The Earthen Chalice

Earthen Chalice

Evidence-based health guidance

Introduction

Surface facts

Most people would view the human skin as our most important point of contact to the outside world. After all, the skin protects us from heat, cold, harmful chemicals and dangerous microbes, and yet it is so sensitive that we can even feel a weak breeze picking up. But if we look at the total surface area, the human intestines are actually larger on the inside than our skin is on the outside.[1, 2] While our digestive tract is only about five meters long, the large and small intestine have countless folds and creases that are layered with tiny tentacles, not unlike an origami octopus. In that way, the intestines are in a more active and direct contact with the things we eat than our skin is in contact with the outside air. This allows us to effectively absorb most of the nutrients and fluids from our food. But there is one other advantage to a large surface area: the ability to house microbes.

maxresdefault
Fig. 1: Your inner octopus

Secret kidney

The total number of microbes populating our digestive tract at any given time is very close to the number of human cells in our body.[3] That means we’re half microbe by number – even if not by weight. All those bacteria together weigh around 200 g, which is “only” as much as one or two average kidneys.[4] Because of this, and because the gut flora produces many metabolically active substances, the microbiome is often called a forgotten organ.[5] Science is slowly but steadily remembering this organ, and by now we know that more than 1,000 different species of bacteria can be found in the human intestines, while the average person houses at least 150 of these.[6] Individual people share many of the bacterial species, but there is still enough variety to create a “bacterial fingerprint” of each person’s microbiome.[7] The exact composition of the gut flora depends less on your genes, and more on the early years of your personal history.[8, 9] Shortly after birth, the intestine of a baby is populated by friendly bacteria from the mother’s vaginal flora and breastmilk, and has an immature and very unstable bacterial profile.[10] After the introduction of a nutritious solid food diet, the microbiome rapidly matures into an adult profile that is stable and resistant against invading microbes.[11, 12] In cases of malnutrition the gut flora cannot develop and stays at an immature stage, but can mature temporarily whenever enough nutrients are present.[13]

 

The healthy microbiome

Floral functionality

There used to be this popular idea that every gut flora needs to contain a certain selection of bacterial species to be considered healthy, a so-called “core microbiome.” But analyses from all over the world clearly show that what is really important is not the classification of the bacteria, but their function within the current life situation. For example, infants fed with breast milk tend to have high numbers of bacteria that can digest lactose. From the point where solid plant foods enter the diet, bacteria that can break down fiber become more common.[12] The type (genus and/or species) of these bacteria can be very different from person to person, but they generally have the same functionality or “job” within the total microbiome.[14] Which of these functional types of bacteria are dominant then depends on both the past and the current diet. In rural areas of Africa, where the diet is traditionally made up by large amounts of fiber-rich foods, the typical microbiome was found to contain large amounts of fiber-digesting bacteria. This was not the case with samples from the EU and the US, which were dominated by amino-acid digesting bacteria, probably shaped by high animal protein intake.[15, 16]

The gut flora as a whole is a kind of alchemical powerhouse.[17] One of its main jobs is the digestion (“fermentation”) of fiber to produce short-chain fatty acids, which can be used as an energy source by the intestine itself, and can provide up to 10% of your total daily caloric intake.[18-20] Many of these fatty acids are signal molecules that can reduce inflammation, strengthen the gut wall, regulate the immune system and influence satiety and insulin sensitivity.[19, 21-23] On top of that, the gut flora seems to take on several different “useful” roles depending on the diet. In carnivores and humans consuming high amounts of meat, the gut bacteria adapt to digest amino acids, produce vitamins that may lack in the diet and break down carcinogenic substances found in charred meat. In herbivores and humans with high fiber intake, the gut flora is specialized to digest fiber and to produce amino acids. Adaptations of the microbiome to a herbivore or carnivore diet can happen within the short time frame of only one day. It’s possible that this is a mechanism optimized for the short-term changes in the diet of hunter-gatherer humans, with high meat availability after a successful hunt, and a diet otherwise based on fiber-rich plant-matter.[24-26]

V0025560 An alchemist at a furnace with a large 'receiver', with diag Credit: Wellcome Library, London. Wellcome Images images@wellcome.ac.uk http://wellcomeimages.org An alchemist at a furnace with a large 'receiver', with diagrams of alchemical apparatus. Woodcut, 1658. 1658 after: Johannes Rudolph GlauberPublished: 1658 Copyrighted work available under Creative Commons Attribution only licence CC BY 4.0 http://creativecommons.org/licenses/by/4.0/
Fig. 2: The gut flora fermenting some fiber... probably
 

The not-so-healthy microbiome

Balance is key

While a balanced and stable gut flora is necessary for health, an imbalanced microbiome is a culprit in disease from as early as directly after birth. Infants with disturbed or reduced microbiomes in the first 100 days of life tend to develop more allergies either immediately or years later.[27-32] Influences that can cause disturbances in the gut flora are early (preterm) birth, delivery via caesarean section and/or antibiotic therapy.[33-36] Exposing the mother during pregnancy, or the child after birth, to environments rich in diverse bacterial species, such as farms or day-care facilities, seems to reduce allergy development.[37-42]

Adult microbiomes are generally very stable, but can be disturbed by antibiotic therapy, infection with invasive microbes, an unhealthy diet or even “just” psychological stress.[16, 24, 43-45] As the result of such a disturbance, the gut flora loses many species of bacteria and enters an unstable, low-diversity state. After the negative factors have been removed, an incomplete recovery to a degraded, but stable state takes place.[14] A reduced or imbalanced gut flora, also called “dysbiosis,” can worsen or even cause a number of diseases of the digestive tract, like malabsorption of nutrients, indigestion, irritable bowel syndrome and others.[46-48] More than that, dysbiosis can also have a profoundly negative influence on the immune system and the central nervous system, and can contribute to obesity, inflammation, ageing and cancer incidence.[49-53]

 

Probiotics

Regaining what was lost

Once a gut flora is imbalanced or has low diversity, the most logical thing to do is re-colonize it. This can be achieved using so-called “fecal microbiota transplantations,” which involve taking stool samples from a donor, extracting the bacteria and giving them to a patient. This technique has been used with success for disturbed microbiomes, but has led to unexpected weight gain in some people.[54-56] It is never exactly clear which bacteria are contained in the transplant, so choosing a healthy donor is very important.

Commercial probiotics, in comparison, contain only a few well-known species of bacteria that are traditionally found in fermented milk products.[57] It would seem like having so few species of bacteria in a probiotic preparation will at least make it easier to analyse their positive effects. Unfortunately, even the effects of supplementing a single species will depend on the current microbiome, diet, medications, psychological stress and many other factors. This would explain why even recent, large-scale meta-reviews come to the conclusion that there is no definite health effect for taking probiotics.[58-66] It’s also unlikely that the meager 1-20 different bacterial species that are contained in probiotics can improve the diversity of the more than 1,000 different species and subspecies found in the human microbiome.[67] That said, taking a probiotic preparation can increase the number of the supplemented bacteria in the gut for a short time. In this way, it’s possible that they out-compete harmful microbes and provide food and metabolites for other friendly bacteria that can then populate the flora.[68-73] On the other hand, they could also drive out good bacteria and cause gastrointestinal side-effects in healthy people, or infections in immunodeficient people.[74-77] All in all, probiotics seem like a relatively safe and promising, but somewhat unpredictable option to improve the micobiome.[78]

 

Prebiotics

Feeding what was found

There is yet another way in which one can try to balance an out-of-whack gut flora. Instead of introducing live bacteria to your system, the idea of prebiotics is to feed select parts of what you already have. It’s easy to confuse pre- and pro-biotics, not only because the words are similar but also because their naming is very much counter-intuitive. Maybe it can help you to remember the meanings if you take the “pre” to mean “present”, as in, a present from you to your gut flora in gratitude for all its years of service. And similar to chocolate bunnies given to children at Easter, this is the kind of present that will be eaten right away – or “fermented”, to use the bacteria-appropriate word. Ideally, prebiotics are intended to feed only some select kinds of bacteria which are believed to be overall beneficial for health.[79]

The most popular prebiotic is probably inulin, a type of fiber called “non-digestible oligosaccharide.” These kinds of fiber can be found in chicory and other vegetables and are especially popular with lactic acid bacteria from the genus Lactobacillus and Bifidobacterium.[80] As these are also the bacteria used in probiotics, both kinds of supplements have the same goal: increase the amount of beneficial lactic acid bacteria in the gut, once by seeding (probiotics) and once by feeding (prebiotics). On top of that, prebiotic fibers are used by our friendly microbes to produce short-chain fatty acids, which can have all kinds of positive effects on the metabolism, as mentioned in the section about floral functionality.[81] This is probably one of the main arguments in favor of prebiotics. After all, even if you have a healthy gut flora, it can’t produce any beneficial substances if it doesn’t have the base material. On the other hand, the potential risks are similar to those we see with probiotics. In comparison to the natural balance of different fibers found in a typical vegetable, prebiotics are more like chemical substances. They are heavily processed and are taken in high concentrations and without their usual “food matrix” (that is, the entire rest of the vegetable). As such, their impact on the gut flora is unpredictable, even though side effects are rare and usually only consist of mild digestive troubles.[82]

easter-nest-2157015_1280 - Copy
Fig. 3: May feed your soul, but not your gut flora
 

Dietary fiber

Sir, I’m gonna need that kidney bean

Neolithic humans certainly didn’t go out to gather probiotic pills or hunt for chicory fiber. So how is it that we believe we need those specialized health products to be well? One aspect of it is certainly just effective marketing. The other one is that Neolithic humans also didn’t have fast food joints and desk jobs. The modern lifestyle puts unusual stresses on practically all aspects of our health, and that certainly includes our gut flora. Highly refined ingredients like sugar and alcohol feed bacteria we don’t want and suppress those we would need. Diets dominated by comfort foods lack the nutrients the flora needs to flourish in diversity. The result is mild to moderate dysbiosis and negative effects on areas of our life that we never even remotely thought were connected to the gut flora, including our brain health, mood and the way we interact socially.[53, 83] With that said, there’s no reason not to use the natural pre- and probiotics of our ancestors to improve our modern lives. It was Hippocrates who suggested to “let food be thy medicine”, and had there been any pharmaceutical companies in ancient Greece, he may just have vanished under mysterious circumstances. In the end, even modern science agrees that choosing the proper foods is the single most important thing you can do to optimize the gut flora. Better than any product could, no matter how well it may be marketed.

The answer is almost disappointingly simple: it’s the fiber. Short-chain fatty acids are probably the single most important metabolite produced by the gut flora, and they’re essentially made from soluble fiber.[84-88] Which foods contain soluble fiber? Whole grains, legumes and vegetables. On top of that, raw vegetables contain a large selection of beneficial bacteria on their surface, and so they double as natural probiotics.[89] Some of these bacteria have even been suggested for use in future probiotic supplements.[90] But why wait? You can make use of the probiotic power of all different kinds of fruits, berries and vegetables right now by simply integrating them into your diet.[89] In addition, you can protect your gut flora by limiting the consumption of processed foods, sugar and alcohol. Day-to-day stress levels can be reduced by structuring your work schedule ahead of time and leaving some time slots open for rest & relaxation in your time off. Your friendly flora is sure to appreciate it.

Kidney-comparison - Copy
Fig. 4: Spooky similarities
 

Frequently asked questions (FAQ)

 

Sources

  1. Helander, H.F. and L. Fändriks, Surface area of the digestive tract–revisited. Scandinavian journal of gastroenterology, 2014. 49(6): p. 681-689.
  2. Gallo, R.L., Human skin is the largest epithelial surface for interaction with microbes. Journal of Investigative Dermatology, 2017. 137(6): p. 1213-1214.
  3. Sender, R., S. Fuchs, and R. Milo, Revised estimates for the number of human and bacteria cells in the body. PLoS biology, 2016. 14(8): p. e1002533.
  4. Molina, D.K. and V.J. DiMaio, Normal organ weights in men: part II—the brain, lungs, liver, spleen, and kidneys. The American journal of forensic medicine and pathology, 2012. 33(4): p. 368-372.
  5. O’Hara, A.M. and F. Shanahan, The gut flora as a forgotten organ. EMBO reports, 2006. 7(7): p. 688-693.
  6. Qin, J., et al., A human gut microbial gene catalogue established by metagenomic sequencing. nature, 2010. 464(7285): p. 59-65.
  7. Browne, H.P., et al., Culturing of ‘unculturable’human microbiota reveals novel taxa and extensive sporulation. Nature, 2016. 533(7604): p. 543-546.
  8. Zoetendal, E.G., et al., The host genotype affects the bacterial community in the human gastronintestinal tract. Microbial ecology in health and disease, 2001. 13(3): p. 129-134.
  9. Turnbaugh, P.J., et al., A core gut microbiome in obese and lean twins. nature, 2009. 457(7228): p. 480-484.
  10. Dominguez-Bello, M.G., et al., Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proceedings of the National Academy of Sciences, 2010. 107(26): p. 11971-11975.
  11. Palmer, C., et al., Development of the human infant intestinal microbiota. PLoS biol, 2007. 5(7): p. e177.
  12. Koenig, J.E., et al., Succession of microbial consortia in the developing infant gut microbiome. Proceedings of the National Academy of Sciences, 2011. 108(Supplement 1): p. 4578-4585.
  13. Subramanian, S., et al., Persistent gut microbiota immaturity in malnourished Bangladeshi children. Nature, 2014. 510(7505): p. 417-421.
  14. Lozupone, C.A., et al., Diversity, stability and resilience of the human gut microbiota. Nature, 2012. 489(7415): p. 220-230.
  15. De Filippo, C., et al., Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa. Proceedings of the National Academy of Sciences, 2010. 107(33): p. 14691-14696.
  16. Wu, G.D., et al., Linking long-term dietary patterns with gut microbial enterotypes. Science, 2011. 334(6052): p. 105-108.
  17. Nicholson, J.K., et al., Host-gut microbiota metabolic interactions. Science, 2012. 336(6086): p. 1262-1267.
  18. Lin, H.V., et al., Butyrate and propionate protect against diet-induced obesity and regulate gut hormones via free fatty acid receptor 3-independent mechanisms. PloS one, 2012. 7(4): p. e35240.
  19. Rooks, M.G. and W.S. Garrett, Gut microbiota, metabolites and host immunity. Nature reviews immunology, 2016. 16(6): p. 341-352.
  20. Rosenbaum, M., R. Knight, and R.L. Leibel, The gut microbiota in human energy homeostasis and obesity. Trends in Endocrinology & Metabolism, 2015. 26(9): p. 493-501.
  21. Meijer, K., P. de Vos, and M.G. Priebe, Butyrate and other short-chain fatty acids as modulators of immunity: what relevance for health? Current Opinion in Clinical Nutrition & Metabolic Care, 2010. 13(6): p. 715-721.
  22. Kuo, S.-M., The interplay between fiber and the intestinal microbiome in the inflammatory response. Advances in Nutrition, 2013. 4(1): p. 16-28.
  23. Lee, C.J., C.L. Sears, and N. Maruthur, Gut microbiome and its role in obesity and insulin resistance. Annals of the New York Academy of Sciences, 2020. 1461(1): p. 37-52.
  24. David, L.A., et al., Diet rapidly and reproducibly alters the human gut microbiome. Nature, 2014. 505(7484): p. 559-563.
  25. Muegge, B.D., et al., Diet drives convergence in gut microbiome functions across mammalian phylogeny and within humans. Science, 2011. 332(6032): p. 970-974.
  26. Hawkes, K., J.F. O´ Connell, and N.G. Blurton Jones, Hunting income patterns among the Hadza: big game, common goods, foraging goals and the evolution of the human diet. Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences, 1991. 334(1270): p. 243-251.
  27. Arrieta, M.-C., et al., Early infancy microbial and metabolic alterations affect risk of childhood asthma. Science translational medicine, 2015. 7(307): p. 307ra152-307ra152.
  28. Boutin, R.C. and B.B. Finlay, Microbiota-mediated immunomodulation and asthma: current and future perspectives. Current Treatment Options in Allergy, 2016. 3(3): p. 292-309.
  29. Björkstén, B., et al., Allergy development and the intestinal microflora during the first year of life. Journal of allergy and clinical immunology, 2001. 108(4): p. 516-520.
  30. Sepp, E., et al., Intestinal microbiota and immunoglobulin E responses in 5‐year‐old estonian children. Clinical & Experimental Allergy, 2005. 35(9): p. 1141-1146.
  31. Kalliomäki, M., et al., Distinct patterns of neonatal gut microflora in infants in whom atopy was and was not developing. Journal of Allergy and Clinical Immunology, 2001. 107(1): p. 129-134.
  32. Penders, J., et al., Gut microbiota composition and development of atopic manifestations in infancy: the KOALA Birth Cohort Study. Gut, 2007. 56(5): p. 661-667.
  33. Eggesbø, M., et al., Development of gut microbiota in infants not exposed to medical interventions. Apmis, 2011. 119(1): p. 17-35.
  34. van Nimwegen, F.A., et al., Mode and place of delivery, gastrointestinal microbiota, and their influence on asthma and atopy. Journal of Allergy and Clinical Immunology, 2011. 128(5): p. 948-955. e3.
  35. Russell, S.L., et al., Early life antibiotic‐driven changes in microbiota enhance susceptibility to allergic asthma. EMBO reports, 2012. 13(5): p. 440-447.
  36. Goncalves, C., et al., Repercussions of preterm birth on symptoms of asthma, allergic diseases and pulmonary function, 6–14 years later. Allergologia et immunopathologia, 2016. 44(6): p. 489-496.
  37. Ege, M.J., et al., Exposure to environmental microorganisms and childhood asthma. New England Journal of Medicine, 2011. 364(8): p. 701-709.
  38. Ball, T.M., et al., Siblings, day-care attendance, and the risk of asthma and wheezing during childhood. New England journal of medicine, 2000. 343(8): p. 538-543.
  39. Ege, M.J., et al., Prenatal farm exposure is related to the expression of receptors of the innate immunity and to atopic sensitization in school-age children. Journal of Allergy and Clinical Immunology, 2006. 117(4): p. 817-823.
  40. Gupta, R.S., et al. Hygiene factors associated with childhood food allergy and asthma. in Allergy and asthma proceedings. 2016. OceanSide Publications.
  41. Alfvén, T., et al., Allergic diseases and atopic sensitization in children related to farming and anthroposophic lifestyle–the PARSIFAL study. Allergy, 2006. 61(4): p. 414-421.
  42. Sbihi, H., et al., Thinking bigger: How early‐life environmental exposures shape the gut microbiome and influence the development of asthma and allergic disease. Allergy, 2019. 74(11): p. 2103-2115.
  43. Dethlefsen, L. and D.A. Relman, Incomplete recovery and individualized responses of the human distal gut microbiota to repeated antibiotic perturbation. Proceedings of the National Academy of Sciences, 2011. 108(Supplement 1): p. 4554-4561.
  44. Yang, L., et al., Helicobacter pylori infection aggravates dysbiosis of gut microbiome in children with gastritis. Frontiers in Cellular and Infection Microbiology, 2019. 9: p. 375.
  45. Myers, S.P., The causes of intestinal dysbiosis: a review. Altern Med Rev, 2004. 9(2): p. 180-197.
  46. Dicksved, J., et al., Molecular analysis of the gut microbiota of identical twins with Crohn’s disease. The ISME journal, 2008. 2(7): p. 716-727.
  47. Carroll, I.M., et al., Molecular analysis of the luminal-and mucosal-associated intestinal microbiota in diarrhea-predominant irritable bowel syndrome. American Journal of Physiology-Gastrointestinal and Liver Physiology, 2011. 301(5): p. G799-G807.
  48. Frank, D.N., et al., Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proceedings of the National Academy of Sciences, 2007. 104(34): p. 13780-13785.
  49. Levy, M., et al., Dysbiosis and the immune system. Nature Reviews Immunology, 2017. 17(4): p. 219-232.
  50. Howard, J.M., Intestinal dysbiosis. Complementary Therapies in Medicine, 1993. 1(3): p. 153-157.
  51. Underwood, M.A., Intestinal dysbiosis: novel mechanisms by which gut microbes trigger and prevent disease. Preventive medicine, 2014. 65: p. 133-137.
  52. Carding, S., et al., Dysbiosis of the gut microbiota in disease. Microbial ecology in health and disease, 2015. 26(1): p. 26191.
  53. Morrison, K.E., et al., It’s the fiber, not the fat: significant effects of dietary challenge on the gut microbiome. Microbiome, 2020. 8(1): p. 15.
  54. Smits, L.P., et al., Therapeutic potential of fecal microbiota transplantation. Gastroenterology, 2013. 145(5): p. 946-953.
  55. de Clercq, N.C., et al., Weight gain after fecal microbiota transplantation in a patient with recurrent underweight following clinical recovery from anorexia nervosa. Psychotherapy and psychosomatics, 2019. 88(1): p. 58-60.
  56. Alang, N. and C.R. Kelly. Weight gain after fecal microbiota transplantation. in Open forum infectious diseases. 2015. Oxford University Press.
  57. Vaughan, R., The romantic rationalist a study of Elie Metchnikoff. Medical history, 1965. 9(3): p. 201-215.
  58. López-Moreno, A., et al., Probiotic Strains and Intervention Total Doses for Modulating Obesity-Related Microbiota Dysbiosis: A Systematic Review and Meta-analysis. Nutrients, 2020. 12(7): p. 1921.
  59. Taylor, A.M. and H.D. Holscher, A review of dietary and microbial connections to depression, anxiety, and stress. Nutritional neuroscience, 2020. 23(3): p. 237-250.
  60. Lewis-Mikhael, A.-M., A. Davoodvandi, and S. Jafarnejad, Effect of Lactobacillusplantarum containing probiotics on blood pressure: A systematic review and meta-analysis. Pharmacological Research, 2020. 153: p. 104663.
  61. Nazari, M., et al., Probiotic consumption and inflammatory markers in athletes: a systematic review and meta-analysis. International Journal of Food Properties, 2020. 23(1): p. 1402-1415.
  62. Jiang, J., et al., Effects of probiotic supplementation on cardiovascular risk factors in hypercholesterolemia: A systematic review and meta-analysis of randomized clinical trial. Journal of Functional Foods, 2020. 74: p. 104177.
  63. Barbosa, R.S. and M.A. Vieira-Coelho, Probiotics and prebiotics: focus on psychiatric disorders–a systematic review. Nutrition Reviews, 2020. 78(6): p. 437-450.
  64. Irwin, C., et al., Effects of probiotics and paraprobiotics on subjective and objective sleep metrics: a systematic review and meta-analysis. European Journal of Clinical Nutrition, 2020: p. 1-14.
  65. Preidis, G.A., et al., AGA technical review on the role of probiotics in the management of gastrointestinal disorders. Gastroenterology, 2020. 159(2): p. 708-738. e4.
  66. Lescheid, D.W., Probiotics as regulators of inflammation: A review. Functional foods in health and disease, 2014. 4(7): p. 299-311.
  67. Claesson, M.J., 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): p. e6669.
  68. Brigidi, P., et al., PCR detection of Bifidobacterium strains and Streptococcus thermophilus in feces of human subjects after oral bacteriotherapy and yogurt consumption. International journal of food microbiology, 2003. 81(3): p. 203-209.
  69. Fooks, L. and G.R. Gibson, Probiotics as modulators of the gut flora. British Journal of Nutrition, 2002. 88(S1): p. s39-s49.
  70. Armuzzi, A., et al., The effect of oral administration of Lactobacillus GG on antibiotic‐associated gastrointestinal side‐effects during Helicobacter pylori eradication therapy. Alimentary pharmacology & therapeutics, 2001. 15(2): p. 163-169.
  71. Lesbros-Pantoflickova, D., I. Corthesy-Theulaz, and A.L. Blum, Helicobacter pylori and probiotics. The Journal of nutrition, 2007. 137(3): p. 812S-818S.
  72. Gotteland, M., O. Brunser, and S. Cruchet, Systematic review: are probiotics useful in controlling gastric colonization by Helicobacter pylori? Alimentary pharmacology & therapeutics, 2006. 23(8): p. 1077-1086.
  73. Belenguer, A., et al., Two routes of metabolic cross-feeding between Bifidobacterium adolescentis and butyrate-producing anaerobes from the human gut. Applied and environmental microbiology, 2006. 72(5): p. 3593-3599.
  74. Didari, T., et al., A systematic review of the safety of probiotics. Expert opinion on drug safety, 2014. 13(2): p. 227-239.
  75. Besselink, M.G., et al., Probiotic prophylaxis in predicted severe acute pancreatitis: a randomised, double-blind, placebo-controlled trial. The Lancet, 2008. 371(9613): p. 651-659.
  76. Boyle, R.J., et al., Probiotics for treating eczema. Cochrane Database of Systematic Reviews, 2008(4).
  77. Gerritsen, J., et al., Intestinal microbiota in human health and disease: the impact of probiotics. Genes & nutrition, 2011. 6(3): p. 209-240.
  78. Snydman, D.R., The safety of probiotics. Clinical infectious diseases, 2008. 46(Supplement_2): p. S104-S111.
  79. Gibson, G.R. and M.B. Roberfroid, Dietary modulation of the human colonic microbiota: introducing the concept of prebiotics. The Journal of nutrition, 1995. 125(6): p. 1401-1412.
  80. Roberfroid, M.B., J.A. Van Loo, and G.R. Gibson, The bifidogenic nature of chicory inulin and its hydrolysis products. The Journal of nutrition, 1998. 128(1): p. 11-19.
  81. Roberfroid, M., et al., Prebiotic effects: metabolic and health benefits. British Journal of Nutrition, 2010. 104(S2): p. S1-S63.
  82. Cherbut, C., et al., Acacia gum is a bifidogenic dietary fibre with high digestive tolerance in healthy humans. Microbial Ecology in Health and Disease, 2003. 15(1): p. 43-50.
  83. Thorburn, A.N., L. Macia, and C.R. Mackay, Diet, metabolites, and “western-lifestyle” inflammatory diseases. Immunity, 2014. 40(6): p. 833-842.
  84. Arora, T., R. Sharma, and G. Frost, Propionate. Anti-obesity and satiety enhancing factor? Appetite, 2011. 56(2): p. 511-515.
  85. Scharlau, D., et al., Mechanisms of primary cancer prevention by butyrate and other products formed during gut flora-mediated fermentation of dietary fibre. Mutation Research/Reviews in Mutation Research, 2009. 682(1): p. 39-53.
  86. Hippe, B., et al., Quantification of butyryl CoA: acetate CoA-transferase genes reveals different butyrate production capacity in individuals according to diet and age. FEMS microbiology letters, 2011. 316(2): p. 130-135.
  87. Wilson, A.S., et al., Diet and the human gut microbiome: an international review. Digestive Diseases and Sciences, 2020: p. 1-18.
  88. Ghosh, T.S., et al., Mediterranean diet intervention alters the gut microbiome in older people reducing frailty and improving health status: the NU-AGE 1-year dietary intervention across five European countries. Gut, 2020. 69(7): p. 1218-1228.
  89. Leff, J.W. and N. Fierer, Bacterial communities associated with the surfaces of fresh fruits and vegetables. PloS one, 2013. 8(3): p. e59310.
  90. Vitali, B., et al., Novel probiotic candidates for humans isolated from raw fruits and vegetables. Food Microbiology, 2012. 31(1): p. 116-125.