, Hickey CA, Wolter M, et al. A dietary fiber-deprived gut microbiota degrades the colonic mucus barrier and enhances pathogen susceptibility. Cell. 2016; 167:1339–1353.

73. Chassaing B, Miles-Brown J, Pellizzon M, Ulman E, Ricci M, Zhang L, et al. Lack of soluble fiber drives diet-induced adiposity in mice. Am J Physiol Gastrointest Liver Physiol. 2015; 309:G528–G541.

74. Amar J, Chabo C, Waget A, Klopp P, Vachoux C, Bermúdez-Humarán LG, et al. Intestinal mucosal adherence and translocation of commensal bacteria at the early onset of type 2 diabetes: molecular mechanisms and probiotic treatment. EMBO Mol Med. 2011; 3:559–572.

75. Lakhan SE, Kirchgessner A. Gut microbiota and sirtuins in obesity-related inflammation and bowel dysfunction. J Transl Med. 2011; 9:202.