Defining the Connection: Microbiota and the Environment, Nutrition, and Metabolic Disease

The microbiota plays an important role in health. It has been proposed that modern lifestyles and a Western dietary pattern have resulted in a loss of commensal bacteria and a reduction in the diversity of species present. Normal functioning of the microbiota provides the host with important physiologic and immunological functions. Industrialized living has created an unprecedented evolution of the collective human microbiome, which is influenced by the modernization of medicine, with the use of antibiotics and elective cesarean sections, formula feeding, enhanced hygiene practices, smaller families and reduced dietary fiber intake.1,2

The Western dietary pattern is typically low in dietary fiber and is considered one of the main driving factors in the evolution of the human-microbiota relationship, changing species present and reducing gene diversity.2 Low diversity and its relationship to disease have become apparent with the examination of the microbiome of indigenous populations that have a high fiber intake compared to Western populations,3 as well as comparisons of lean versus obese individuals.4

Chronic diseases have increased dramatically and are thought to be related to dysbiosis, which is a perturbation in bacteria populations, resulting in a loss in the ancient symbiotic relationship. Although dysbiosis has not yet been proven to cause disease in humans, altered microbiota is associated with obesity, diabetes, cardiovascular disease, liver disease, colon cancer, allergies, asthma and other autoimmune diseases.2,5 It is well recognized that chronic inflammation is a common underlying pathophysiology in many modern-day illnesses and can be linked to activity of the microbiota.6 This article will review the functions and development of the microbiota and how modern lifestyles, including nutrition, may have contributed to the changes in species available to humans. Increasing dietary fiber as a means of improving the health of the microbiota will be proposed.

Background: Functions and Development of the Microbiota

The microbiota consists of billions of bacteria that live on the human host. These bacteria reside on the skin and in the nose, but the most abundant and various species reside in the gastrointestinal (GI) tract.7 The understanding of the functions of the bacteria in relationship to human health has advanced immensely over the last 10 to 15 years, with new nonculture-dependent technologies making it possible to establish the genetic makeup of intestinal microbiota. These new technologies make it possible to identify species present, their abundance and their functions based on gene sequencing. Most bacteria are either commensal or pathogenic. Pathogenic bacteria usually reside without causing a problem, except in times of stress, which provide opportunity for those species to replicate.1 The main bacterial phyla living in the human gut are Firmicutes (gram-positive), which in Western cultures make up the highest proportion, Bacteroidetes (gram-negative) and Actinobacteria (gram-positive).8

There are 1,000 known species residing in the gut. It has been suggested that the microbiota of an individual is dominated by one of three genera: Bacteroides, Prevotella and Ruminococcus, referred to as enterotypes, which may be dictated by the diet consumed.8 The microbiota has a symbiotic relationship with its human host, providing protection against pathogens by maintaining a healthy barrier to the external environment (skin and mucosal lining).1,6 The food we consume provides bacteria in the gut with substrates for metabolism, releasing end products such as vitamins, amino acids and short-chain fatty acids (SCFA) that are vital to human health.9 Other functions include release of dietary phytochemicals and the metabolism of xenobiotics.

There is evidence that behavior and brain chemistry are controlled by the normal functioning of the microbiota.6 The microbiota plays an important role in modulating gastrointestinal hormone release and shaping our innate and adaptive immune systems.10 Improper activity of the adaptive immunity due to lack of essential exposure to microbes may increase the risk of allergies and autoimmune disorders.6 Children living in environments in which they are exposed to dirt and animals, which are rich in microbial diversity, are known to have fewer allergies, autoimmune diseases and incidents of asthma.6 Many aspects of our modern lifestyle may contribute to the loss of beneficial species. There is a loss of exposure to beneficial species from excessive hygiene and elective cesarean sections. Exposure to less desirable species from environmental contaminants, unhealthy diets, food additives, advanced glycation end products and circadian disruptions introduces bacteria that might crowd out healthier species.6 Use of antibiotics further reduces commensal species and microbial diversity.1 Further, lack of indigestible carbohydrates (dietary fiber) provides insufficient nutrition to beneficial species, also reducing the metabolic byproducts such as SCFA.2,9

Dysbiosis, Obesity and Diabetes

The prevalence of obesity has increased dramatically with a concomitant rise in Type 2 diabetes. It has been theorized that the microbiota plays a role in obesity and Type 2 diabetes by impairing energy homeostasis. A reduction in healthy bacteria could contribute to low-grade inflammation (endotoxemia), eliciting insulin resistance. Loss of butyrate-producing bacteria due to diets low in fiber may also reduce the secretion of incretins, thereby further reducing insulin sensitivity, fat metabolism and appetite control.8

A review of eight studies reported reduced proportions of the phylum Bacteroidetes accompanied by an increased abundance of Firmicutes in obese individuals compared to lean ones, based on 16S rRNA gene sequencing.11 A comparison of 123 nonobese and 169 obese Danish individuals found the two groups differed significantly in gut microbial gene counts.4 Those with a low gene count were more obese and had more insulin resistance, fatty liver and low-grade inflammation compared to those with a higher gene count. Rosburia and Faecalibacterium prausnitzii, both butyrate-producing bacteria, have been found to be diminished in individuals with Type 2 diabetes, as well as those with metabolic syndrome and obesity.12,13 Faecalibacterium prausnitzii is associated with reduced inflammatory markers. Akkermansia muciniphila, a bacterium involved in strengthening the mucous layer (potentially improving gut barrier function), is inversely associated with obesity.14 A greater abundance of A muciniphila has been associated with healthier metabolic status (fasting glucose, body fat composition and hip-to-waist ratio) in overweight and obese subjects, as well as better weight loss and glycemic improvements in response to dietary intervention.15 It is interesting to note that metformin therapy appears to increase populations of A muciniphila.12 High fecal concentrations of Lactobacillus gasseri, Streptococcus mutans and Escherichia coli were found to be predictive of insulin resistance in obese postmenopausal women.13

Western Lifestyle and an Evolving Microbiota Composition

Evolution of the human gut microbiota has been influenced by diet, environment and, to some extent, genetics.1 It has been demonstrated that populations, including children and adults, living in agrarian environments have a more diverse gut microbiome compared to those living in industrialized environments.

The diets of Westerners are usually high in refined carbohydrates and dietary fat and low in fiber, compared to those living in rural countries.9 Children aged 1-6, living in a rural African village, who consume a diet consisting of cereals (millet and sorghum), legumes (black-eyed peas called Niébé) and vegetables had a microbiota composition that was much higher in the phylum Bacteroidetes with a depletion of Firmicutes compared to children of the same age from Europe.16 The European children’s diet was significantly lower in fiber, higher in refined grains, fat and meat, and their microbiome was genetically less diverse. The African children’s microbiota was abundant in the genus Prevotella and Xylanibacter, known to contain genes for cellulose and xylan hydrolysis, which were completely lacking in the European children. The African children also harbored significantly more butyrate-producing bacteria than the European children. Nondietary factors that might contribute to bacterial composition variability include ethnicity, sanitation, hygiene, geography and climate.

Hunter-gatherers living in rural Tanzania were compared to Italian participants. The Hadza are a community virtually untouched by industrialized lifestyle and have low accessibility to health care but despite this, they have low rates of infectious disease, metabolic disease or nutritional deficiencies.3 They consume 95 percent of their diet from wild foods, mostly from plant-based sources that include wild tubers, leafy greens, baobab fruit, berries and honey. Birds and large game make up 30 percent of their kilocalorie intake. Compared to urbanized Italians, the Hadza had higher levels of microbial richness and biodiversity; an enrichment of Prevotella, Tremonemia, and unclassified Bacteroidetes; and a peculiar arrangement of Clostridiales taza, species that represent an enhanced ability to digest and extract nutrients from fibrous plants. There was an absence of Bifidobacterium, which is surprising because this is thought to be an important foundational species for health.

The reduction in the presence of Helicobacter pylori is an interesting example of bacteria that are disappearing from the human microbiome. H pylori are a species that thrives in the acidic environment of the stomach and are known to exacerbate peptic ulcer disease. This presumed pathogenic bacterium is disappearing from the human microbiota, most likely due to antibiotic therapy.1 Two to three generations ago, more than 80 percent of Americans hosted H pylori. Now, less than 6 percent of American children test positive for H pylori. Peptic ulcer disease and gastric cancer are down, but esophageal reflux, Barrett’s esophagus and adenocarcinoma are increasing. It is hypothesized that H pylori plays a role in regulating ghrelin and leptin, two hormones that play multiple roles in energy homeostasis. Post-prandial ghrelin levels are higher in patients who are deficient in H pylori secondary to antibiotic treatment.1 Higher levels of ghrelin enhance appetite, potentially leading to obesity and Type 2 diabetes.

Nutrition, Prebiotics and Probiotics in Microbiota Health

The amount, type and balance of macronutrients have a profound impact on microbiota composition and physiology. Diet-derived substrates provide energy for microbes. Carbohydrate, protein or fat can influence the composition of bacteria present, as well as the metabolites produced.3,17

Fermentation of non-digestible carbohydrates produces SCFA that play a role in regulating immune function and intestinal hormone production, controlling satiety, glucose sensitivity, fat storage and energy balance.18,19,20 Butyrate may be beneficial in the prevention and treatment of diabetes by enhancing mitochondrial fatty acid oxidation, signaling the secretion of peptide YY and reducing inflammation by improving gut barrier function.13 Inulin-type fructooligosaccharides (FOS) are associated with an increase in SCFA formation, resulting in increased secretion of glucagon-like peptide (GLP)-1 and potentially proglucagon-derived peptide (GLP)-2.20 A high concentration of SCFA may reduce intestinal pH and prevent the growth of pathogenic bacteria. Other benefits include enhanced absorption of minerals and reduced cancer risk.21 Low SCFA production has been implicated in the pathogenesis of intestinal disease and inflammatory bowel disease.13

microbiota-Practical-DiabetologyA short-term study compared a four-day plant-based eating pattern to a four-day animal-based eating pattern in the same subjects. It identified alterations in microbial composition and activity that occurred within a 24-hour period.22 The animal-based eating pattern had a greater impact on growth of specific bacteria and their metabolic activity. There was an observed increase in the abundance of bile-resistant bacteria, Bilophila wadsworthia, Alistipes putredinis and Bacteroides spp, with a concomitant reduction in bacteria that produce SCFA.22 Bile-resistant bacteria are needed to metabolize hepatic bile secretion in response to a high fat intake. Bilophila wadsworthia has been linked to liver cancer12 and inflammatory bowel disease.22

End products of amino acid bacterial fermentation include ammonia, branched chain fatty acids, phenols and indoles, amines and sulfides.23 Interestingly, the low pH exerted by the release of SCFA inhibits peptide degradation, reducing the production of these potentially hazardous metabolites.19 Phosphatidylcholine, found in red meat, liver and eggs, is metabolized by the microbiota to trimethylamine, which is absorbed and further metabolized by the liver to form trimethylamine-N-oxide (TMAO). High levels of circulating TMAO are associated with cardiovascular disease risk.24 Specific bacterial groups responsible for producing TMAO have not been identified.

Metabolic changes from fermentation of fats are not well understood, although fat intake is associated with low-grade inflammation, insulin resistance and higher levels of circulating lipopolysaccharide, which is thought to be due to impaired gut barrier function.23 As mentioned earlier, a high fat intake does increase the production and secretion of bile acids in the intestine.

Human studies on dietary intake and modulation of gut microbiota, particularly for diabetes, are somewhat limited. There are data suggesting that dietary patterns correlate to distinct arrangements of bacteria. Individuals consuming a high-fiber diet tend to have a fecal microbiota high in Prevotella, whereas individuals consuming more protein and fat have a microbiota dominated by Bacteroides.25 These two genera do not tend to co-exist in the intestine. A higher proportion of Prevotella tends to exist in those consuming an agrarian diet, and Bacteroides is associated with a more Western eating style.18 The latter tend to have a lower gene count and are reported to have a higher incidence of obesity and metabolic syndrome.4 Bacterial richness has been associated with diets high in fruits, vegetables and fiber.18 A high intake of whole grains has resulted in an increased abundance of Bifidobacteria spp., as well as increased microbial diversity.9 Blueberries and red wine have been shown to have a bifidogenic effect, while pistachios and almonds have resulted in an increase in butyrate-producing bacteria.9

A two-year intervention with a Mediterranean diet (Med diet) that included 239 patients diagnosed with metabolic syndrome (from the CORDIOPREV study) resulted in an increase in fecal populations of commensal microbes.26 In another subgroup of the CORDIOPREV, 20 obese men with coronary heart disease were randomly assigned to a low-fat, high-complex-carbohydrate diet (LFHCC diet) or a Med diet and were evaluated for changes in bacterial composition of both whole fecal and plasma metabolome.27 Both eating patterns exert a protective effect by increasing the proliferation of commensal species, potentially preventing Type 2 diabetes. The LFHCC diet increased Prevotella and decreased Roseburia genera, while the Med diet decreased Prevotella and increased Roseburia and Oscillospira genera.

Prebiotics are a selectively fermented ingredient that allows specific changes in both the composition and/or activity in the gastrointestinal microbiota that confers benefits upon host well-being and health.19 For a food or ingredient to be a prebiotic, it must:

  • resist gastric acid and absorption in the small intestine;
  • be fermented by the intestinal microbiota; and
  • stimulate the growth of health-promoting species, usually from the genera Lactobacilli and Bifidobacteria.27,19

All known food sources of prebiotics are dietary fiber (mostly soluble fiber), primarily oligosaccharides, inulin, oligofructose, lactulose and resistant starch. There are more data on the effects of dietary fiber on health than on prebiotics. High fiber intakes from both soluble and insoluble sources, including vegetables, whole grains, fruits and legumes, are associated with glycemic control in individuals both with and without diabetes, lower body weight and reduced cardiovascular disease risk.28,29

All fiber meets the first criteria (resisting digestion), but some dietary fibers meet either none or only one of the other criteria.17 Consequently, not all dietary fiber can be considered prebiotic. However, individuals consuming a high-fiber diet are most likely consuming adequate sources of prebiotics. It has been demonstrated that consumption of 5 to 8 grams per day of prebiotics from inulin, oligofructose and FOS can significantly increase fecal Bifidobacteria.19 Proposed health benefits of prebiotics include improvements in intestinal function, mineral absorption, regulation of appetite and improvement in intestinal barrier integrity.17 Food sources of naturally occurring prebiotics include leeks, asparagus, chicory, Jerusalem artichokes, garlic, onions, whole wheat, oats and soybeans.19 Human breast milk is the first prebiotic source (milk oligosaccharides) babies are exposed to, increasing the abundance of the genera Bifidobacterium.18 Babies fed breast milk have a microbiome that differs from formula-fed babies.

Probiotics are defined as live microorganisms that, when administered in adequate amounts, confer a health benefit on the host in a safe and efficacious manner.10 Humans have been consuming probiotic food for centuries, with potential benefits that include aiding digestion, augmenting nutrient assimilation, enhancing immune function and even increasing shelf life prior to refrigeration.30 Most probiotics belong to the genera Lactobacilli and Bifidobacteria and can include yeasts such as Saccharomyces boulardii (brewer’s yeast) and Saccharomyces cerevisiae (baker’s yeast).31 Natural food sources include (but are not limited to) beer, kimchi, fermented soy products (miso, tempeh, tamari and shoyu), pickled ginger and sauerkraut.31

Probiotics are thought to modulate the microbiota, improving gut barrier function, enhancing the release of microbial substances that kill pathogenic bacteria, crowding out pathogenic bacteria and maintaining a healthy pH.10 Studies have offered promising results for improving outcomes for Type 2 diabetes, irritable bowel syndrome, diarrhea, neuropsychiatric disorders and hypercholesterolemia; reducing high blood pressure and the risk of heart disease; and preventing cancer.30,32 However, results of studies are not always consistent and often include very small sample sizes. Sustainable changes in composition of microbiota may not occur with cessation of probiotic supplementation. A systematic review of seven high-quality randomized controlled trials found no effects on fecal microbiota composition in terms of α-diversity, richness or evenness compared to placebo in healthy adults.10 A systematic review of six clinical studies (three including individuals with diabetes, two including pregnant women at risk for gestational diabetes and one including healthy subjects) found that probiotic supplementation reduced inflammatory response and oxidative stress, reduced intestinal permeability, improved insulin sensitivity and reduced autoimmune response compared to placebo.33

Probiotics may offer potential novel therapies for diabetes and obesity, and they are generally recognized as safe. However, at the present time, there are no specific strains or species recommended. There are published recommendations for diarrhea, inflammatory bowel disease, irritable bowel syndrome, necrotizing enterocolitis, allergies and liver disease that were established by consensus opinion from the Fourth Triennial Yale/Harvard Workshop on Probiotic Recommendations in 2015.5 Probiotic supplementation can be expensive. Those sold as food items are not subject to FDA regulation. Use of probiotics in clinical practice for diabetes may or may not improve outcomes. Even though there are recognized microbial profiles associated with metabolic dysfunction, each individual has his or her own unique bacterial composition, making responses to therapy highly variable.

Conclusions

There is evidence that the human microbiome has evolved with our modern lifestyle. Many environmental and medical factors are thought to have contributed to this depletion of beneficial bacteria, potentially contributing to chronic diseases, including Type 2 diabetes. Most experts agree that nutrition plays a prominent role because what we eat also feeds the bacteria in our gut. Although individuals may respond differently to changes in diet due to the variability in their gut profile, increasing dietary fiber intake is an important step in improving metabolic function. High intake of dietary fiber and whole grains has been found to increase the diversity of the microbiota.2 A diverse microbiota tends to be more resilient; more species present increases both functionality and stability.17 Epidemiological studies have demonstrated that fiber intake from whole grains, fruits and vegetables is associated with significantly reduced risk of Type 2 diabetes as well as lower all-cause and cardiovascular mortality.34-36 Regular consumption of fiber reduces Type 2 diabetes risk by decreasing glucose absorption and promoting healthy body weight, and foods high in fiber are high in beneficial nutrients and antioxidants.19 A low-fiber diet does not provide sufficient nutrition to the microbiota, potentially reducing gene diversity and commensal species.2

Most Americans consume about half of the recommended 25 to 38 grams of fiber per day. Consumption usually comes from sources not particularly high in fiber such as flours, grains and potatoes, while least consumed are fruits, legumes and nuts.19 The microbiota ferments soluble fiber, releasing metabolites such as SCFA that provide metabolic benefits. Prebiotic fiber provides additional benefits by promoting growth of the species Bifidobacteria and Lactobacilli. Some experts assert that the current recommendation for fiber intake is sub-therapeutic and that 55 grams of fiber is needed for modulating the microbiota for the reduction of obesity, diabetes and other chronic diseases.2 Eating patterns high in fiber (> 50 g/day) have been found to be effective in improving glycemic control in people with diabetes, but may be challenging to achieve.37 Interestingly, analysis of well-preserved coprolites of typical adult male hunter-foragers indicate that the intake of inulin from plants was close to 135 grams per day.19 To get > 50 grams, an individual would need to consume 3 servings of whole grains, 2 servings of legumes, 5 servings of vegetables, 4 servings of fruits and 1 serving of nuts per day, making sure to select some servings from prebiotic sources.

For individuals whose current consumption is closer to 15 grams a day, a gradual increase in fiber would be advisable to avoid gastrointestinal distress. Working up to at least 25 to 38 grams is an important goal for all individuals. Further increasing to 50 to 55 grams may be even more beneficial for enhancing microbiota health and improving glycemic control. However, future studies are needed to confirm these outcomes. Currently, there are no specific guidelines for using supplemental prebiotics and probiotics in clinical practice for diabetes. For more information, visit International Scientific Association for Probiotics and Prebiotics.

Other modifiable factors affecting the microbiota are excessive hygiene, overuse of antibiotics and elective cesarean sections. Getting enough sleep, being out in nature, physical activity and managing stress may also improve the composition of the microbiota.38 Choosing foods high in dietary fiber and reducing fatty foods and refined carbohydrates, along with other lifestyle habits, may improve the health of the bacteria and the host and may reduce the risk of chronic diseases, including diabetes.

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