Microbes: The Very Stuff of Life
Microbes were the first inhabitants of planet earth, and the sole inhabitants for the first 3 billion years, or so. They created the oxygen we breathe and the soil in which we grow our food. And evolutionary biologists generally agree that microbes are our ancestors — for humans and all other living species. Microbes are not only at the root of all that supports life on earth, they are the very stuff of life. We could not survive without them.
Our Gut Microbiota and Its Genome, the Microbiome
The Human Microbiome Project was launched in 2007 by the National Institute of Health. Advances in DNA sequencing technologies enabled the project to assess the microbial communities living on and within the human body. Research has found that our gut microbiota and its genome (microbiome) interact with food, environmental chemicals, antibiotics, and other pharmaceuticals to impact our health.
Essential for Health
Our bodies are host to a vast microbial ecosystem — living in symbiosis with us. These microbes include bacteria, fungi, viruses, protozoa, and other species, all of which have co-evolved with the human host. Although some are pathogens and can threaten our health, microbes are also essential for health. For example, they produce some vitamins that we cannot make on our own, break down our food to extract nutrients, control our metabolism, regulate our appetite and control our weight, help our immune systems recognize dangerous pathogens, produce anti-inflammatory compounds that fight off other disease-causing microbes, and they generate a number of neurotransmitters that impact our mood and are essential for a healthy brain and nervous system.
There are approximately 150–200 common and approximately 1000 less common bacterial species in the human intestinal tract. Researchers have found that a strong and robust core microbial community lays the foundation for health and longevity.
Changing the Course of Illness
The colon is more densely populated by microorganisms than any other place on earth. Genetic sequencing of the microorganisms in our poop gives us valuable insight into our health and risk of disease. Opportunistic, pathogenic bacteria are normal inhabitants of our intestinal tracts but when out of balance, their microbial signatures are associated with disease and chronic illness. The gastrointestinal tract must maintain tolerance to commensals (“good” bacteria) and dietary antigens (foreign bodies) while remaining responsive to pathogenic stimuli. If the microbial balance is disrupted, inappropriate inflammatory processes can result, leading to a diseased state. (1) While many strains of bifidobacteria are associated with gut health, an overabundance of some strains, such as bifidobacteria adolescentis for example, correlate with food allergies, autoimmunity, and dementia. Prevotella is also associated with good health when in balance. However, increases in prevotella bacteria correspond with a reduction in bacteroides species, which are protective in patients with new-onset rheumatoid arthritis. Elevated prevotella can also be associated with other autoimmune disorders, joint aches, headaches, and metabolic disorders. An imbalance in our microbial ecosystem is believed to account for at least some of the dramatic rise in autoimmune and inflammatory disorders in parts of the world where our symbiotic relationship with the microbiota has been the most affected.
On a cellular level, the dynamic crosstalk between intestinal epithelial cells, intestinal microbes, and local immune cells represents one of the fundamental features of normal intestinal homeostasis. These interactions are essential for mounting protective immunity to pathogens. The natural homeostasis of gut microbial communities changes during many disease pathologies including metabolic syndrome, diabetes, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), and celiac disease. In many cases, there is evidence implicating various dietary factors in the onset of these diseases.
Gut Microbiota and Your Immune System
Over the past few years, the field of immunology has been revolutionized by the growing understanding of the key role our colon’s microbiota plays in our immune system’s function and our overall health. The microbiota is necessary to induce regulatory mechanisms intended to support mucosal integrity and keep systemic immunity in balance so that while we are tolerant of harmless bacteria, we are still able to form adequate responses to pathogens.
Short Chain Fatty Acids Support the Mucosal Layer and Systemic Immunity
The clearest example of this balance involves the end products of microbiota’s fermentation of plant polysaccharides — substances called short-chain fatty acids (SCFAs). Eat more fiber and you’ll increase microbial SCFA production, which decreases the intestinal pH. This prevents the growth of potentially pathogenic bacteria such as E. coli — and SCFAs promote gut barrier integrity and reduce unnecessary immune responses and inflammation. Conversely, diminished mucosal nutrition may lead to mucosal atrophy, diminished fluid absorption, and eventually to colitis. SCFAs have also been shown to affect colonic mucosal blood flow, ileal motility, cecal mucin secretion, and mucosal cell proliferation.
Although the beneficial effects of fiber are often attributed to the increased production of SCFAs, soluble fiber can also affect other intestinal characteristics influencing intestinal health, such as increased fecal bulk, shortened colonic transit time, changes in the composition of the gut microbiota, lowered intraluminal pH, and changed bile acid profiles. Sadly, most Americans only eat about half the recommended 30 grams of fiber daily, which can negatively affect both the amount and diversity of bacterial species in the gut.
Lipopolysaccharides — a case for low-fat meals and probiotic supplementation
Lipopolysaccharides (LPS), also known as lipoglycans, are large molecules consisting of a lipid and a polysaccharide (sugar). Lipopolysaccharides are present in the cell walls of gram-negative bacteria. (The gram stain test has been traditionally used to quickly classify bacteria into two broad categories according to their cell wall: gram-positive or gram-negative. Most healthy commensals are gram-positive bacteria. However, pathogens can be either gram-positive or gram-negative.)
Overgrowth of pathogenic bacteria results in an increase in LPS levels, which triggers the production of pro-inflammatory cytokines in the gut. LPS is known to be a major initiator of intestinal epithelial cell autophagy (cell death). If a person has high levels of LPS in the gut, the risk of developing leaky gut increases — that is, the normally tight junctions of the intestinal wall are compromised. If the lining of the intestine is leaky, LPS can be released into the bloodstream. In the bloodstream, LPS is a potent toxin. These toxins can be a source of systemic low-grade inflammation or they can drive a sudden and acute inflammatory reaction. They are associated with chronic inflammation, depression, morbid obesity, and insulin resistance.
Numerous studies indicate that dietary saturated fat and long-chain fatty acids contribute to elevated serum LPS. (Ghanim) Studies also indicate that health-promoting strains of bifidobacteria probiotics can effectively inhibit LPS-induced autophagy and restore gut homeostasis. (Han)
Trimethylamine N-oxide (TMAO) — A Gut-Heart Connection
Trimethylamine N-oxide (TMAO) is a common metabolite in animals. In humans, there exists a positive correlation between elevated plasma levels of TMAO and an increased risk for major adverse cardiovascular events and death. Despite the accumulating evidence that elevated TMAO levels are associated with elevated risk of heart attack and stroke, it is questioned whether TMAO itself is the mediator, or whether it is a bystander in the disease process.
Heritability of TMAO was studied in a genome-wide association study (GWAS) involving 1973 humans. It concluded that genes play only a marginal role in determining TMAO levels. However, it has been determined that a number of factors including diet, gut microbial flora, liver enzymes, and kidney function do play key roles in determining our serum TMAO levels. (15 Valesquez)
Human and animal studies suggest that several families of bacteria are involved in TMA/TMAO production. Animal studies have shown that TMAO accumulates in the serum of animals colonized with TMA-producing bacteria, but not in animals colonized with bacteria that do not generate TMA from choline in vitro. (In vitro means taking place in a test tube, culture dish, or elsewhere outside a living organism.)
A simplified model of the metabolic process is as follows: When we ingest certain nutrients, such as choline (a vitamin-like nutrient abundant in meat, egg yolks, and dairy products) and L-carnitine (a nonessential amino acid found in red meat as well as some energy drinks and supplements), the gut bacteria that break it down produce a compound called trimethylamine (TMA). The liver then converts TMA into trimethylene N-oxide (TMAO). Increased TMAO levels are associated with platelets becoming more prone to clotting. It is hypothesized that TMAO directly alters platelet function, increasing thrombosis (blood clotting) potential, and thus elevating heart attack and stroke risk.
Studies suggest that positively altering the gut microbiota may help to reduce damage to blood vessels, resulting in a stronger cardiovascular system, which points to targets for potential new heart disease therapies. Although, studies have also found that vegans and those who avoid animal products have low levels of circulating TMAO. (16 Zhu)
High-fat, Low-fiber Diets
Gut microbiota regulate genes that affect inflammation, the development of insulin resistance (prediabetes), and fat deposition. All of these abnormalities, driven by interactions between our diet and our microbiome, are triggered by high-fat low-fiber diets. (5,6) It is not surprising that, during the latter half of the 20th century, escalating consumption of fat, sugar and artificial sweeteners in Western countries parallels increased incidence of Crohn’s Disease — a type of inflammatory bowel disease whereby the immune system attacks the digestive tract.
Often, it is not the presence of a pathogen that indicates disease or disease risk, but rather dysbiosis — an imbalance in our microbial ecosystem. Researchers are discovering that dysbiosis is not only associated with many disease states but is the root cause. Dysbiosis is an overgrowth of harmful bacteria and diminished numbers of commensals — the good bacteria in our gut. Rebalancing the gut ecosystem with proper nutrition is key to preserving and restoring gut health as well as overall health. The gut microbiota is able to affect its environment, as well as cast systemic effects.
An overgrowth of harmful bacteria and diminished numbers of commensals — the good bacteria in our gut — has been linked to the following dietary, environmental, and lifestyle factors:
- Animal fat
- Acid-suppressing drugs
- Birth-control pills
- Chlorinated water
- Herbicides (on fruits and vegetables)
- Hormone therapy
- Nutrient-poor diet
- Sugar and artificial sweeteners
Gut dysbiosis has been associated with the following conditions:
- Alzheimer’s disease
- Anexoria nervosa
- Ankylosing spondylitis
- Autoimmune diseases
- Cardiovascular disease
- Chronic fatigue syndrome
- Chronic inflammation and age-related diseases
- Chronic kidney disease
- Colorectal cancer
- Crohn’s disease
- Depression and anxiety
- Fatty liver disease
- Inflammatory bowel disease
- Irritable bowel syndrome
- Lung cancer
- Metabolic disease
- Multiple sclerosis
- Pancreatic cancer
- Parkinson’s disease
- Prostate cancer
- Rheumatoid arthritis
- Small intestinal bacterial overgrowth (SIBO)
- Transient ischemic stroke
- Type 1 diabetes
- Type 2 diabetes
- Ulcerative colitis
Refined sugars mediate the overgrowth of opportunistic bacteria like C. difficile (8) and C. perfringens. (9). The onset of dysbiosis is typically accompanied by bloating, as too much sugar results in overgrowth of lots of undesirable species whose waste products include bloat-forming gas. Excessive sugar consumption can also cause overgrowth of yeast species such as candida, which is associated with fatigue, leaky gut syndrome, and many other health problems.
￼￼New evidence suggests that the gut microbiota play a crucial role in the metabolism and bioavailability of certain dietary compounds to the host — in particular, polyphenols. Polyphenol-rich, plant-based foods and drinks include fruits, vegetables, herbs, spices, and teas. Most polyphenols in the diet escape digestion in the human small intestine and enter the colon, where they are subject to catabolism by the complex microbiota. The healthful benefits of polyphenols are not limited to their antioxidant properties but are related to bacteria releasing phenolic compounds resulting from microbial metabolism.
Researchers are identifying the specific gut bacteria responsible for specific health effects. Some of the gut-derived bioactive polyphenol metabolites have been found to be brain-penetrating metabolites. Bioactive polyphenol metabolites ultimately influence mechanisms associated with the promotion of resilience against psychological and cognitive impairments related to stress. Scientists believe that these metabolites will prove instrumental in combating age-related diseases and age-related cognitive decline.
Moreover, polyphenols stimulate the growth of beneficial bacteria such as Lactobacilli and Bifidobacteria and inhibit the growth of pathogenic bacteria. In other words, they exhibit a prebiotic-like effect. In turn, this contributes to overall health as well as gastrointestinal health.
Potential Role of Gut Microbes in Psychiatry
Understanding the influence of gut microbiota on host health, including brain health, is one of the most exciting areas in medicine. Emerging research from both animal and human studies suggests that the function and health of the brain, along with the rest of the central nervous system, is modulated by complex interactions with our gut microbiota. Although research into the complex signaling pathways involved is still in its infancy, studies lead researchers to conclude the gut microbiota plays an important role in cognitive function, sociality, hippocampal-dependent memory, anxiety, depression, temperament, and stress response.
Multiple routes of communication between the gut and brain have been recognized. Many researchers consider the vagus nerve to be the principal communication route. Other routes in the gut-brain axis include neurotransmitters, the immune system, spinal pathways, and short chain fatty acids.
Research has demonstrated that we are dependent on a spectrum of essential neurochemicals produced by microbes. For example, germ-free rodents, who were raised without exposure to bacteria, display altered sociability with autistic-like patterns of behavior. Researchers have also found that the serotonergic system does not develop appropriately in the absence of microbes. (The serotonergic system is a system of nerve cells that uses serotonin as its neurotransmitter. It plays a key role in emotional health.) (Dinan)
Furthermore, animal studies have demonstrated that long-term stress triggers low-grade inflammation that disturbs gut microbiota. And murine studies have shown that the presence or absence of exposure to certain microorganisms contributes to individual differences in stress vulnerability. (Langgartner)
Research on human subjects has demonstrated that dysbiosis can be reversed and reversal has measurable effects on cognitive performance. For example, a recent small-scale human study tested the effect of a probiotic (a strain of Bifidobacterium longum) on stress response in 22 healthy males and found that the intervention group benefited from improved memory and reduced stress compared to controls. (Allen)
Microbiome Analysis Begins With Your Dietary Enterotype
The human intestinal microbiota is composed of more than 1000 species of bacteria. An enterotype is a classification of living organisms (humans in our case), based on the bacteriological ecosystem in its (our) gut microbiome. DNA sequencing of microbes is now used for phylogenetic classification — phylum, class, order, family, genus, and species.
Gram staining enables bacteria to be examined using a light scope. Gram-negative and gram-positive organisms are distinguished from each other by differences in their cell walls. Some gram-positive bacteria are commensal and some are pathogens. The same holds true for gram-negative bacteria.
The intestinal microbiota is dominated by five main phyla. Examples of common genera are in parenthesis:
1. Firmicutes (Gram-positive. Ex: Lactobacillus, Clostridium, Eubacterium, Faecalibacterium, Roseburia), 2. Bacteroidetes (Gram-negative. Ex: Bacteroides, Prevotella, Rikenella), 3. Actinobacteria (Gram-positive. Ex: Bifidobacteria), 4. Proteobacteria (Gram-negative. Ex: Salmonella, Helicobacter), and 5. Verrucomicrobia (Gram-negative. Ex: Akkermansia)
The composition of an adult’s gut microbiota is largely influenced by long-term dietary and lifestyle habits. In adult Western populations, Firmicutes and Bacteroidetes are usually prevalent and Actinobacteria and Proteobacteria are less represented. Lactobacillus, Bifidobacteria, and Akkermansia are more prevalent in people with lean phenotypes. Those who eat a diet high in animal protein and fat promote an increase in microbes that thrive in a high-protein, high-fat environment (e.g. Bacteroides). In contrast, consuming a diet rich in plant foods promotes a very different gut ecology (e.g. Prevotella).
The hunter-gathers in Burkina Faso, in rural Africa, have little to no obesity, autism, allergies, cancer, diabetes, depression, or digestive disorders. Analysis of their microbiome finds a prevalence of Bifidobacteria, Akkermansia, Faecalibacterium, Roseburia, and Bacteroides. Their microbiome may very well provide a blueprint for a healthy, rich gut ecosystem.
Your Microbiome is Unique to You
Your microbiome is complex, varied, ever-changing, and unique to you. Evidence suggests that our genetics pre-programs the ecology of our GI tracts. However, there is growing evidence that the microbial ecology can be influenced by several epigenetic factors. It is a product of the genes you inherited, but also, whether you were born naturally or via c-section, whether you were breastfed or bottle fed, whether you took antibiotics and the kinds of antibiotics you took, whether you’ve lived a high-stress or low-stress life, and whether you took antacids, oral contraceptives, steroids, and so on.
Diet Plays the Dominant Role in Shaping Gut Microbiota
Research indicates that diet and stress play the dominant roles in shaping gut microbiota. And our microbiota play a significant role in determining whether we absorb and assimilate the nutrients we consume. Food can’t be fully broken down and nutrients and vitamins can’t be properly absorbed without adequate amounts of essential gut bacteria. Changing key bacteria populations may transform healthy gut microbiota into a disease-inducing entity, and conversely, changing key populations may transform disease-inducing microbiota into a health-inducing entity.
Studies have shown that diets rich in saturated fat or in polyunsaturated fat affect the gut microbiome composition and the host immune system. In one study, mice fed fish oil showed increased levels of Lactobacillus and Akkermansia while those fed on lard had increased levels of Bilophila, which has been shown to be correlated with colitis. (Devokota).
The “Western” diet, which is high in sugar and fat, causes dysbiosis which affects both host GI tract metabolism and immune homeostasis. Lifestyle and dietary interventions can reverse dysbiosis and promote a healthy microbial ecosystem.
A Colorectal Cancer Enterotype
At The Harlin Center, we have a series of panels that are used to assess patients gut microbiota and the corresponding association with specific diseases and conditions. For example, dietary intake of red meat, poultry, dairy, and eggs are consistently associated with relative increases in certain bacteria and decreases in others. This profile has been referred to as a colorectal carcinoma enterotype. With a personal or familial history of colorectal carcinoma, an elevated genetic risk score for colon cancer, and the microbiome fingerprint of colon cancer risk, we recommend patients reduce their intake of animal products and maintain regular interval surveillance testing for colon cancer. (10)
Obesity and Artificial Sweeteners
In 2014, a team of Israeli scientists concluded from studies of mice that ingesting artificial sweeteners might lead to—of all things—obesity and related ailments such as diabetes. This was not the first animal study to note this link. Researchers have also found that people who used artificial sweeteners were more likely than others to be overweight and more likely to have impaired glucose tolerance.
Stanford University microbiologist David Relman says his findings suggests that the bacteria in the human gut may not only influence our ability to extract calories and store energy from our diet but also have an impact on the balance of hormones, such as leptin, that shape our very eating behavior, leading some of us to eat more than others in any given situation. It has also been found that the ratio of Bacteroidetes to Firmicutes bacteria increases as fat people lose weight, suggesting that an imbalance in bacteria manipulates the genes in ways that trigger the storage of fat rather than its breakdown for energy. (11)
Microbes — On the Frontline Against Environmental Toxins
Microbial diversity is one of the hallmarks of health. So protecting and preserving ones microbiota is key to preserving and protecting one’s health. Yet it is not easy. Oral and gut microbiota are on the frontline in our body’s defense against ingested toxins and mounting evidence indicates that they suffer the first casualties. Aside from our skin, the gastrointestinal tract is our first physical and biological barrier against toxins such as pesticides, heavy metals, and food additives. Animal studies have shown that exposure to common environmental toxins can significantly alter microbiota composition. How microbes react to the exposure has the potential to affect the host’s response. Researchers have found that ingested toxins can harm our microbiota, but toxins can also be modified by the microbiota to be more or less toxic to the host or the microbiota itself. However, toxicant-induced changes to the microbiota may themselves induce host effects — independent of the toxicant’s effect on the host. (Richardson)
Synthetic emulsifiers, such as maltodextrin, Polysorbate 80, and carboxymethylcellulose, are widely used in foods (particularly yogurt, sauces, and salad dressings), cosmetics, and even some probiotics. These processed “foods” create irritation and inflammation that the mucosa must defend against. The microvilli of the mucous membrane in the small intestine absorb nutrients into the blood. This is made more difficult when these membranes become clogged or damaged by eating synthetic emulsifiers. If you purchase probiotics on your own, check the list of other ingredients.
Our Microbiome Analysis
Our analysis of your gut microbiome results includes an examination of the SCFA producing organisms, along with “good” bacteria associated with health and those associated with specific disease states. From this analysis, we’ll get a sense of whether or not your diet contains adequate fiber and health-promoting components. Our dietary and probiotic recommendations will help you restore good gut bacteria so you can get back on track to a healthier, happier you.
A Focused Look at Micronutrients
Our analysis includes an assessment of intestinal microbiota known to synthesize vitamins, including cobalamin (vitamin B12), vitamin B6, pantothenic acid (vitamin B5), niacin (vitamin B3), biotin, tetrahydrofolate (generated from dietary forms of folate) and vitamin K. Taken together, this group of bacteria makes valuable contributions to genomic stability and cardiovascular health.
Deficiencies in Vitamin A have been shown to affect the composition of the microbiota and, in turn, impair the immune response. Most notably, low levels of vitamin A are associated with higher levels of the pathobiont Bacteroides vulgatus. High levels of B. vulgatus have been linked to chronic inflammatory bowel disease and obesity. (10, 11)
Prescribing a Healthy Gut Protocol Relies on Multiple Factors
Your gut microbiota data, information on the tens of trillions of organisms living in your gut, will tell us whether your gut ecology is in, or out of, balance. That is, whether it contributes to your health and well being or whether it contributes to poor health.
The gut microbiome is complex, but moreover, prescribing a healthy gut protocol relies on multiple factors: a well-taken medical history, a complete physical exam, a comprehensive genetic risk evaluation, analysis of your dietary diary, and an assessment of your stress level and sleeping habits — not just an analysis of your gut microbial ecology.
At The Harlin Center, we recommend specific dietary interventions that offer a means for altering the intestinal microbial structure, changing the course of many intestinal and systemic disorders. You may be given a prescription for specific dietary and lifestyle modifications, a limited duration prescription for a specific medical food (probiotic), and, if appropriate, a prebiotic supplement.
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