The Wide-Ranging Role of the Microbiome
'You Are What You Eat' Is Proving More True Than Ever Before
David A. Johnson, MD
September 15, 2015
Here is a verbatim transcript of a recent talk (not overly technical) given by one of the world's leading gastroenterologists.
It is food for thought [pun intended!] considering how much we gastro-eosophagectomy patients' internal flora has been affected by surgery,drugs and dietary changes. GW
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Using the Microbiome to Treat Disease
Hello. I am Dr David Johnson, professor of medicine and chief of gastroenterology at Eastern Virginia Medical School in Norfolk, Virginia.
I recently edited a book on the human microbiome's role in health and disease, and would like to share with you what I have learned during that process—chiefly, a provocative new way of looking at the human microbiome as an adjunctive, if not a primary treatment, for a variety of diseases.
Dietary Influence on the Microbiome
It is well known that the gut serves as the largest immune system in the body. Recent research, however, has extended our understanding to the crosslink between gut immunogenicity and the host microbiome, as well as the subsequent effect this may have on a broader range of disease activities. The focus of this talk is on how exactly existing diet and potential modifications to it may influence these effects.
A study in germ-free mice has shown that the gut can be humanized with human gut flora and has demonstrated that switching from a plant-based to a Western-based high-fat and -sugar diet causes distinct shifts in the microbiome.[1] Such shifts can occur very rapidly. A subsequent study in humans has shown that the transformation of the gut microbiome can occur by dietary effect within 1 day.[2] It has therefore become a prominent question how much of a role bacterial flora play in systemic diseases, rather than simply in the day-to-day processing of the food groups that we eat.
There has also been a growing recognition that selected dietary intake may favorably increase the human microbiome through what is called a prebiotic effect.[3,4] "Prebiotics" is a general term referring to the chemicals that induce the growth and/or activity of commensal microorganisms (bacteria or fungi) and their contribution to their host's well-being. The most common example is found in the gastrointestinal (GI) tract, where prebiotics can alter the distribution of the organisms in the gut microbiome. A prebiotic then confers healthful benefits upon the host while not necessarily emphasizing one bacterial group over another.
Risk for Cancer
When considering the models where the microbiome may have a more prominent role than previously thought, the first area that comes to mind is cancer.
GI Cancers
The majority of our microbiome's diversity resides in the colon. A recent study has linked certain pathogenic bacteria with the development of colorectal cancer.[5] The current thought is that selected microbiomes can mediate a chronic inflammatory environment, which contributes to the progression of colorectal cancer.
The incidence of cancer in rural native Africans is lower compared with African Americans, something that has been attributed to a higher amount of indigestible polysaccharides in the diet of the former.[5] The role of diet in the adenoma-carcinoma sequence is therefore of particular interest. Undigested polysaccharides passing into the gut, primarily as dietary fiber, are metabolized by the microbiome into short-chain fatty acids. These are then converted into acetate, propionate, and butyrate, the latter two of which inhibit intracellular histone deacetylases. These in turn down regulate the proinflammatory cytokines (interleukin [IL] 6 and 12, in particular) and induce differentiation of T cells into regulatory T cells. In total, this process leads to a decrease in the inflammatory mediators in the colon.[5]
An individual's diet and unique microbiome are therefore thought to influence the proinflammatory state of the colon via both immunologic and metabolite-mediated mechanisms, potentially contributing to the progression of the adenoma-carcinoma sequence in colon cancer. This underlines the importance of fiber for colon cancer prevention.
Conversely, a high-fat diet has been shown to promote small-bowel cancers. In a study[6] where mice were given a high-fat diet, researchers were able to demonstrate an acceleration to small-bowel cancer in the KRAS expression mouse model. Further analysis[6] showed that performing a fecal transplant from the KRAS high-fat diet mice into healthy KRAS mice induced the latter to develop small-bowel cancer. Importantly, the researchers could decrease the cancer risk in these mice by transforming the microbiome through the use of antibiotics.
Breast Cancer
Diet and microbiome are also postulated to influence the course of breast cancer, which 1 out of 7 women in the United States are at risk of developing. It is thought that this disease develops through bacterial-mediated metabolism of estrogen and the microbiome-dependent maturation of T cells. There is an abundance of short-chain fatty acids in the high-fiber diet that increase a number of helpful bacteria (eg, Bacteroides) in the gut microbiome. These microbiomes metabolize ligands in the diet into potent phytoestrogens that have been shown to inversely affect the risk for breast cancer.[7]
In contrast, estrogen is a major hormonal growth promoter of breast cancer that is conjugated in the liver and secreted in the bile. The microbiome, however, is capable of deconjugating this estrogen and increasing its reabsorption. Once again, evidence shows that breast cancer risk may be diminished with a high-fiber, low-fat diet.[7]
Inflammatory Bowel Disease
There has been a growing focus on the impact that dietary influences can have on inflammatory bowel disease, although the causal relationship remains somewhat unclear.
Mice deficient in IL-10, an anti-inflammatory cytokine, have been shown to develop spontaneous colitis due to T-helper cell activation. Colitis is prevented, however, when the mice are reared in a germ-free environment, which eliminates the role of the gut microbiome. When these mice are then exposed to specific gut flora, they can experience a reinduction of colitis, suggesting the important role the microbiome plays. In addition, when these mice are fed a high-fat diet, you can induce small intestinal inflammation.[8]
This has relevance for our patients with Crohn disease, in whom a decrease in certain bacteria (eg, Bacteroides) can be demonstrated and then reversed with the use of antibiotics. This lends support to our use of antibiotics in Crohn patients in order to shift the microbiome.
It is known that short-chain fatty acids have an immunomodulatory effect that can decrease the amount of certain inflammatory cytokines, which has been shown in a mouse model study with colitis.[9] More recent data[10] have looked at the dietary effects of the aryl hydrocarbon receptor (AHR), which functions as an anti-inflammatory and detoxification pathway in the gut. There are a variety of exogenous and AHR ligands, ranging from fruits and vegetables to bacterial metabolites, that have been shown to be downregulated on intestinal biopsies in patients with IBD. Incubation of the biopsies with the AHR agonist induced IL-22 production. This collectively suggests that induction of AHR by dietary means may have a profound effect. In a murine model study,[11] AHR deficiency leads to disrupted intraepithelial lymphocytes that causes an increased immune cell activation and mucosal epithelial damage.
Another indirect dietary source for these AHR ligands is tryptophan, which is found in fish and vegetables. There is evidence that tryptophan is metabolized by gut Lactobacillus to an AHR ligand in the gut, with such activation altering the microbiome in ways that enhance the mucosal inflammatory protection and resistance against bacterial translocation.[12]
This has encouraged me to recommend the consumption of fish and vegetables to my patients with inflammatory bowel disease. We certainly think that there is a role for AHR in this process, so perhaps it is true that we are what we eat.
Transmissible Obesity
These findings are also applicable to metabolic syndrome and the obesity epidemic.
The transfer of the gut microbiome from genetically obese mice to germ-free mice can increase the body mass index of the latter very quickly, suggesting that the gut microflora can dictate the phenotype of obesity in a transmissible fashion. The bacterial degradation of certain indigestible polysaccharides has also been established and is crucial to the generation of short-chain fatty acids and metabolites. These metabolites regulate gut hormones that control satiety by binding to free fatty acid receptors, in particular free fatty acid 2 and 3 receptors, which are responsive to gut microbiome manipulation.[13]
The Real Risk of Artificial Sweeteners
Interesting data[14] also exist that are challenging our understanding of the use of artificial sweeteners. Findings indicate that artificial sweeteners can actually induce glucose intolerance via alterations in the gut microbiome, an observation that has been shown now in both mice and humans. In non-genetically altered mice, both lean and high-fat diet groups develop marked glucose intolerance compared with controls after consuming a variety of artificial sweeteners. Once again, treatment with antibiotics eliminated this, thereby fulfilling the postulate of causality and reversal by antibiotics.
A notable shift in the microbiome has been observed here, particularly via an overrepresentation of Bacteroides species. Therefore, using artificial sweeteners in patients with a proclivity toward diabetes or actual diabetes as an adjunct to decrease glucose absorption may be paradoxical, given the risk that we can adversely affect the gut microbiome.
Non-alcoholic Fatty Liver Disease
Targeted manipulation of the microbiome has also shown promise for non-alcoholic fatty liver disease. A variety of things present in the gut are associated with non-alcoholic fatty liver disease. Certain diet inductions of non-alcoholic fatty liver disease have been evident, most notably methacholine- and choline-deficient diets. These too are reversible when mice are given antibiotics, providing more evidence that upregulation of cytokines may be induced by certain diets.[15] Low-fat diets have proven to have a particularly positive effect in this population, which has led me to recommend them to my patients with non-alcoholic fatty liver disease, alongside weight loss and diabetic control.
Improving Artery Health
The traditional high-fat, low-fiber Western diet has been linked to multiple inflammatory diseases outside the GI tract, and is well known to be a significant risk factor for atherosclerosis. Several findings have identified this association.
Phosphorylcholine metabolites produced by the gut microbiome promote cardiovascular disease. Foods rich in phosphorylcholine include eggs, milk, liver, red meat, poultry, fish, and shellfish. There are also identifiable links to subsequently exposed myocardial infarction patients and the presence of a significant risk factor called trimethylamine N-oxide (TMAO). Phosphorylcholine is converted to trimethylamine (TMA) by the gut microflora, which is then metabolized to TMAO. This is present as an indirect biomarker in patients with cardiovascular disease, with TMAO activation shown to decrease after treatment with antibiotics in human patients.
When compared with a Western diet, a Mediterranean diet, which is particularly low in red meat consumption, is known to decrease the risk for cardiovascular disease. The gut flora metabolism of L-carnitine, an abundant nutrient in red meat, produced TMAO-accelerated atherosclerosis in both mice and humans. This establishes L-carnitine as a type of TMA that is also converted to TMAO by the gut microbiome. This is increased by what we see as an expression of certain bacteria in the gut. With regard to atherosclerosis, there is a strong rationale for pushing patients toward the Mediterranean diet, low in the production of TMAOs.
Asthma and Allergies
In the past several decades, there has been a dramatic increase in chronic inflammatory diseases, such as asthma and allergies. The association between asthma and the potential for gut immunoregulation is particularly striking.
Recent studies[16,17] have identified dysbiosis in both the gut and the pulmonary microbiome in asthma, with subsequent bacterial induction palliating these symptoms. There is evidence that shifting the microbiome in these patients can lead to disease improvement. The overriding concept is that through dietary fiber-increased short-chain fatty acid production and shifting to a certain subspecies of Bacteroides, it may be possible to decrease the activation of antigens promoting the upregulation of asthma. It therefore may be beneficial to move such patients to a low-fat diet, in turn shifting the microbiome and bacterial balance with a significant potential benefit.
Interestingly, researchers studying this approach in asthma patients have analyzed the tight junctions and found that bacterial translocation was enhanced more in the high-fat diet.[17] This suggested yet again that translocation up regulates immunogenicity, and that asthma patients can benefit from a low-fat, high-fiber diet.
Challenging Modern Treatment Concepts
What I have sought to do with this presentation is not to provide you with simple answers, but rather to encourage you to look at diet and its influence on the gut microbiome in an out-of-the-box fashion. The diseases I've mentioned here are very commonly treated with medications. However, we need to also start considering diet as a potential adjunctive, if not primary, treatment for many of these diseases. This would take us beyond statins for atherosclerotic patients or tumor necrosis factor (TNF) inhibitors for our IBD patients, and provide us with more comprehensive possibilities in the way that we look at these disease states.
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References
1. Turnbaugh PJ, Ridaura VK, Faith JJ, Rey FE, Knight R, Gordon JI. The effect of diet on the human gut microbiome: a metagenomic analysis in humanized gnotobiotic mice. Sci Transl Med. 2009;1:6ra14.
2. David LA, Maurice CF, Carmody RN, et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature. 2014;505:559-563. Abstract
3. Gibson GR, Probert HM, Loo JV, Rastall RA, Roberfroid MB. Dietary modulation of the human colonic microbiota: updating the concept of prebiotics. Nutr Res Rev. 2004;17:259-275. Abstract
4. Slavin J. Fiber and prebiotics: mechanisms and health benefits. Nutrients. 2013;5:1417-1435.
5. Louis P, Hold GL, Flint HJ. The gut microbiota, bacterial metabolites and colorectal cancer. Nat Rev Microbiol. 2014;12:661-672. Abstract
6. Schulz MD, Atay C, Heringer J, et al. High-fat-diet-mediated dysbiosis promotes intestinal carcinogenesis independently of obesity. Nature. 2014;514:508-512. Abstract
7. Shapira I, Sultan K, Lee A, Taioli E. Evolving concepts: how diet and the intestinal microbiome act as modulators of breast malignancy. ISRN Oncol. 2013:2013;693920.
8. Leone VA, Cham CM, Chang EB. Diet, gut microbes, and genetics in immune function: can we leverage our current knowledge to achieve better outcomes in inflammatory bowel diseases? Curr Opin Immunol. 2014;31:16-23. Abstract
9. Smith PM, Howitt MR, Panikov N, et al. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science. 2013;341:569-573. Abstract
10. Fukumoto S, Toshimitsu T, Matsuoka S, et al. Identification of a probiotic bacteria-derived activator of the aryl hydrocarbon receptor that inhibits colitis. Immunol Cell Biol. 2014;92:460-465. Abstract
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