adaptive immune system
The body’s defense system that learns and remembers how to react against foreign invaders.
Chemical messengers that initiate and regulate the immune response.
A severe immune reaction triggered when cytokines flood the bloodstream in excessive amounts, causing extreme damage or death.
An imbalance in the number and diversity of a person’s natural gut microbiota.
See lipopolysaccharide (LPS).
A group of bacterial communities living together in the gut.
fecal microbiota transplant (FMT)
The transfer of fecal bacteria and microbes from a healthy individual to a diseased recipient in order to restore their microbiota balance.
The presence of DNA in an individual from a distantly related population.
Do not retain the color of the crystal violet Gram stain; have an outer cell membrane with endotoxins on their surface.
Retain the color of the crystal violet Gram stain; easily absorb foreign material because they do not have an outer cell membrane.
The bidirectional signaling pathway between the gastrointestinal tract and the central nervous system.
The collective genetic material of all the microorganisms in the intestine.
The bacteria, fungi, and viruses that live inside your intestine.
Under-stimulation of the immune system because of an environment that is too clean that results in an overreaction to harmless stimuli; believed to increase the incidence of allergies and autoimmune diseases.
human leukocyte antigen (HLA)
Molecules that present fragments of pathogenic proteins to the immune system’s T- and B-cells for elimination.
Occurs when the lining of the intestinal tract develops cracks or holes, setting the stage for tissue damage that leads to inflammation.
The main component of the outer membrane of gram-negative bacteria; potent stimulators of the immune system that can lead to chronic inflammation if they reach the bloodstream.
An imbalance between the production of free radicals and antioxidant defenses.
Specialized plant fibers that the human body can not digest that act as food for probiotic bacteria.
“Good” bacteria that improve or restore the balance of microorganisms in the intestine, conferring health benefits to the host.
short-chain fatty acids (SCFAs)
The main communication molecules between the host and gut microbiota.
The intestine has become one of the most important organs in terms of disease protection, because of its microbiome.
The gut microbiota refers to the bacteria, fungi, and viruses that live inside your intestine. There are many trillions of these cells in the human body, weighing as much as five pounds and out-numbering human cells by as many as 10 to one. Together, the gut microbiota and its microbiome — the collective genetic material of all the microorganisms in the environment — function as an extra organ in your body. This organ plays an important role in your health; from metabolism to behavior, immunity to disease.
A diverse gut microbiome is generally associated with better health, as there is always a microbe available to fulfill a function should another be unable.
From birth, humans begin building their gut microbiome as they interact with their environment, reaching a certain composition with age. This composition is dynamic in nature and can be modified by various factors throughout life.
One of the first exposures to microbes in newborns is during the birthing process. During vaginal births, infants are enriched with good bacteria from the mother’s vaginal microbiota whereas children born via C-section don’t receive this benefit. This puts the latter group at higher risk for developing an imbalanced gut microbiome, leading to higher rates of asthma, allergies, obesity, and autoimmune disorders than those born vaginally.
The composition of microbiota in the gut depends more on the geographic origin of populations, rather than being genetically-influenced. However, studies have shown that significant variations within individuals of the same community do exist, and these differences can be attributed to ethnicity. It’s been found that members of the same race have microbiota compositions more similar than those of different racial backgrounds.
Another factor found to influence the gut microbiota is socioeconomic status (SES), with individuals in higher SES neighborhoods found to have greater diversity in their microbiota. This is in part due to diet, as individuals in more affluent neighborhoods tend to have diets that are enriched for fresh fruits and vegetables, relative to simple carbohydrates, fats, and sugars. With a lower diversity in the gut microbiota, the host craves and consumes more food, eventually resulting in obesity, defined by a body mass index (BMI) greater than 30.
People tend to belong to one of two microbiome groups based on their long-term eating patterns. These groups of bacterial communities living together in the gut, known as enterotypes, are:
- Prevotella (plant-based diet) — a diet of primarily carbohydrates: high-fibre grains, legumes, fruits, and vegetables; as well as sweets and pastries.
- Bacteroides (Western diet) – a diet of primarily animal protein and fats, plus refined sugar.
Research in this area is ongoing and new evidence suggests that there may be a third enterotype, Enterobacteriaceae, in the gut microbiota of Asian populations with a high consumption of starch-rich foods, such as rice.
It’s possible for a person’s enterotype to change by making alterations to his or her diet. Knowing which enterotype an individual has, and how to change it, may help doctors in prescribing the most effective drugs and dietary practices for patients.
Diet and microbiota health
A healthy diet keeps the composition of gut microbiota in balance.
Gut microbiota are vital to our health through their influence on various metabolic activities. The bacteria in the gut help to synthesize vitamins, aid in the absorption of minerals, and metabolize drugs and food toxicants. As well, there are some components of dietary fiber that humans are unable to break down due to a lack of required enzymes. The “good” bacteria in the gut, known as probiotics, are able to digest non-absorbable fiber and resistant starches to produce short-chain fatty acids (SCFAs). SCFAs are the main communication molecules between the host and gut microbiota.
The most common SCFAs are acetate, propionate and butyrate, which provide a major source of energy and nutrients to the host cells, and stimulate the production of innate immune cells. Acetate is used by muscle, propionate is used by the liver to produce ATP (an energy source for cellular processes), and butyrate is an important anti-inflammatory metabolite for the intestine.
A healthy diet that minimizes inflammation can reduce the incidence of various disorders, including some cancers and Covid-19. A change in diet can alter the composition of the gut microbiome, and your overall health, in a relatively short period of time. It does this by making different nutrients available, which in turn changes the bacterial species that dominate inside the intestine. This imbalance in the number and diversity of a person’s natural gut microbiota is known as gut dysbiosis, and has been associated with several chronic disorders.
Gut health can be improved by:
Eating probiotic foods containing live “good” bacteria that help restore the gut to a healthy state after dysbiosis. They do this by “reseeding” the intestine with beneficial strains of bacteria. Probiotics are found in fermented foods such as yogurt, sauerkraut, kombucha, pickles, and kefir.
Consuming fiber-rich foods that increase butyrate production. Butyrate has anti-inflammatory properties and help maintain the intestinal barrier. Foods that contain a lot of fiber include legumes, whole grains, fruit, and vegetables.
Increasing your intake of prebiotics, which are specialized plant fibers that the human body can not digest. Instead they act as food for probiotics, stimulating their growth and thus maintaining a healthy gut microbiome. Prebiotics can be found in foods such as potatoes, artichokes, asparagus, garlic, barley, underripe bananas, oats, wheat bran, and apples.
Eating foods rich in polyphenols, which are plant compounds found in red wine, tea, dark chocolate, berries, olive oil, nuts, and whole grains. Polyphenols are micronutrients broken down by the microbiome to stimulate healthy bacterial growth, and are also powerful antioxidants.
Trying a plant-based diet to help increase gut microbiota diversity and reduce levels of disease-causing bacteria, inflammation, and cholesterol.
Limiting the amount of meat consumed. In diets high in meat and animal products, there are increased abundances of bacteria that may promote inflammation in the gut.
Limiting your intake of artificial sweeteners such as aspartame, which increase blood sugar by stimulating the growth of unhealthy bacteria in the gut microbiome.
Take antibiotics only when necessary: Antibiotics kill good bacteria as well as bad bacteria in the gut microbiome, contributing to gut dysbiosis and antibiotic resistance.
While a large selection of probiotic supplements are available, keep in mind that the Food and Drug Administration has not yet approved them, although they do regulate probiotics in food to some extent. Before taking any probiotic supplement, speak to your healthcare provider, as they may be able to recommend safe and effect products.
Immunity and inflammation
Gut microbiota influence the level of inflammation in the body and the accompanying risk of disease.
Inflammation is the body’s automatic defense response to a foreign pathogen and is necessary to fight illness and promote healing. However, when inflammation becomes chronic it can result in diseases such as obesity, atherosclerosis, and cancer.
Bacteria in the gut communicate with immune cells through powerful chemical messengers called cytokines that initiate and regulate the immune response, beginning with inflammation. Cytokines recruit immune cells to fight pathogens and can enhance the ability of these cells to move from the circulation to the site of infection. However, if cytokines are not controlled they can flood the bloodstream, triggering a severe immune reaction that can cause extreme damage or even death. This is known as a cytokine storm, and can happen in autoimmune diseases such as lupus and rheumatoid arthritis.
Some gut microbiota may associate with anti-inflammatory cytokines, while others may interact with cytokines that promote inflammation both locally and systemically. Pro-inflammatory micro-environments are generally associated with driving the development of disease.
The microorganisms in the gut also regulate the permeability of the intestinal wall, with certain species of bacteria promoting a leaky gut. When this happens, metabolites produced by the bacteria leave the gut and enter the bloodstream, initiating an immune response. One such metabolite is a Lipopolysaccharide (LPS), a large molecule that is the main component of the outer membrane of Gram-negative bacteria such as E. coli. Gram-negative bacteria, so-called because they do not retain the color of the crystal violet Gram stain, are difficult to kill due because of their outer lipid membrane.
Also called endotoxins, LPS are potent stimulators of the immune system that do not cause harm if they remain in the gut. However, if they reach the bloodstream, LPS can prolong the inflammatory response, promoting further permeability of the intestine, leading to a chronic cycle of inflammation. Eventually, systemic inflammation, illness, and even sepsis can occur.
Gut dysbiosis and disease
A healthy gut microbiota balance is important for optimal metabolic and immune function, as well as disease prevention.
Every individual is unique, and so is the specific combination of bacterial species in a person’s gut. As such, optimal gut microbiota composition can vary from person to person.
Gut dysbiosis has been associated with several chronic diseases such as inflammatory bowel disease, multiple sclerosis, autism spectrum disorder, and obesity. The imbalance may be caused by things like antibiotic use, accidental chemical consumption or more often, diet. Disruption of the gut bacteria allows competing pathogenic organisms to become established and cause illness.
Probiotics help maintain and restore a healthy gut microbiome, ensuring optimal function. Bacteria of the Lactobacillus genus are the most prominent probiotics in the gut, with more than 100 different known species. These bacteria are Gram-positive, meaning they retain the color of the crystal violet Gram stain and easily absorb foreign material because they do not have an outer cell membrane. Lactobacilli help to improve a myriad of conditions including treating diarrhea, preventing eczema and colic, lowering cholesterol, and reducing swelling of rheumatoid arthritis. Lactobacilli can also boost the immune system and inhibit the growth of cancer cells in the colon and mammary glands.
As the name implies, Lactobacilli produce lactic acid as a by-product of glucose metabolism. Certain species, such as L. acidophilus, produce primarily lactic acid, while other species, such as L. fermentum, also produce hydrogen peroxide, creating conditions in the gut that disallow the growth of pathogenic bacteria. Lactic acid also increases the absorption of minerals such as calcium, magnesium and iron.
Like Lactobacilli, members of the Bifidobacteria genus also produce lactic acid, providing much of the energy used by intestinal wall cells in maintaining the protective barrier in the gut. There are nearly 50 species of Gram-postive Bifidobacteria, whose functions include digesting fiber and complex carbohydrates, producing B and K vitamins, preventing food poisoning, and fighting tumors. One species in particular, B. bifidum, can help repair stomach ulcers caused by Helicobacter pylori.
Conversely, there are Gram-negative bacteria in the gut with LPS on their surface that induce inflammation and contribute to disease. One such genus, Bacteroides, are bile-resistant pathogens found in most anaerobic infections. These bacteria can be beneficial if retained in the intestine where they digest carbohydrates, providing a significant proportion of an individual’s daily energy requirement. However, if Bacteroides escape the gut and enter the bloodstream, they can cause sepsis and other serious illnesses. Unfortunately, Bacteroides have the highest antibiotic resistance rates of all anaerobic bacteria, making treatment difficult.
Proteobacteria are a large group of bacteria that include many healthy gut species, as well as several well-known pathogens, such as Escherichia, Salmonella and Helicobacter. An increasing amount of studies have shown Proteobacteria to be a “microbial signature” of disease, as their abundance is increased in the microbiota composition of those affected by chronic disorders. This includes metabolic disorders, such as obesity and diabetes; inflammatory conditions, including irritable bowel disease, Crohn’s disease and ulcerative colitis; and lung diseases, such as asthma.
Microbiota may represent a novel target for the development of new therapeutic strategies to manage a wide range of disorders.
Changes in the gut microbiome are implicated in several autoimmune conditions including lupus, type 1 diabetes, rheumatoid arthritis and multiple sclerosis.
Autoimmune disease results from a malfunctioning adaptive immune system, which is the body’s defense system that learns and remembers how to react against foreign invaders. In autoimmune disease, cells of adaptive immunity mistakenly produce antibodies against one or more of the body’s own proteins, and thus attack healthy cells.
Development of an autoimmune disease is often traced to alterations in the human leukocyte antigen (HLA) genes, which code for molecules that present fragments of pathogenic proteins to the immune system’s T- and B-cells for elimination. The immune cells then recognize and attack intruders carrying those same fragments. Normally T- and B-cells ignore the body’s own cells, but in autoimmune disease this doesn’t happen.
HLA genes are highly polymorphic, meaning they occur in several different forms. The genetic variation in HLA genes results in changes to the structure and binding capabilities of the molecules that present pathogenic protein fragments to immune cells. Researchers have found that the inability to present pathogenic proteins leads to distinct changes in gut microbial composition and structure, namely a decrease in probiotic Lactobacillus species. HLA polymorphism could therefore be a significant factor in controlling immune responses to microbes in the gut, thus driving autoimmunity.
Further influencing development of autoimmune disease is the large number of genes in the gut microbiome, estimated to be more than 22 million genes. The proteins produced by these bacterial genes are scrutinized by the immune system and are usually found to be harmless. However, sometimes bacterial proteins that activate immune cells contain fragments that closely resemble those of normal human proteins. The likelihood of these similarities is high, as there are roughly 100 times as many microbial genes compared to human genes. In such cases of molecular mimicry, the immune system gets confused and starts recognizing human proteins as threats. Immune cells begin reacting against bacteria, and then end up reacting against our own self proteins.
There exists variation in the incidence and severity of autoimmune disease among ethnic groups, although the reasons remain unclear. Of great interest in the modern genomic era is the study of admixture in populations and the resulting association with autoimmune and infectious disease.
Genetic admixture is the presence of DNA in an individual from a distantly-related population, which results from interbreeding of two previously isolated populations. Mexican Mestizos (individuals of European and Amerindian ancestry) are a well-studied admixed population because of their high incidence of autoimmune disease and the potential ability to discover disease-associated genes through admixture mapping.
A method of gene mapping, admixture mapping looks to determine the location of genes that contribute to variations in diseases between different ancestral lineages within an admixed population. By measuring how often genetic markers called ancestry informative markers (AIMs) appear next to each other in different populations, genetic diversity can be estimated. With each passing generation, groups of genes that are inherited from a single parent are split up, making the population more genetically diverse.
Given that microorganisms are strong agents of natural selection, genetic variation that protects against pathogens presents an advantage for host survival. It is likely that in the case of these immune-related genes, an autoimmune disorder is an unrelated consequence of selection of the resistance gene. As such, high levels of HLA polymorphism are an advantage, providing resistance against multiple pathogens and explaining the susceptibility to autoimmune disease in certain populations.
The hygiene hypothesis
When it comes to the formation of the immune system, exposure to microbes is essential for future health.
Humans are exposed to a myriad of microorganisms in the first few years of life, building their microbiome as they interact with the world around them. These first microbes are critical for the development of the adaptive immune system, which remembers how to react against foreign pathogens after encountering them, allowing for a faster immune response upon repeat exposure.
When a young child’s environment is too clean, or hygienic, the immune system is under-stimulated and can overreact to harmless environmental stimuli, such as pollen. This is known as the hygiene hypothesis and it is believed to be the origin of the increasing incidence of allergic and autoimmune disease in developed countries.
In the last 200 years, a hygiene revolution has taken place in industrialized nations across North America and Europe, with drastic improvements to sanitation and water quality. With these changes, people began washing their hands, their food, and their environments, thus decreasing their exposure to bacteria. This in turn led to a decline in infectious diseases among these populations.
One such example occurred in Scandinavia during the 19th century. When Scandinavians became more hygienic, the incidence of Tuberculosis (caused by Mycobacterium tuberculosis) decreased significantly. However, these hygienic changes resulted in an increase in autoimmune diseases such as diabetes, multiple sclerosis, arthritis, and lupus.
Neurological and neuropsychiatric disorders
The gut microbiome is often referred to as a “second brain” due to its complex network of neurons embedded in the gut wall.
Recent studies have shown that microbes in the intestine can influence neural development, brain chemistry and a range of behavioral outcomes. The opposite is also true, with the brain being able to influence the gut microbiota. When experiencing even mild stress the microbial balance is altered and can leave an individual more vulnerable to infection.
The gut-brain axis refers to the bidirectional signaling pathway between the gastrointestinal tract and the central nervous system, whereby bioactive compounds produced by gut bacteria influence brain function. The vagus nerve appears to be the main signaling pathway of the gut-brain axis, as the effects of gut microbiota on behavior, stress response, and brain biochemistry are found to disappear when the vagus nerve is severed.
Bacteria of the intestine play an important role in:
- neuropsychiatric disorders such as depression, anxiety and schizophrenia;
- neurological disorders such as autism spectrum disorder, multiple sclerosis, Parkinson’s disease and Alzheimer’s disease;
- cognitive processes such as learning and memory.
Research is currently being done to understand how certain bacterial species affect various brain disorders. For example, it’s known that Clostridia bacterial pathogens in the gut generate the short-chain fatty acid propionate, which is known to disrupt the production of neurotransmitters, while members of the Bifidobacterium and Lactobacillus genera have shown the most potential in relieving symptoms of certain central nervous system disorders.
To understand this further, we look at the gut microbiota’s influence on autism spectrum disorder (ASD). Approximately 40% of ASD patients experience gastrointestinal symptoms, so it’s no surprise that researchers have shown the microbiome of autistic children to be less diverse and overgrown with harmful bacteria than that of neurotypical siblings and healthy controls.
Preliminary studies examining the role of gut microbes on social brain function are promising. In a study at Arizona State University, children with ASD took the antibiotic vancomycin for two weeks to remove existing bacteria, then received gut microbes from donors without autism for seven or eight weeks. At the end of the 18-week study, the children’s gastrointestinal symptoms had reduced by 80% and autistic behaviors had improved. After two years improvement remained, with the children reporting being affected by their autism 47% less than they had been at the beginning of the trial. As well, the children had increased gut-bacterial diversity and greater numbers of healthy gut bacteria, such as Bifidobacteria and Prevotella.
Among all diseases and syndromes linked to the gut microbiome, cancer is one of the most complex and widely studied.
Dysbiosis in the intestine associated with chronic inflammation is connected to several types of cancer, including colon, breast, liver, pancreas, and prostate cancers. In fact, there is a bidirectionality between the gut microbiome and cancer in that the development of cancer may alter the microbiome and, in turn, changes in the microbiome may affect cancer progression.
Studies have determined that the gut microbiome can either suppress the proliferation of tumors or promote their growth. Some genera of bacteria, such as Lactobacillus and Bifidobacteria, are known to prevent tumor formation, while other genera such as Bacteroides and Clostridium have been associated with an increase in tumor growth rate.
Short-chain fatty acids produced when probiotics digest fibers may be involved in tumor suppression. Butyrate and propionate inhibit an enzyme in tumor cells called histone deacetylase, which causes abnormal transcription of key genes that regulate cell proliferation, cell-cycle regulation and cell death, leading to tumor formation.
Other molecules derived from probiotics help to regulate the immune system, triggering an indirect response against tumor development. For example, Lactobacilli may stimulate the activation of immune cells such as natural killer (NK) cells, dendritic cells, and T cells, which in turn leads to the elimination of cancerous cells.
Lactobacillus rhamnosus GG (LGG) is the most studied probiotic bacteria in cancer today. LGG are being used as a supportive treatment for anti-cancer therapies due to their ability to counteract pro-inflammatory molecules, gastrointestinal toxicity, as well as cancer growth. It has been shown in several in vitro tumor models (including colorectal, ovary, breast, cervical, and hepatic) that LGG is able to reduce the ability of cancer to both proliferate and metastasize.
Harmful species of gut microbiota may increase in abundance due to dysbiosis, producing cytokines and toxins that increase inflammation and cause tumor promotion. These toxins can induce breaks in the host’s cellular DNA via the generation of oxidative stress, which is an imbalance between the production of free radicals and antioxidant defenses. Oxidative stress contributes to mutations that initiate tumor development and progression, and can also interfere with the body’s response to DNA damage and repair. This is found to happen both with localized cancers of the gastrointestinal tract, as well as with other distal cancers throughout the body.
Bacteria in the gut have also been shown to stimulate tumor formation indirectly by blocking function of immune cells that normally stop tumor growth. For example, Fusobacterium nucleatum inhibits NK cell activity in order to recruit cells that suppress immune function to the tumor site, therefore allowing cancer cells to proliferate.
It’s important to note that although there are examples of pathogenic bacteria capable of promoting cancer cell development, no strong bacterial oncogenic driver has yet been identified.
Gut microbiota influences the severity of COVID-19 infection and the strength of your immune system response.
Many factors contribute to the severity of symptoms experienced by those with Covid-19. SARS-CoV-2, the virus that causes the illness, disproportionately affects those who are obese, have underlying conditions such as diabetes, are older, and belong to an ethnic minority.
Researchers have found that patients with severe Covid-19 have high levels of circulating pro-inflammatory cytokines, as well as an altered gut microbiota composition. It appears there exists a spectrum of microbial composition among mild, moderate, severe, and critical Covid-19 patients. Furthermore, some patients continue to show gut dysbiosis as long as 30 days after the virus is no longer found in the body. This could explain why certain patients, knows as long-haulers, experience persistent symptoms over weeks and months.
In the United States, African Americans and Latinos are the ethnicities with the highest rate of infection and death from Covid-19, however this is independent of genetics. In fact, it’s the response of their immune system that affects the severity of their reaction. These populations are often less hygienic, immunologically speaking, due to living in a lower SES communities with diets that promote an unbalanced microbiome, inflammation, and obesity. With a higher rate of systemic inflammation, and thus more circulatory cytokines, these populations are more susceptible to having a severe immune reaction to SARS-CoV-2.
In individuals with obesity and diabetes, it appears that glucose is responsible for fueling the damage caused by SARS-CoV-2. The virus targets and binds to a specific protein on the surface of body cells called ACE2. Diabetes and obesity cause high levels of glucose in the body, which increases the amount of ACE2 proteins on the surface of immune cells called monocytes and macrophages. Thus, the virus infects the very immune cells that should be attacking it, and causes these cells to release an abundance of inflammatory cytokines. The higher the levels of glucose, the more successful the virus is at infecting the cells, and the greater the possibility of a life-threatening cytokine storm.
This same inflammatory profile is also evident in some people over the age of 60, and is known as inflammageing. While genetics can influence inflammageing, the gut microbiota are also involved.
Fecal microbiota transplant
Once considered a last resort therapy, fecal microbiota transplant has been regulated as an experimental drug in the United States since 2013.
Fecal microbiota transplant (FMT) is the process of transferring fecal bacteria and other microbes from a healthy individual to a diseased recipient in order to restore their microbiota balance.
FMT is used as a treatment for C. difficile-associated disease, which kills approximately 15,000 people in the United States each year. Research consistently finds that FMT is 85-90% effective in people for whom antibiotics have not worked, or the infection has recurred after antibiotic treatment. Often, one FMT treatment is enough to rid the patient of infection.
Fecal donors are carefully screened for chronic medical diseases and gastrointestinal infections to ensure a healthy transplant. Administration of the FMT is done through a colonoscope, enema, or by mouth in the form of a capsule. All procedures are done in a clinical environment to ensure safety.
Research is currently being done to determine other conditions that FMT may be used to treat. Success has been shown with irritable bowel syndrome and ulcerative colitis, and even a case of a patient with treatment-resistant bipolar I disorder. Eventually, FMT may be used to treat a variety of diseases including diabetes, multiple sclerosis, obesity, arthritis, and asthma.