What Happens when the Microbiome Goes Awry?
Dysbiosis of gut bacterial communities can cause disease. Dysbiosis means a disruption of the healthy microbe population towards a less-diverse and less-stable microbiome that allows overgrowth of potentially damaging and disease-causing bacteria. Dysbiosis can be caused not only by detrimental organisms but also by aging, smoking, intake of antibiotics and influences from the diet (1). Gut dysfunction is associated with symptoms that can be severe such as bloating, abdominal pain and diarrhea but, more importantly, is also linked to increased susceptibility to a substantial variety of diseases (2).
Research is finding links between many cancers and the gut bacterial community.
A 2019 study found that men with prostate cancer had less diversity in bacterial species than men without cancer (3).
Short-chain fatty acids produced by a healthy microbiome inhibit inflammation and regulate production of immune cells so that cancer is suppressed but, in dysbiosis, the overgrowth of harmful bacteria in the microbiome can produce substances such as secondary bile acids that promote the initiation and growth of colorectal cancer (1,2,4).
Research has also discovered that the general inflammation caused by gut dysbiosis can encourage metastases (spread) of cancers such as breast cancer (5).
These associations do not ascertain cause and effect, however ongoing study should shed more light on these relationships.
Obesity is characterized by excess accumulation of body fat and low-grade systemic inflammation. Lifestyle behaviours are the underlying cause of weight gain but there is also a link between changes in the microbiome and obesity. Diet choices have a profound impact on the composition of the gut microbiome and different dietary patterns are associated with distinct bacterial species present in the intestine. Dietary-induced changes in gut microbes can occur after only a few days and are reversible. (6)
An obesity-producing diet tends to lower species diversity, ushering in substantial changes in both the health of the intestines and their function. Studies show that the microbes that thrive in the gut of an obese person not only have increased capability to extract energy from food but also cause a rise in inflammation and can trigger breakdown of the gut barrier allowing toxins to enter the bloodstream. The result is an increase in body weight; escalation of lipid levels in the bloodstream; a rise in insulin resistance; and an upsurge of inflammation throughout the whole body (6). On the other hand, healthier diets are associated with a high diversity of bacterial species in the gut and an improved microbiome.
Feeding our gut bacteria their optimal food can help us to prevent obesity. High fiber foods such as legumes (beans, chickpeas, lentils) and whole-grain bread are examples of foods that help our beneficial bacteria prosper and allow them to create short-chain fatty acids. The trick here is the amount of time it takes for foods to travel the long distance from the mouth to the end of the human digestive tract. It can take hours, maybe even a whole day, before a food will reach the colon where the majority of our gut bacteria live. It is not until then that those little creatures begin the fermenting process and the benefit for the human host begins. Just the fact that fermentation is happening in the colon leads to satiation and reduced hunger in the human host with the result that the amount of food eaten the rest of the day and even into the next day is significantly less. This is called the “second meal effect” (7,8). Recent studies have pinpointed the short-chain fatty acid propionate, which is produced through fermentation by gut bacteria, as one of the major constituents that bring about reduced appetite in meals subsequent to those containing high fiber (9,10). One study noted that energy intake was decreased by 14% at a buffet meal following a previous meal that was rich in fiber (9).
It has been observed that, even when people eat exactly the same foods, their blood sugar level can vary greatly. In a blinded randomized controlled dietary intervention, blood sugar levels changed depending on the microbes making up the gut microbiome (11).
Alterations of the gut microbiome are associated with both type-1 and type-2 diabetes. Impairment in the intestinal barrier and variations in immunity promote the development of type-1 diabetes while low-grade inflammation is one of the most important factors in the progression of type-2 diabetes. Obesity caused by a high-fat diet only adds to the problem with increases in inflammation pushing towards increased resistance to insulin. (12,2).
A study on infants genetically predisposed to developing type-1 diabetes showed that a marked drop in gut microbiome species diversity along with an increase in inflammation-favouring microbes occurred just before the onset of the disease (13).
The liver is in close contact with the intestinal tract and exposed to its microbiota and their metabolites and a disrupted gut microbiome has long been associated with liver disease (14). Dysbiosis in the gut causes inflammation in the intestines, breakdown of the thin intestinal barrier and an increase in toxic products produced by the microbes dominating the disturbed environment in the intestines. These factors contribute to the development of liver diseases such as non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease and cirrhosis (15) and hasten the progression of NAFLD to its more severe form, non-alcoholic steatohepatitis (NASH) (16).
The microbes in the gut can affect levels of lipids in the bloodstream. A 2015 study found that the species that make up the gut microbiome influence changes in Body Mass Index (BMI) and blood levels of triglycerides and high-density lipoproteins (HDL-cholesterol) making the gut microbiome a significant component in the development of cardiovascular disease (17).
Other studies have shown that patients with congestive heart failure commonly have overgrowth of dangerous microorganisms including Candida species in their intestines. The amount of inflammation that results along with the extent of the breakdown of the intestinal barrier is linked to the seriousness of their disease (18).
The most interesting link between diet, the microbiome and cardiovascular disease was discovered only a very few years ago when a molecule called trimethylamine (TMA) was linked to the buildup of cholesterol in the atherosclerotic plaques in our arteries and a resulting increase in the risk of heart attack, stroke and death. Food choices have an enormous impact on the species of microorganisms that make up the gut microbiome. Consumption of choline-containing foods such as eggs, milk and meats (including poultry and seafood), and carnitine-containing foods such as meat, fish, poultry and milk have been found to encourage the growth of bacteria that thrive on choline and carnitine, producing TMA during their digestion of these nutrients (19,20). TMA is converted into trimethylamine N-oxide (TMAO) in the liver and ends up in the bloodstream. Unfortunately, TMAO is toxic to the blood vessels and promotes escalated atherosclerotic plaque build-up in the arteries. In fact, the level of L-carnitine in the bloodstream along with high TMAO levels can accurately predict risk of cardiovascular disease and major adverse cardiac events. Vegans and vegetarians eat diets low in both choline and carnitine and consequently their gut microbiomes do not contain TMA-producing bacteria. The human body can produce sufficient carnitine to meet health needs (21). Plant-based foods contain small amounts of choline, enough to obtain the amount necessary for health but not enough to cause the production of TMA (22,23,2).
Diseases of the Gut
Inflammatory bowel diseases (IBD) such as ulcerative colitis and Crohn’s disease are at least partly attributed to a damaged immune response due to dysbiosis of the gut microbiome. Their symptoms of bloating, cramps and abdominal pain come from the excess of gas and toxic products produced by harmful microbes in the gut. Microbiomes of people with IBD show high instability and they fluctuate away from a healthful state more than those of healthy people. Such variations are associated with flare-ups of IBD. Research is ongoing to discover whether the microbiome changes are the cause or the result of these diseases (24,25,26).
Diseases of the Brain and Central Nervous System
The gut is in almost constant contact with the brain and central nervous system through the gut-brain axis of which the vagus nerve is a part. This communication system works in two directions although most messages originate in the gut and travel to the brain. Evidence is emerging that, through this message system, the gut microbiome can influence cognition, emotion and behavior and contribute to mental illness (27). Changes in the gut microbiota can indirectly influence the central nervous system through effects on the immune system. But direct signals regarding the relative state of gut health can also influence mood, producing feelings of anxiety or well-being (28). For instance, in major depressive disorder, healthier bacterial species in the gut are reduced and potentially harmful species are increased. It is not as yet clear whether this is a cause or a result of the mental illness (27,29).
Serotonin is a chemical messenger that is important for proper function of the digestive system. However it is also the key neurotransmitter in the gut-brain axis and a natural mood stabilizer and its presence is associated with better mood and reduced depression. Gut microbiota appear to control serotonin production. In fact, the majority of the serotonin needed for the human body is produced in the gut (30).
Depression is also linked to chronic, low-grade inflammation which can be the result of altered gut function. Inflammation can play a role in psychiatric disorders as well, such as bipolar disorder, schizophrenia and post-traumatic stress disorder (31).
Other neurological conditions are also associated with an unhealthy gut. It has been suggested that misfolding of proteins in the brain may be the cause of disorders such as multiple sclerosis (MS), autism spectrum disorders, and Parkinson’s disease. Inflammation originating in the gut may be a cause of protein misfolding (32,33). In addition, patients with MS and Parkinson’s disease show development of antibodies that point to increased intestinal permeability (34,35). Autistic children also appear to have less diverse gut microbiomes (2).
Cognitive decline and Alzheimer’s Disease are diseases of aging. Simply growing older can induce dysbiosis of the microbiome and the disturbed immune function and increased oxidative stress that seem to play a part in the development of these conditions. Animal studies have discovered an association between a high-fat diet and cognitive decline (36,37). In addition, proper functioning of the gut is necessary to extract the polyphenols, antioxidants and unsaturated fats from the diet that offer protection to neuronal cells from the ravages of aging (27).
Where do we stand today with our microbiome?
An interesting paper was published by two eminent microbiome researchers Justin and Erica Sonnenburg in June, 2019 (38). It suggests that the epidemic of chronic lifestyle-related illnesses plaguing humans today comes down to a disconnect between us and our microbiome. Human beings and their microscopic inhabitants evolved together in mutual benefit over millions of years of evolution. Then along came the era of industrialization. The advent of processed food with its large reduction in fiber content; increasing consumption of animal-based foods; and the transformation of jobs from active pursuits such as farming and fishing to indoor work performed sitting at a desk were huge changes in lifestyle.
Gut bacteria, with their quick replication and ability to transfer DNA directly to another bacterium, have managed to adapt much more quickly to these changes than the human genome which generally requires several generations to induce modifications. Thus the gut microbiota of the industrialized societies of today are very different than those of our ancestors. Bacteria that once helped us deal with digestion of fiber are now being pushed out by other bacterial species that thrive on substrates such as mucous and animal protein. Add to this the fact that the antibiotics and other medications we now count on are causing deterioration of our microbiomes by destroying the species diversity that is so important for our health (39,40). Our altering microbiome is trying to keep pace with the changes in its environment but, in doing so, it has become incompatible with our genes and our biology and has left us vulnerable to the chronic diseases of our day and age. The Sonnenburgs suggest that human evolution may eventually be successful in producing genetic changes that will protect us from the devastating chronic diseases that we are now facing. However, at this point, we humans may be in conflict with our microbiomes (38).
Though this theory sounds ominous, we can remain hopeful. There are easy steps that can be taken immediately to encourage the tiny inhabitants of our intestines to return to activities that promote a more symbiotic relationship with them. Avoiding processed foods, reducing our intake of animal protein, eating whole unprocessed plant-derived foods and cutting down on antibiotic use will all help.
Still to come…..
In the next two parts of this article on the gut microbiome we will look at how to encourage your healthiest microbiome.
1 Zitvogel, L., Galluzzi, L., Viaud, S., Vétizou, M., Daillère, R., Merad, M., Kroemer, G. Cancer and the gut microbiota: An unexpected link. Sci Transl Med. 2015; 7(271):271ps1.
2 Zhang, Y.-J., Li, S., Gan, R.-Y., Zhou, T., Xu, D.-P., Li, H.-B. Impacts of Gut Bacteria on Human Health and Diseases. Int J Mol Sci. 2015 Apr; 16(4): 7493–7519.
3 Ma, X., Chi, C., Fan, L., Dong, B., Shao, X. et al. The Microbiome of Prostate Fluid Is Associated With Prostate Cancer. Front Microbiol. 2019; 10: 1664.
4 Louis, P., Hold, G.L, Flint, H.J. The gut microbiota, bacterial metabolites and colorectal cancer.
Nat Rev Microbiol. 2014 Oct;12(10):661-672.
5 Rosean, C.B., Bostic, R.R., Ferey, J.C.M., Feng, T.-Y., Azar, F.N. et al. Preexisting Commensal Dysbiosis Is a Host-Intrinsic Regulator of Tissue Inflammation and Tumor Cell Dissemination in Hormone Receptor–Positive Breast Cancer. Cancer Res 2019;79(14):3662–3675.
6 Patterson, E., Ryan, P.M., Cryan, J.F., Dinan, T.G., Ross, R.P., Fitzgerald, G.F., Stanton, C. Gut microbiota, obesity and diabetes. Postgrad Med J. 2016 May;92(1087):286-300.
7 Ibrügger, S., Vigsnaes, L.K., Blennow, A., Škuflić, D., Raben, A., Lauritzen, L., Kristensen, M. Second meal effect on appetite and fermentation of wholegrain rye foods. Appetite. September 2014; 80:248-256.
8 Mollard, R.C., Wong, C.L., Luhovy, B.L., Cho, F., Anderson, G.H. Second-meal effects of pulses on blood glucose and subjective appetite following a standardized meal 2 h later. Appl Physiol Nutr Metab 2014;39:849-851.
9 Byrne, C.S., Chambers, E.S., Morrison, D.J., Frost, G. The role of short chain fatty acids in appetite regulation and energy homeostasis. Int J Obes (Lond). 2015 Sep; 39(9): 1331–1338.
10 Byrne, C.S., Chambers, E.S., Alhabeeb, H., Chhina, N., Morrison, D.J., Preston, T., Tedford, C., Fitzpatrick, J., et al. Increased colonic propionate reduces anticipatory reward responses in the human striatum to high-energy foods. Am J Clin Nutr. 2016 Jul; 104(1): 5–14.
11 Zeevi, D., Korem, T., Zmora, N., Israeli, D., Rothschild, D. et al. Personalized Nutrition by Prediction of Glycemia Responses. Cell. 2015 Nov 19;163(5):1079-1094.
12 Sharma, S., Tripathi, P. Gut microbiome and type 2 diabetes: where we are and where to go? Journal of Nutritional Biochemistry. 2019;63:101-108.
13 Kostic, A.D., Gevers, D., Siljander, H., Vatanen, T., Hyötyläinen, T. et al. The dynamics of the human infant gut microbiome in development and in progression toward type 1 diabetes. Cell Host Microbe. 2015 Feb 11;17(2):260-273.
14 Tilg, H., Cani, P.D., Mayer, E.A. Gut microbiome and liver diseases. Gut. 2016. Gut 2016;65(12):2035-2044.
15 Schnabl, B., Brenner, D.A. Interactions Between the Intestinal Microbiome and Liver Diseases.
Gastroenterology. 2014 May; 146(6): 1513–1524.
16 Henao-Mejia, J., Elinav, E., Jin, C., Hao, L., Mehal, W.Z., Strowig, T., Thaiss, C.A., Kau, A.L., Eisenbarth, S.C., Jurczak, M.J., Camporez, J.P., Shulman, G.I., Gordon, J.I., Hoffman, H.M., Flavell, R.A. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature. 2012 Feb 1;482(7384):179-185.
17 Fu, J., Bonder, M.J., Cenit, M.C., Tigchelaar, E.F., Maatman, A., Dekens, J.A. et al. The Gut Microbiome Contributes to a Substantial Proportion of the Variation in Blood Lipids. Circ Res. 2015 October; 117(9):817-824.
18 Pasini, E., Aquilani, R., Testa, C., Baiardi, P., Angioletti, S., Boschi, F., Verri, M., Dioguardi, F. Pathogenic Gut Flora in Patients With Chronic Heart Failure. JACC: Heart Failure. March 2016; 4(3): DOI: 10.1016/j.jchf.2015.10.009
22 Koeth, R.A., Wang, Z., Levison, B.S., Buffa J.A., Org, E., et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med. 2013 May; 19(5): 576–585.
23 Aron-Wisnewsky, J., Clément, K. The gut microbiome, diet, and links to cardiometabolic and chronic disorders. Nat Rev Nephrol. 2016 Mar;12(3):169-181.
24 Halfvarson, J., Brislawn, C.J., Lamendella, R., Vázquez-Baeza, Y., Walters, W.A. et al. Diseases of the Gut:. Dynamics of the human gut microbiome in inflammatory bowel disease. Nat Microbiol. 2017 Feb 13;2:17004.
25 Kennedy, P.J., Cryan, J.F., Dinan, T.G., Clarke, G. Irritable bowel syndrome: A microbiome-gut-brain axis disorder? World J Gastroenterol. 2014 Oct 21; 20(39): 14105–14125.
26 Distrutti, E., Monaldi, L., Ricci, P., Fiorucci, S. Gut microbiota role in irritable bowel syndrome: New therapeutic strategies. World J Gastroenterol. 2016 Feb 21; 22(7): 2219–2241.
27 Rogers, G.B., Keating, D.J., Young, R.L., Wong M.-L., Licinio, J., Wesselingh, S. From gut dysbiosis to altered brain function and mental illness: mechanisms and pathways. Mol Psychiatry. 2016 Jun; 21(6): 738–748.
28 Forsythe, P., Bienenstock, J. Kunze, W.A. Vagal pathways for microbiome-brain-gut axis communication. Adv Exp Med Biol. 2014;817:115-133.
29 Jiang, H., Ling, Z., Zhang, Y., Mao, H., Ma, Z., Yin, Y. et al. Altered fecal microbiota composition in patients with major depressive disorder. Brain Behav Immun. 2015 Aug;48:186-194.
30 O’Mahony, S.M, Clarke, G., Borre, Y.E., Dinan, T.G., Cryan, J.F. Serotonin, tryptophan metabolism and the brain-gut-microbiome axis. Behav Brain Res. 2015 Jan 15;277:32-48.
31 Berk, M., Williams, L.J., Jacka, F.N., O’Neil, A., Pasco, J.A., Moylan, S., Allen, N.B., Stuart, A.L., Hayley, A.C., Byrne, M.L., Maes, M. So depression is an inflammatory disease, but where does the inflammation come from? BMC Med. 2013 Sep 12;11:200.
32 Soto, C. Unfolding the role of protein misfolding in neurodegenerative diseases. Nat Rev Neurosci. 2003; 4(1):49-60.
33 Ochoa-Repáraz, J. Mielcarz, D.W., Begum-Haque, S., Kasper, L.H. Gut, bugs, and brain: role of commensal bacteria in the control of central nervous system disease. Ann Neurol. 2011; 69(2): 240-247.
34 Qin, L., Wu, X., Block, M.L., Liu, Y., Breese, G.R., Hong, J.S., Knapp, D.J., Crews, F.T. Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia. 2007; 55(5):453-462.
35 Camara-Lemarroy, C.R., Metz, L., Meddings, J.B., Sharkey, K.A., Wee Yong, V. The Intestinal Barrier in Multiple Sclerosis: Implications for Pathophysiology and Therapeutics. Disclosures Brain. 2018;141(7):1900-1916.
36 Qiao, Y., Sun, J., Ding, Y., Le, G., Shi, Y. Alterations of the gut microbiota in high-fat diet mice is strongly linked to oxidative stress. Appl Microbiol Biotechnol. 2013; 97(4):1689-1697
37 Deschamps, V., Barberger-Gateau, P., Peuchant, E., Orgogozo, J.M. Nutritional factors in cerebral aging and dementia: epidemiological arguments for a role of oxidative stress. Neuroepidemiology. 2001; 20(1):7-15.
38 Sonnenburg, E.D., Sonnenburg, J.L. The ancestral and industrialized gut microbiota and implications for human health. Nat Rev Microbiol. 2019 Jun;17(6):383-390.
39 Panda, S., El khader, I., Casellas, F. et al. Short-Term Effect of Antibiotics on Human Gut Microbiota. PloS ONE. 2014;9(4):e95476.
40 Maier, L., Pruteanu, M., Kuhn, M. et al. Extensive impact of non-antibiotic drugs on human gut bacteria. Nature. 2018; 555: 623–628.
Leave a Comment