• The gut microbiome is a versatile organ that is affected by various factors, particularly diet and environmental exposures, and it can contribute to health or illness, depending on its composition.
• The root cause of many chronic conditions and symptoms stems from inflammation, which is modulated by the gut microbiome.
• Diet, food choices, and method of food preparation can affect the gut microbiome and influence disease.
• Environmental exposures and food chemicals can contribute to dysbiosis and have an adverse effect on health.
The gut microbiome has taken center stage with regard to understanding disease and what causes chronic medical conditions and symptoms. More than 100 trillion microorganisms coexist within each of us. They can affect our health, and we can modulate their existence by our actions and the things we are exposed to. The gut microbiome, composed of various fungi, viruses, and bacteria, is a vital part of the human host. The gut flora provide vitamins and short-chain fatty acids and play a significant role in the intestinal immune system and inflammation.46
In normal, healthy intestinal mucosa, tight junctions seal the spaces between cells and form ion- and size-selective gateways. Various parts of the gastrointestinal tract allow different degrees of permeability through these junctions. A wide variety of triggers can cause increased intestinal permeability, which can lead to mucosal inflammation, chronic symptoms, and various medical conditions. The gut microbiome is one of the layers of defense in the intestinal tract that contributes to the intestinal barrier, and it helps determine what can cross the epithelium by usual and regulated means.11
A significant amount of research is being done to better understand how changes to the gut microbiome can modulate disease. Epigenetic changes are thought to occur in response to a wide variety of factors, including weight, physical activity, nutrition, and environmental and emotional exposures. The microbiome can affect these factors, and vice-versa. Low-molecular-weight substances produced by the gut microbiota can interact with the cellular environment, affecting the signaling pathways and gene expression that regulate cell death, inflammation, and differentiation.54 It is nearly impossible to have a discussion on genetics and health and not include the gut microbiome. This is a rapidly growing area in medicine and research. Understanding the gut microbiome and its interaction with the epigenome and diseases will help physicians to improve disease prevention and treatment.
Chopra and Tanzi18 eloquently described how high-fat, high-carbohydrate diets can contribute to intestinal permeability and allow endotoxin and other harmful substances to cross into the bloodstream and provoke an immune response that results in inflammation. This proinflammatory state is thought to contribute to insulin resistance and obesity, even in the face of normal caloric intake.18
Changing the diet to include more healthy foods, such as fiber, fruits, and vegetables, can intervene in the process by cultivating a more favorable gut microbiome. This has implications for management of a wide variety of conditions, including obesity, diabetes, heart disease, allergy, and autoimmune disorders. The gut microbiota can produce substances such as vitamins that are favorable to health, but they can also produce harmful substances such as toxic metabolites. The mucous barrier of the intestinal tract works together with a diverse microbiome to favor a strong proportion of beneficial bacteria and to keep the harmful bacteria from causing disease.20 A healthy diet is an excellent way of maintaining a robust and diverse microbiome.
It is not just diet and nutrition that can modulate the gut microbiome and have an impact on health. Environmental toxins, exposures, and stressors can influence the gut microbiota, and it seems prudent to include the gut microbiome when assessing how environmental factors can affect human health.22 For example, antibiotic use early in life can alter the gut microbiome and is associated with later obesity.70 One study demonstrated how seasonal changes can contribute to shifts in the composition of the gut microbiome in a special population of communal-living people known as the Hutterites in North America. It was postulated that dietary changes due to the availability of fresh produce during a particular season contributed to changes in the gut microbiome. Other factors such as outdoor activity, sun exposure, and temperature should also be considered, although they were not directly measured.57
Although pesticide exposure was not considered or evaluated in the Hutterite study, there are data regarding the importance of considering this issue when evaluating changes in the gut microbiome. One experiment with female rats showed that maternal exposure to chlorpyrifos, an insecticide that can cross the placenta, resulted in several effects in newborn rats that lasted into adulthood, including microbial dysbiosis, alteration of nutrient absorption, changes in the intestinal barrier, and stimulation of the immune system.19 Although many factors can influence the gut microbiome during a lifetime, exposure to pesticides is a particularly important one because the impact can have both short-term and longer-lasting effects.
This information highlights the significance of the gut microbiome and factors that can influence it. Eating an appropriate diet and avoiding certain types of environmental exposures can improve the composition of the gut microbiome, thereby modulating inflammation and the incidence of certain diseases and conditions. Understanding these influences on the gut microbiota is a key concept that can help guide clinicians when counseling patients about following a healthy diet and lifestyle.
The gut microbiome is versatile. Many factors can influence the composition of the gut microbiome on a daily basis. The diversity of bacterial species in the gut microbiome is affected by changes in diet through competition for substrates and tolerance of intestinal conditions.28 Dysbiosis, an imbalance of the flora in the gut microbiome, has been associated with many different conditions (Box 6.1), including, but not limited to, diabetes, colon cancer, colon polyps, inflammatory bowel disease, and obesity.72
Data support the influence of the gut microbiome on mood and behavior,53 neurologic conditions such as Parkinson disease,49 and coronary artery disease.8,30,75 Research has also demonstrated the influence of the microbiome on a wide array of other medical conditions. The American Heart Association has stated that the gut microbiome is a potential risk factor for diabetes, obesity, and heart disease because microbial dysbiosis can alter intestinal permeability and induce systemic inflammation.24 The statement also emphasized the significant impact of diet on the composition of the gut microbiome. For example, bacterial species from the phylum Tenericutes and the genus Desulfovibrio have been associated with the production of trimethylamine-N-oxide (TMAO), a metabolite implicated in cardiovascular risk that is produced as a result of metabolic reactions driven by the microbes when they encounter dietary components such as carnitine and phosphatidylcholine.24 Although much research is still needed, the evidence on the importance of diet and nutrition in human health is compelling. Understanding how diet and proper nutrition influence this most important “organ” in the human body could have a substantial impact on the clinical course of patients with many different conditions.
Plant nutrients (i.e., phytonutrients) are effective in preventing infection by pathogenic organisms. They can be taken as supplements or integrated into a well-balanced diet. A recent study demonstrated how anethole, carvacrol, cinnamaldehyde, eugenol, capsicum oleoresin, and garlic extract lead to changes in gene expression in the colon. In particular, eugenol, which can be found in cloves, nutmeg, cinnamon, and basil, stimulates the inner mucus layer, a key barrier to microbes in the colon. The investigators thought that this occurred by means of “microbial stimulation” because there was an abundance of bacterial families in the order Clostridiales present. This change led to resistance of colonization by Citrobacter rodentium, which has pathogenic similarities to Escherichia coli.73
Lactobacillus supplementation has reduced inflammation and proteinuria associated with renal dysfunction in rats, suggesting that it can play a protective role against the progression of chronic kidney disease.76 Another study showed that rats that had segmented, filamentous bacteria as part of their gut microbiomes had improved immunity and resistance to Staphylococcus aureus pneumonia. The presence of this type of bacteria also led to increased levels of interleukin-22 (IL-22), which was also protective against severe staphylococcal pulmonary infection.29 The evidence supporting the effects of alterations in the gut microbiome in the setting of various diseases is growing.
One of the easiest ways to modulate the gut microbiome is through the diet. Including certain foods and nutrients in the diet to promote particular species of microbes can offer positive health effects. Prebiotics, which are nondigestible foods that provide nourishment for beneficial bacteria, and probiotics, which are supplements of beneficial microbes that can improve the microbial balance, can help to maintain good gut health. Nutritional supplements that combine prebiotics and probiotics are called synbiotics, and they are thought to work synergistically together to improve human health.75 Chapter 14 provides a comprehensive list of prebiotics and probiotics.
When an infant is born, the sterile gut of the fetus is colonized by the maternal gut microbiome from the genital tract and colon in addition to the birth environment. Commonly identified bacteria include Bifidobacterium, Ruminococcus, Enterococcus, Clostridium, and Enterobacter.54 There can be a substantial influence on the gut microbiome of the infant based on whether the delivery was vaginal or via cesarean section and whether the infant is breast fed or bottle fed. Maternal diet and infant nutrition play a role very early on in the establishment of a child’s gut microbiome, which can influence the child’s epigenome and predispose to conditions such as obesity and cardiovascular disease later in life.
The gut microbiome is dynamic. A diet that is high in fiber can produce more short-chain fatty acids in the colon. Butyrate, a short-chain fatty acid, can act as a chemotherapeutic agent.54 Alternatively, a diet high in fat and red meat can increase the risk of colon cancer and cardiovascular disease by means of N-nitroso compounds and heterocyclic aromatic amines. Bacteria digest the l-carnitine in red meat and convert it to toxic substances that can promote heart disease and other problems.54
The importance of the gut microbiome can not be overstated; researchers and clinicians continue to explore ways to influence the course of many chronic health issues facing patients today. The following sections review special topics related to the dietary influences on the gut microbiome, as well as the importance of nutrition on the gut microbiome for overall health.
Water is a vital part of the human diet and a critical route for chemical exposure. Millions of Americans drink water containing more than the recommended levels of arsenic (>10 µg/L). This problem largely reflects the lack of regulations regarding private wells. Diabetes, cardiovascular disease, and several malignancies have been associated with arsenic ingestion. In a study using mice, arsenic exposure contributed to a significant change in the gut microbiome which was strongly associated with changes in the flora-related metabolites that impact energy harvesting, short-chain fatty acid production, and adipogenesis.40 The specific composition of the gut microbiome has also been associated with susceptibility to toxins such as arsenic.39
One study found that although the levels of arsenic in water may not be enough to directly cause hepatotoxicity, low levels could contribute to sensitization to nonalcoholic fatty liver disease and enhance damage to the liver caused by a diet high in fat. However, supplementation with the prebiotic oligofructose contributed to changes in the gut microbiome that had protective effects in the liver when there was arsenic exposure.44 Oligofructose is part of a class of soluble fibers (i.e., inulin fiber) that are considered prebiotics. These studies demonstrate how dietary changes, such as including prebiotics, can modulate beneficial changes in the gut microbiome to protect against the detrimental effects of arsenic. They also remind us how drinking water containing toxins such as arsenic can alter the microbiome and lead to increased vulnerability to certain diseases.
Chlorinated water has been shown to change the gut microbiome, particularly by reducing Clostridium perfringens, Clostridium difficile, organisms of the family Enterobacteriaceae, and Staphylococcus species. These changes were associated with increased formation of colon tumors.61 This raises the point that some commensal flora play a role in tumor formation, and exposures to certain chemicals such as chlorine can alter the composition of the gut microbiome and influence this process.
Low-level cadmium exposure in water changes the composition of the gut microbiome. Exposure to cadmium may increase serum lipopolysaccharide levels and cause inflammation of the liver, which may subsequently lead to problems with energy homeostasis. When mice were exposed to low levels of cadmium for 10 weeks, they had increased levels of hepatic triacylglycerol and serum levels of free fatty acids and triacylglycerol.77
Summary of Water Contamination
Good health can depend one’s drinking water source. For example, emissions from nearby industries can impact the amounts of heavy metals in water. Arsenic has been found in more than one half of the hazardous waste sites proposed to be a part of the national priority list maintained by the Environmental Protection Agency (EPA). Approximately 2.3% of the U.S. population may have elevated urine levels of cadmium, and water is one of several sources of cadmium exposure.68 In January 2016, the water crisis in Flint, Michigan, was uncovered, and the public discovered that the city’s drinking water was contaminated with lead, a heavy metal that has toxic effects on many organ systems.
Certainly drinking water is important for your health, but taking measures to understand where the water comes from and what pollutants it might contain is also important. Information such as annual reports from municipal suppliers and results from testing of wells can help one determine whether to implement a home water filtration system to protect against contaminants (see Chapter 5).
Fertilizers and Pesticides
Perhaps as important as the type of food we eat, so too is the quality. Eating organic foods has health benefits because growers of those foods use the natural microflora of the soil as nutrients. Conventional agricultural techniques use chemically modified fertilizers and pesticides that pollute the water and soil. Disruption of the ecologic balance of the soil can affect the gut microbiome and put human health at risk.3
Some studies demonstrate that maternal exposure to farms, stables, and animals in utero can boost fetal immunity and decrease allergic and asthmatic reactions after birth.48 Dr. Daphne Miller, in her book Farmacology, outlines this strategy and suggests spending time on a sustainable farm as a preventive strategy for allergies and asthma.48 This drives home the concept that the soil is just as important as the food; although eating healthy plants is good, considering how they are grown and avoiding genetically modified foods is even better.
Glyphosate is the active ingredient in the most widely used herbicide as of 2016, Monsanto’s Roundup.50 Traces of this chemical have been found in sugar, corn, soy, and wheat. This dangerous substance inhibits the cytochrome P450 enzyme, which plays a significant role in detoxifying xenobiotics (i.e. foreign substances not usually made or present in the host). Disruption of this process works in synergy with disruption of the gut ecology and synthesis of aromatic amino acids and sulfate transport. The downstream sequelae are thought to contribute to the development of diabetes, obesity, depression, autism, Alzheimer’s disease, cancer, and cardiovascular disease.60
The concept that environmental toxins cause disruption of homeostasis is known as exogenous semiotic entropy.60 Understanding how nutrition and environmental chemicals interact additively or synergistically to affect the gut microbiome and health can help clinicians better understand various diseases and disorders.
The food chain is the primary route of exposure for chemicals known as endocrine disruptors. These chemicals include fertilizers, pesticides, and herbicides. Residues of these substances can be directly ingested, and they can alter natural phytoestrogen compounds in edible plants. There can be additive effects when multiple pesticide residues are ingested.43 Persistent organic pollutants and pesticides have been associated with type 2 diabetes. The chemicals can undergo transformation with exposure to natural sunlight that can further increase their toxicity.65 The gut microbiome is affected by these substances, and the resulting changes affect metabolomics and can alter the protective inner layer of the gut and lead to some of the conditions mentioned.
Food choices are important for maintaining good health. Considerations include whether fruits and vegetables are organically grown or grown with the aid of harmful pesticides and fertilizers. Food safety systems should be used to assess the risk of chemicals along the food chain and how they can affect target organs.43 Without appropriate assessment in place, ingestion of contaminated food by children and adults can have serious health implications, especially during the prenatal development.
Genetically modified organisms (GMOs) contain genetic material that has been altered by the use of genetic engineering techniques. Most corn and soybean crops in the United States have been genetically engineered to withstand the application of herbicides for weed control. The use of herbicides in farming is thought to contribute to changes in the gut microbiome that select for resistance genes.31 Antibiotic-resistant organisms may result from the genetic changes in foods that are transferred to the gut flora, subsequently impacting human health.
Glyphosate and 2,4-dichlorophenoxyacetic acid (2,4-D) have been classified as possible carcinogens.50 Genetic transformation of foods has the potential to produce allergens or toxins that could alter the nutritional quality of the food.36 In the gut microbiome, these ingested foods are processed by the commensal flora, and the toxic metabolic byproducts produced can cause a variety of pathologic conditions. Moreover, the gut microbiome changes as a result of exposure to these chemicals, allowing different populations of microbes to dominate and persist in the gut.
Dysbiosis is a key factor in the development of many health problems. Although herbicides have helped farmers with weed management without destroying the crop itself, genetic modification of crops poses a hazard to human health.36,50 The emergence of glyphosate-resistant weeds raises another health concern because farmers are being forced to apply the herbicide multiple times, apply additional herbicidal chemicals, and alter their farming methods.1,2 As problems with resistance escalate, further genetic modifications are needed within the food chain, affecting humans and animals that ingest these crops. With obesity reaching epidemic proportions in the United States and nonalcoholic fatty liver disease becoming one of the top indications for liver transplantation, the effects of growing and eating GMOs should be seriously considered.
The chemicals used to produce foods can be harmful to the gut microbiome and health. For example, the food industry has used chemicals called emulsifiers to help ensure long shelf life and good texture of its products, but data supporting the negative health effects of emulsifiers is mounting. Processed foods are thought to strongly contribute to the obesity epidemic. Obesity is associated with low-grade inflammation and altered gut microbiome, and emulsifiers promote dysbiosis and dysfunction of the gut barrier. These substances, also called obesogens, are thought to be associated with metabolic disorders and weight gain.13
Potassium bromate is a food chemical that has substantial harmful effects. It has long been used in breads as an additive to strengthen the dough. Many countries have banned its use, but it continues to be allowed in the United States. It is considered to be a carcinogen, and it can cause oxidative damage to DNA,78 which may contribute to breakdown of the protective barrier in the gut and lead to increased intestinal permeability.
Carboxymethylcellulose and polysorbate-80, two emulsifiers, were shown to contribute to low-grade inflammation, metabolic syndrome, and obesity in mice. In mice that were predisposed to colitis, these substances triggered significant colonic inflammation. The composition of the gut microbiome in the exposed mice was found to be different from that in controls, and inflammation increased as an effect of the emulsifiers.16
Carrageenan, another emulsifier, is made from red seaweed. It is often found in organic and nonorganic dairy products and is used in toothpaste to create a smooth texture. It activates a proinflammatory cascade and induces inflammation in colonic cells. The types of flora found in the colon as a result of exposure to carrageenan may affect the development of colonic neoplasia or inflammatory bowel disease.4 Exposure to several different emulsifiers may alter the gut microbiome in such a way that a particular individual could become more susceptible to problems such as inflammatory bowel disease when also exposed to carrageenan.
Some authorities think that use of carrageenan should be reconsidered because degraded carrageenan is a known carcinogen in animal models, and undegraded carrageenan has cancer-promoting effects. Exposure to acid in the stomach can convert undegraded carrageenan to the degraded form, and food processing may allow for contamination of the food product with degraded carrageenan.69 The impact this food additive has on the gut microbiome and the potential health hazards that can ensue are worthy of consideration.
Another class of food chemicals that deserves attention is artificial sweeteners. Millions of people worldwide use artificial sweeteners with the hope that they will lose weight. However, data support the opposite finding; the sweeteners contribute to metabolic derangements and glucose intolerance by altering the gut microbiome.67
Various microbial communities are involved in several important processes in which the gut, diet, and metabolism are closely intertwined.10 Studies have shown that nonnutritive sweeteners are associated with increased risk of diabetes, obesity, and metabolic syndrome. Some of the proposed mechanisms include interference with established responses to glucose and energy homeostasis and disruption of the gut microbiome, which leads to glucose intolerance and stimulation of the insulin response by interference with sweet-taste receptors found throughout the digestive tract.55 When artificial sweeteners provoke an insulin response without the presence of a corresponding caloric load, the person may have increased cravings for sweet foods. In this way, diet soda and other foods that use artificial sweeteners can actually lead to a higher risk of obesity. The means by which nonnutritive sweeteners impact metabolism and energy homeostasis are complex and are probably related to a variety of peripheral and central mechanisms,9 some of which still need to be elucidated.
The use of artificial sweeteners deserves attention as we look for ways to optimize patients’ health and reduce factors that can contribute to the problems they are trying to avoid. Although the food industry and society have been attempting to move toward more natural sweeteners, such as those derived from Stevia rebaudiana, with the hope that health concerns would be reduced, one study has questioned whether this type of sweetener acts as an endocrine disruptor.64 Although natural sweeteners are thought to be preferable to other nonnutritive sweeteners, further research is needed before more definitive recommendations can be made.
The use of antibiotics in dairy products and meats is a concern. When oral antibiotics are taken for an infection, other microbes in the gut are also affected. Often overlooked are exposures of food products to antibiotics and the impact this may have on the gut microbiome, which can certainly be altered by antibiotics.51
In many farming practices, it is common to deliver antibiotics to animals in their feed to act as a growth promoter and to prevent disease. It is estimated that every individual in the United States consumes more than 27 g of antibiotics each year because of this practice.51 Agricultural use has significantly contributed to the development of antibiotic resistance and severe infections worldwide.
Diversity of the gut microbiome is an important factor in modulating inflammation, diabetes, cardiovascular disease, obesity, and many other conditions. Exposure to antibiotics on a chronic basis decreases biodiversity and may be an important driver of inflammation. Reduced biodiversity of the gut microbiome can increase susceptibility to certain enteric infections, alter the microbiome after infection, and create more severe intestinal pathology.63 The result is a vicious cycle of dysbiosis.
Use of hormones such as recombinant bovine growth hormone, which is used in the dairy industry to boost the milk production, is a controversial subject. This hormone may have a role in the development of obesity, although it would be an indirect one because the growth hormone is not thought to be active in humans.65 Any foreign substance has the potential to change the microbiome and gut ecology. Even organic milk, which does not have added hormones, potentially has higher levels of estrogens in it because the cows that are producing the milk are kept in a constant state of pregnancy.
The amount of hormones that pass into milk and dairy products are a concern.14 However, the data on the impact of hormones in dairy products on the gut microbiome and risk of malignancies such as prostate, breast, and endometrial cancer are controversial, and further investigation is warranted.
Some foods are irradiated to increase their shelf life and reduce foodborne illnesses. Meats are irradiated to eradicate gram-negative organisms that contribute to spoilage.52 Irradiation is also used on mushrooms to prolong quality because their postharvest life is only a few days despite the use of drying techniques. Electron beam irradiation, an emerging technique, may be used. One study proposed that this method decontaminates mushrooms and improves their antioxidant activity.27 Another study suggested that applying gamma irradiation with freezing or oven drying preserves the total tocopherols and could be a useful combination.26
Food irradiation is thought to be a safe practice that can improve community health issues.25 If there are no major changes to the food itself and an improved chemical and nutrient profile results, there should not be a substantial negative impact on the gut microbiome, but further studies are necessary. The irradiation process does destroy microbes on foods, and the altered microbial profile may or may not have sequelae in the human gut. It is important to understanding to what degree particular foods should be irradiated so that they maintain their integrity.
Microwaving is a common method of heating and cooking. Although it is not possible to comment on the changes that every type of food undergoes when microwaved and what the sequelae on the gut microbiome may be, we offer a few examples. A study done by Lopez-Berenguer and colleagues showed that there was a general decrease in human bioactive compounds in broccoli, except for minerals, when it was microwaved. Vitamin C was degraded and leached, and phenolic compounds and glucosinolates were lost due to leaching in water. Longer cooking times and larger water volumes were associated with a greater degree of nutrient loss, and it was suggested that these methods should be avoided.38
Considering the safety of microwaved foods is important. Although the heat from microwaves may be capable of sterilization, heating and cooking of frozen food products in a microwave oven is not always even. Parts of the package may not be heated and cooked as well as others.62 This could potentially make some foods unsafe and put consumers at risk for enteric infections.
Perhaps more important than the process of microwaving itself is the surface with which the foods are in contact during the process. Melamine is a chemical used to produce cooking utensils, plates, plastic products, and fertilizer in some countries. Plastic tableware from China is manufactured using a melamine-formaldehyde resin. The U.S. Food and Drug Administration (FDA) suggests that poisoning from melamine can cause kidney failure, nephrolithiasis, blood pressure problems, and death. A 2014 study strongly suggested that foods should not be microwaved with melamine-formaldehyde tableware. Microwaving can affect the overall migration of this substance into the food, especially with repeated cycles of heating.56
Although the FDA suggests that migration is most likely when heating acidic foods, the official suggestion for consumers is to avoid microwaving with melamine-formaldehyde plastic tableware. A discussion about microwaving foods, including infant formula, in various types of containers is beyond the scope of this chapter, but consumers should be aware of the effects of various cooking methods as well as the surface material of the containers in which the foods are heated.
Further studies regarding the effects of microwaving on the gut microbiome and disease are warranted, but it seems logical that ingesting foreign substances such as melamine and eating foods with a lower than usual nutrient profile can affect the microbiome, gut health, and overall nutrition. Studies show that microwaving foods causes a loss of valuable nutrients and vitamins. There also is concern that the process of heating may change the food’s chemistry, contributing to free radical development and other negative health effects. This may be one of many factors influencing disease and health problems in the United States and worldwide.
Environmental Chemicals and Other Factors
Environmental chemicals and other factors can alter the gut microbiome and human health. Xenobiotics are exogenous foreign substances that are not naturally produced or found in an organism. Many environmental chemicals fall into this category, including pollutants, cosmetics, drugs, and dietary components.33 An increasing body of evidence shows that interactions between xenobiotics and the gut microbiome modulate chemical toxicity and cause or exacerbate various diseases.
The gut microbiome helps to process nutrients, chemicals, and other substances. It plays an important role in metabolism and in sequestration and transformation of xenobiotics; the sequelae of these processes can lead to functional changes in the gut microbiome.41 For example, there are arsenic-associated genes in E. coli, Staphylococcus spp., and Bacteroides. The gut microbiome may also play a role in metabolizing polycyclic aromatic hydrocarbons. In a similar way, the microbiome of the skin can metabolize toxins in air pollution before absorption.22
The emerging view of environmental toxins includes genetics, epigenetics, exposures, metabolism, and xenobiotic processing by the microbiota. Whether a toxin is considered an obesogen, diabetogen, airborne chemical, metal, or other exposure, there are important considerations when it comes to the environment and how it impacts the gut and overall health (Fig. 6.1).
Obesogens and Diabetogens
Certain agents contribute to the development of obesity and diabetes mellitus. They are categorized as obesogens and diabetogens, respectively. Men with type 2 diabetes have reduced levels of organisms of the phylum Firmicutes. Blood glucose levels have been associated with altered ratios of Bacteroidetes to Firmicutes and Bacteroides-Prevotella to Clostridium coccoides–Eubacterium rectale. Diabetics also have more organisms of the class Betaproteobacteria.66
Understanding what factors contribute to the presence or absence of certain microbial strains has clinical significance. For more than a decade, experts have proposed that certain environmental toxins can contribute to obesity and diabetes.32 Associations have been proposed for the following chemicals: dichlorodiphenyldichloroethylene (DDE), hexachlorobenzene (HCB), highly chlorinated polychlorinated biphenyls (PCBs), dioxin, and chlordane. Occupational exposures to insecticides and herbicides such as chlordane, heptachlor, chlorpyrifos, diazinon, alachlor, cyanazine, and trichlorfon have also been described.66
Agricultural chemicals such as DDE can be excreted in breast milk, which creates an exposure for the child. Although chemicals such as HCB, a carcinogenic fungicide, have been banned, it is possible that epigenetic marks made by exposure of prior generations could be passed down through generations.74 The production of PCBs was banned in the United States, but waterways and buildings remain contaminated with these toxic, probably carcinogenic chemicals.
Compounds known as organotins are organic derivatives of tin, and they are used commonly to stabilize plastics. Tributyltin and related compounds can be transferred to the food supply through contact with materials such as parchment paper and food containers, and they can induce adipocyte differentiation.65 Studies of how the various microbial communities in the gut respond to these exposures are needed to determine whether interactions with organotins favor development of obesity and diabetes.
Other common endocrine disruptors include bisphenol A (BPA) and other plastic components (see Chapter 2). BPA is commonly used in plastics and the lining of metal cans. Metabolites of this substance can be found in up to 90% of adults and children. BPA can impair the immune system and its responses. It can also contribute to the development of type 1 diabetes, at least in the mouse model.6 This alteration in the immune system is a mechanism by which low-grade inflammation and dysbiosis contribute to the risk of metabolic syndrome and obesity.15 One review demonstrated associations between BPA and adverse perinatal, childhood, and adult outcomes such as metabolic disease, reproductive disorders, and developmental defects.59
BPA has received a lot of attention, spurring the development of BPA-free containers and metal cans. This may help reduce the overall exposure to BPA, but it will not eliminate it given the widespread use of BPA in many other products. Moreover, manufacturers often replace BPA with similar chemicals, such as bisphenol S (BPS) and bisphenol F (BPF), which may have similar health concerns.17 Further studies are needed to determine the health implications of topical exposure to BPA and related chemicals.
Triclosan is a common substance that can be found in cleaning supplies, toothpastes, and soaps (see Chapter 9). This environmental chemical has the potential to alter gut microbiota, endocrine function, and body mass index (BMI).37 Triclosan can be found in personal care products, and a related compound called congener triclocarban can be found in numerous children’s toys. The fact that triclosan can be detected in human blood and urine implies that it is absorbed systemically and can have more than just a topical effect.37 Few epidemiologic studies directly link triclosan to type 1 and type 2 diabetes, but contact with this substance has been associated with rhinitis, food allergy, and low thyroid hormone levels.6
Flame retardants such as polybrominated diphenyl ethers (PDBEs) are widely used chemicals and are considered to be endocrine disruptors. Humans can be exposed by inhalation of indoor air and by food ingestion. In rats, this type of chemical can cause a variety of responses, including elevated tumor necrosis factor-α levels, hyperglycemia, and decreased insulin levels.6Although good-quality epidemiologic studies in humans are lacking, this substance should at least be considered a risk factor for diabetes based on some of the physiologic responses it helps to propagate.
Phthalates are another group of compounds that are commonly used in cosmetics, pharmaceuticals, and food packaging as plasticizers.6,65 They can contaminate food products, especially fatty foods, due to lipophilicity, and they have been associated with dysregulation of sex hormones, obesity, and insulin resistance.65 Phthalates can induce oxidative stress and inflammation and have been associated with type 2 diabetes and asthma.6
This review has only touched on some of the environmental chemicals associated with obesity and diabetes, but we hope that it raises the awareness of clinicians about the many factors involved in the development of metabolic syndrome and its sequelae. Although caloric intake and food choices are important, they may not be the only driving factors in the obesity epidemic. Being cognizant of external factors, chemicals, and environmental exposures may help in managing the diversity of the gut microbiome and optimizing health.
Systemic Nickel Allergy Syndrome
Changes in the gut microbiome have been associated with allergy, and it is interesting to consider whether probiotics can modulate the allergic response and reduce symptoms. Systemic nickel allergy syndrome is a condition that may offer some insight. The syndrome can include symptoms of contact dermatitis and gastrointestinal symptoms with ingestion of nickel-containing foods. Those with this condition must follow a restrictive diet.
One study suggested that supplementation with Lactobacillus reuteri could help patients with this condition who must follow a low-nickel diet.58 Supplementation helps to reduce the frequency and severity of symptoms. The study results suggested that the microbiome and particular microbial populations may play a significant role in the modulation of allergy and treatment of food allergy, at least for exposures to nickel.
Other topics are pertinent to the discussion of gut dysbiosis. In addition to diet, nutrition and environmental toxins, various pathologic conditions underscore the significance of the microbiome in optimizing health through diet and toxin avoidance.
Autism is associated with gut dysbiosis with overgrowth of anaerobic organisms such as Clostridium, Bacteroidetes, and Desulfovibrio.60 One hypothesis is that early in childhood infections and the use of antibiotics set the stage for an imbalance in gut flora. This impairs the immune system and allows for increased intestinal permeability. Subsequently, neurotoxic compounds, and xenobiotics are produced and absorbed, affecting the gut-brain axis.47
Delivery of intraventricular propionic acid and short-chain fatty acids (produced by the anaerobic bacteria found in those with autism spectrum disorders) to rats resulted in autistic-type behaviors such as abnormal movements, repetitive actions, cognitive deficits, and decreased social interactions.42 This finding highlights how alterations in the gut microbiome can be a risk factor for autism. In the era of genomics, it is interesting to speculate whether the diet and environmental exposures of the mother in combination with inherited epigenomic modifications resulting from DNA methylation could impact the gut microbiome of the child and thereby predispose him or her to autism.
Environmental risk factors that have been proposed in susceptible individuals include diet, maternal diabetes, prenatal or perinatal stress, parental age, medications, zinc deficiency, supplements, pesticides, and infections.35 There is likely a complex interplay among various factors, and the gut may be at the center. Use of this interplay to develop novel therapies or interventions could help management and avoid risk factors. One study suggested that treating high-risk infants with very high levels of lysozymes could suppress the growth rate of clostridia and reduce the risk of developing autism.71 Although the answer to autism may not be in lysozyme therapy alone, this study raises the point that modulation of the gut microbiome by many of the previously described mechanisms may play an important role in prevention or treatment.
At the center of any discussion of cancer is the epigenome, which includes the sleeve of chemical compounds overlying DNA that modulates actions of the genome. The gut microbiome interacts with the genome and epigenome, and all of these factors are affected by diet, nutrition, and environmental toxins. Changes in the intestinal environment have been associated with progression of adenomas and tumor formation in the colon. A study demonstrated that bacterial biofilms in the colon could make the colonic tissue more susceptible to carcinogenesis by upregulation of polyamine metabolites in the host tissues.34
Adding probiotics to a diet rich in cruciferous vegetables and green tea polyphenols is one way to bring about epigenetic changes in bacterial DNA or their target genes to help reduce the risk of colon cancer.54 This approach addresses some of the proposed hypotheses regarding the causes of colon cancer, such as inflammation, bacterial toxins, and toxic microbial metabolites.12 It certainly refines the concept behind the adenoma-carcinoma sequence and emphasizes that manipulation of the gut microbiota can have a therapeutic or preventive role in management of colonic neoplasia.23
Discussion of cancer and the microbiome is not limited to colon cancer. The microbiota influence the metabolism of estrogen and deconjugation reactions modulated by some bacterial species and could cause increased absorption of free estrogens. Elevated estrogen levels can promote development of breast, ovarian, and endometrial cancers.54
The development of liver and lung cancer may also be influenced by the gut microbiota. Toll-like receptors (e.g., TLR4) in the liver can be activated by microbial lipopolysaccharides and can result in injury and inflammation in liver tumors. Chronic inflammation and chromatin modifications are two proposed mechanisms involved in chronic obstructive pulmonary disease (COPD) and lung cancer.54 Inflammation and alterations in the gut microbiome and the intestinal barrier are emerging as key concepts in the development of a variety of cancers, and exposures to environmental toxins and dietary factors drive these changes.
Research has demonstrated the key role that the gut microbiota play in a variety of neuropsychiatric conditions. The gut contains approximately 100 million neurons, more than the spinal cord, and it produces most of the body’s serotonin.18 It seems logical that there would be some connection between the gut and the nervous system. Studies using rodents have demonstrated that the gut influences emotion, stress, pain, and brain neurotransmitters. Some investigators suggest that the gut microbiota are involved in brain signaling and that the brain can alter the gut’s microbial composition.45
Gut microbiota communicate with the central nervous system by several methods, including neural, endocrine, and immune pathways; this is how they influence brain function and behavior.21 Understanding these mechanisms may improve our understanding of cognition, mood, personality, sleep, and many conditions ranging from autism to schizophrenia and may provide a platform on which to develop novel interventions and therapies.10
Chronic stress is a problem that plagues many people. A growing body of evidence supports the hypothesis that the gut microbiome plays a role in early programming and later responses to acute and chronic stress. Using this information to develop strategies to mitigate stress could prove helpful to many.7
Future of the Microbiome
Medicine is evolving at a rapid pace. Research into the gut microbiome’s impact on human health is uncovering exciting findings and providing information never before considered. More research is needed to understand how the microbiome-gut-brain axis works and how interactions between the epigenome and the gut microbiome alter disease expression.
DNA methylation, the epigenetic process by which methyl groups are added to DNA to modify function, is proving to be one of the major factors in understanding disease because of the role it plays in epigenetic modulation of gene regulation. Fully understanding the role that nutrition and the gut play in this process is important. Educating patients about a healthy diet and lifestyle and empowering them to take command of their future by avoiding certain environmental toxins will prove to be one of the best interventions health care providers can offer. In the coming years, more refined diagnostic testing will likely become available. This will give patients and clinicians an idea of what health problems they have or may develop based on their microbial profile and degree of epigenomic alterations. Novel therapies and interventions aimed at modulating the gut microbiome will be developed to help prevent disease and detoxify the body to alter the disease course.
Interactions among diet, nutrition, and environmental toxins modulate the gut microbiome and affect a vast array of medical conditions. The purpose of reviewing these issues was not to create a sense of alarm but to raise awareness about the influences nutrition and environmental exposures can have on the gut microbiome and health. Exciting research is surfacing regarding the importance of gut health and the role of particular microbes in health, disease, and longevity.5 We propose that for many conditions, from obesity to diabetes and cardiovascular disease to autism and schizophrenia, interactions among the gut microbiome and various complex pathways, including the endocrine, nervous, metabolic, and immune systems, will prove to be central to controlling inflammation, diminishing gut permeability, and healing patients.
It is not possible for humans to live in a bubble and avoid all environmental exposures. However, we hope that providing information about these issues will give clinicians the tools to educate and treat their patients. Using the power of the microbiome can allow health care providers to tailor prevention strategies and influence the course of disease.
Eating a well-balanced, healthy, antiinflammatory diet with plenty of colorful fruits and vegetables and probiotic foods is a great place to start. The key to gut health is biodiversity of the gut microbiome, and this type of diet can help to establish and maintain good health. We also suggest that consumers be aware of what they are buying and using on a regular basis. Reading the labels on foods is just as important as reading the labels on cosmetic products, soaps, tableware, and food containers. Eating organic foods whenever possible and making an effort to purchase products that are healthy and safe and do not contain harmful chemicals is a good practice to follow (see Chapters 8, 11 and 14).
• Many factors are involved in modulation of disease, and one of the central players is the gut microbiome. Giving patients current information and advising them about gut health can influence overall health outcomes and promote well-being. The following key points are emphasized:
• Intestinal permeability and inflammation are the root cause of many diseases, and the gut microbiome plays a vital role in this process.
• Understanding what constitutes a good diet is key to ensuring gut microbial health.
• Avoid nonnutritive sweeteners and emulsifiers.
• Drink filtered water.
• Eat well-washed produce, and choose organic when possible.
• Avoid processed foods, meat manufactured with antibiotics, and dairy products produced with hormones.
• Avoiding harmful environmental toxins can protect the gut microbiome and influence disease.
• Use glass, ceramics, or stainless steel instead of plastics when cooking or heating foods to avoid BPA, BPS, BPF, and other harmful chemicals.
• Use cosmetics and personal care items that are free from harmful chemicals such as triclosan and phthalates.
• Pregnant women should consider vaginal delivery and breast feeding if possible.
• Many conditions, including obesity, cancer, neurologic disease, autism, inflammatory bowel disease, irritable bowel syndrome, allergies, asthma, kidney disease, liver disease, and cardiac disease, are impacted by the composition of the gut microbiome.
• Understanding the factors that influence the gut microbiome is key to appreciating how to counsel patients to live healthy lifestyles.
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