16. Liang D, Leung RKK, Guan W, et al. Involvement of gut microbiome in human health and disease: brief overview, knowledge gaps and research opportunities. Gut Pathog. 2018;10:3. https://doi.org/10.1186/ s13099-018-0230-4
17. Sender. Are we really vastly outnumbered?
18. Du Preez S, Corbitt M, Cabanas H, Eaton N, Staines D, Marshall-Gradisnik S. A systematic review of enteric dysbiosis in chronic fatigue syndrome/myalgic encephalomyelitis. Syst Rev. 2018;7:241. https://www.ncbi.nlm.nih.gov/ pmc/articles/PMC6302292/
19. Lobionda S, Sittipo P, Kwon HY, Lee YK. The role of gut microbiota in intestinal inflammation with respect to diet and extrinsic stressors. Microorganisms. 2019;7. http://dx.doi.org/10.3390/microorganisms 7080271
20. Zeng MY, Inohara N, Nuñez G. Mechanisms of inflammation-driven bacterial dysbiosis in the gut. Mucosal Immunol. 2017;10:18–26. https://pubmed.ncbi.nlm.nih.gov/27554295/
21. Fasano A. All disease begins in the (leaky) gut: role of zonulin- mediated gut permeability in the pathogenesis of some chronic inflammatory diseases. F1000Res [Internet]. 2020;9. http://dx.doi.org/10.12688/ f1000research.20510.1
22. Sturgeon C, Fasano A. Zonulin, a regulator of epithelial and endothelial barrier functions, and its involvement in chronic inflammatory diseases. Tissue Barriers. 2016;4:e1251384. https://pubmed.ncbi.nlm.nih.gov/28123927/
23. Fasano A. Leaky gut and autoimmune diseases. Clin Rev Allergy Immunol. 2012;42:71–78. https://pubmed.ncbi.nlm.nih.gov/22109896/
24. Michielan A, D’Incà R. Intestinal permeability in inflammatory bowel disease: pathogenesis, clinical evaluation, and therapy of leaky gut. Mediators Inflamm. 2015;2015:628157. https://pubmed.ncbi.nlm.nih.gov/26582965/
25. Lerner A, Jeremias P, Matthias T. Gut-thyroid axis and celiac disease. Endocr Connect. 2017;6:R52–58. https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC5435852/
26. Turner JR. Intestinal mucosal barrier function in health and disease. Nat Rev Immunol. 2009;9:799–809. https://pubmed.ncbi.nlm.nih.gov/19855405/
27. Vancamelbeke M, Vermeire S. The intestinal barrier: a fundamental role in health and disease. Expert Rev Gastroenterol Hepatol. 2017;11:821–34. https://pubmed.ncbi.nlm.nih.gov/28650209/
28. Szentkuti L, Riedesel H, Enss ML, Gaertner K, Von Engelhardt W. Pre-epithelial mucus layer in the colon of conventional and germ-free rats. Histochem J. 1990;22:491–97. https://pubmed.ncbi.nlm.nih.gov/1702088/
29. Johansson MEV, Jakobsson HE, Holmén-Larsson J, Schütte A, Ermund A, Rodríguez-Piñeiro AM, et al. Normalization of host intestinal mucus layers requires long-term microbial colonization. Cell Host Microbe. 2015;18:582– 92. https://pubmed.ncbi.nlm.nih.gov/26526499/
30. Ibid.
31. Marcobal A, Southwick AM, Earle KA, Sonnenburg JL. A refined palate: bacterial consumption of host glycans in the gut. Glycobiology. 2013;23:1038–46. https://pubmed.ncbi.nlm.nih.gov/23720460/
32. 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;167:1339–53.e21. https://pubmed.ncbi.nlm.nih.gov/27863247/
33. Martens EC, Neumann M, Desai MS. Interactions of commensal and pathogenic microorganisms with the intestinal mucosal barrier. Nat Rev Microbiol. 2018;16:457–70. https://pubmed.ncbi.nlm.nih.gov/29904082/
34. Engevik MA, Luk B, Chang-Graham AL, Hall A, Herrmann B, Ruan W, et al. Bifidobacterium dentium fortifies the intestinal mucus layer via autophagy and calcium signaling pathways. MBio. 2019;10. http://dx.doi.org/10.1128/ mBio.01087-19
35. Morrison DJ, Preston T. Formation of short chain fatty acids by the gut microbiota and their impact on human metabolism. Gut Microbes. 2016;7:189–200. https://pubmed.ncbi.nlm.nih.gov/26963409/
36. Lewandowski ED, Kudej RK, White LT, O’Donnell JM, Vatner SF. Mitochondrial preference for short chain fatty acid oxidation during coronary artery constriction. Circulation. 2002;105:367–72. https://pubmed.ncbi.nlm.nih.gov/11804994/
37. Schönfeld P, Wojtczak L. Short- and medium-chain fatty acids in energy metabolism: the cellular perspective. J Lipid Res. 2016;57:943–54. https:// pubmed.ncbi.nlm.nih.gov/27080715/
38. Mollica MP, Mattace Raso G, Cavaliere G, Trinchese G, De Filippo C, Aceto S, et al. Butyrate regulates liver mitochondrial function, efficiency, and dynamics in insulin-resistant obese mice. Diabetes. 2017;66:1405–18. https:// pubmed.ncbi.nlm.nih.gov/28223285/
39. Gao Z, Yin J, Zhang J, Ward RE, Martin RJ, Lefevre M, et al. Butyrate improves insulin sensitivity and increases energy expenditure in mice. Diabetes. 2009;58:1509–17. https://pubmed.ncbi.nlm.nih.gov/19366864/
40. Henagan TM, Stefanska B, Fang Z, Navard AM, Ye J, Lenard NR, et al. Sodium butyrate epigenetically modulates high-fat diet-induced skeletal muscle mitochondrial adaptation, obesity and insulin resistance through nucleosome positioning. Br J Pharmacol. 2015;172:2782–98. https://pubmed.ncbi.nlm.nih.gov/25559882/
41. Donohoe DR, Garge N, Zhang X, Sun W, O’Connell TM, Bunger MK, et al. The microbiome and butyrate regulate energy metabolism and autophagy in the mammalian colon. Cell Metab. 2011;13:517–26. https://pubmed.ncbi.nlm.nih.gov/21531334/
42. Espín JC, Larrosa M, García-Conesa MT, Tomás-Barberán F. Biological significance of urolithins, the gut microbial ellagic Acid-derived metabolites: the evidence so far. Evid Based Complement Alternat Med. 2013;2013:270418. https://pubmed.ncbi.nlm.nih.gov/23781257/
43. Ferreira CM, Vieira AT, Vinolo MAR, Oliveira FA, Curi R, Martins F dos S. The central role of the gut microbiota in chronic inflammatory diseases. J Immunol Res. 2014;2014:689492. https://pubmed.ncbi.nlm.nih.gov/25309932/
44. Salguero MV, Al-Obaide MAI, Singh R, Siepmann T, Vasylyeva TL. Dysbiosis of Gram-negative gut microbiota and the associated serum lipopolysaccharide exacerbates inflammation in type 2 diabetic patients with chronic kidney disease. Exp Ther Med. 2019;18:3461–69. https://pubmed.ncbi.nlm.nih.gov/31602221/
45. Anderson G, Maes M. Gut dysbiosis dysregulates central and systemic homeostasis via suboptimal mitochondrial function: assessment, treatment and classification implications. Curr Top Med Chem. 2020;20:524–39. https://pubmed.ncbi.nlm.nih.gov/32003689/
46. McGivney A, Bradley SG. Action of bacterial endotoxin and lipid A on mitochondrial enzyme activities of cells in culture and subcellular fractions. Infect Immun. 1979;25:664–71. https://pubmed.ncbi.nlm.nih.gov/114491/
47. Mishra DP, Dhali A. Endotoxin induces luteal cell apoptosis through the mitochondrial pathway. Prostaglandins Other Lipid Mediat. 2007;83:75–88. https://pubmed.ncbi.nlm.nih.gov/17259074/
48. Frisard MI, Wu Y, McMillan RP, Voelker KA, Wahlberg KA, Anderson AS, et al. Low levels of lipopolysaccharide modulate mitochondrial oxygen consumption in skeletal muscle. Metabolism. 2015;64:416–27. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4501015/
49. Jeger V, Brandt S, Porta F, Jakob SM, Takala J, Djafarzadeh S. Dose response of endotoxin on hepatocyte and muscle mitochondrial respiration in vitro. Biomed Res Int. 2015;2015:353074. https://pubmed.ncbi.nlm.nih.gov/25649304/
50. Giloteaux L, Goodrich JK, Walters WA, Levine SM, Ley RE, Hanson MR. Reduced diversity and altered composition of the gut microbiome in individuals with myalgic encephalomyelitis/chronic fatigue syndrome. Microbiome. 2016;4:30. https://pubmed.ncbi.nlm.nih.gov/27338587/
51. Hwang C, Ross V, Mahadevan U. Micronutrient deficiencies in inflammatory bowel disease: from A to zinc. Inflamm Bowel Dis. 2012;18:1961–81. https:// pubmed.ncbi.nlm.nih.gov/22488830/
52. Joustra ML, Minovic I, Janssens KAM, Bakker SJL, Rosmalen JGM. Vitamin and mineral status in chronic fatigue syndrome and fibromyalgia syndrome: a systematic review and meta-analysis. PLoS One. 2017;12:e0176631. https:// pubmed.ncbi.nlm.nih.gov/28453534/
53. Maes M, Mihaylova I, Leunis J-C. Increased serum IgA and IgM against LPS of enterobacteria in chronic fatigue syndrome (CFS): indication for the involvement of gram-negative enterobacteria in the etiology of CFS and for the presence of an increased gut-intestinal permeability. J Affect Disord. 2007;99:237–40. https://pubmed.ncbi.nlm.nih.gov/17007934/
54. King DE, Mainous AG 3rd, Lambourne CA. Trends in dietary fiber intake in the United States, 1999–2008. J Acad Nutr Diet. 2012;112:642–48. https:// pubmed.ncbi.nlm.nih.gov/22709768/
55. Eaton SB, Konner M. Paleolithic nutrition. A consideration of its nature and current implications. N Engl J Med. 1985;312:283–89. https://pubmed.ncbi.nlm.nih.gov/2981409/
56. Smits SA, Leach J, Sonnenburg ED, Gonzalez CG, Lichtman JS, Reid G, et al. Seasonal cycling in the gut microbiome of the Hadza hunter-gatherers of Tanzania. Science. 2017;357:802–6. https://pubmed.ncbi.nlm.nih.gov/28839072/
57. Hiel S, Bindels LB, Pachikian BD, Kalala G, Broers V, Zamariola G, et al. Effects of a diet based on inulin-rich vegetables on gut health and nutritional behavior in healthy humans. Am J Clin Nutr. 2019;109:1683–95. https:// pubmed.ncbi.nlm.nih.gov/31108510/
58. Davani-Davari D, Negahdaripour M, Karimzadeh I, Seifan M, Mohkam M, Masoumi SJ, et al. Prebiotics: definition, types, sources, mechanisms, and clinical applications. Foods. 2019;8. http://dx.doi.org/10.3390/ foods8030092.
59. Gibson GR, Hutkins R, Sanders ME, Prescott SL, Reimer RA, Salminen SJ, et al. Expert consensus document: The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of prebiotics. Nat Rev Gastroenterol Hepatol. 2017;14:491–502. https://pubmed.ncbi.nlm.nih.gov/28611480/
60. Birt DF, Boylston T, Hendrich S, Jane J-L, Hollis J, Li L, et al. Resistant starch: promise for improving human health. Adv Nutr. 2013;4:587–601. https:// pubmed.ncbi.nlm.nih.gov/24228189/