The Microbiome in Health and Disease

The internal linings and external skin surface of the body are composed of epithelial cells that are colonized by microorganisms that comprise the human microbiome. These microbial communities consist of primarily bacteria but also viruses, protozoa, fungi and archaea,which are single cell organisms distinct from bacteria. These microbes colonize the epithelial surfaces of the intestines, lung, bladder, vagina, and skin, each with a distinct pattern of beneficial residents. 

Over 95% of this composite microbiome exists in the digestive tract, primarily the colon, where its actions are essential for gut homeostasis exerting local as well as systemic effects. Estimates vary as to their numbers which are in the trillions, and conservatively are equal to or more likely exceed the number of cells in the body. In addition, it possesses a vastly greater genetic diversity, with 100x the amount of genomic content as our human genome.

Normal Digestion 

Multiple components are required to provide optimum digestion of our foods and requires an interconnected synchronized system that allows foods to be transported,p rocessed and absorbed along the intestinal tract with the elimination of any of their waste products.

 The mouth provides adequate chewing and saliva to moisten food and breakdown starch to initiate the digestive process. Swallowing propels it into the stomach which provides a reservoir for food, acid secretion to break down food, and motility or movement into the small intestine. It also regulates appetite and feelings of satiety via hormonal interaction with the nervous system. The small intestine continues the digestive process by combining pancreatic enzymes with bile produced in the liver to break down fats, proteins, carbohydrates, vitamins and minerals where they are absorbed into the circulation along with water. And the large intestine primarily absorbs water and electrolytes from indigestible food to create solid waste, which it stores until eliminated, and it has a beneficial microbial community that ferments undigestable carbohydrates to produce short chain fatty acids (SCFA), as well as synthesizing vitamin K and certain B vitamins that can be absorbed. THE SCFA offer barrier protection and an energy source for the colon cells as well as heping regulate inflammation and the immune responses. 

Microbiome Contributions in the Digestive System

That Are Altered in Dysbiosis or Microbial Imbalances

  • Regulates immune functions by assisting in regulating epithelial function, limiting exposure to immune system reactions.

  • Protection from pathogens

  • Undigested dietary carbohydrates in fiber can be metabolized to SCFA, short chain fatty acids, needed for intestinal cell energy, especially for colon cells

  • Prevents the accumulation of by products from gut metabolism that are toxic

  • Metabolizes some proteins to allow specific amino acids to be taken up by bacteria and converted to other molecules. As an example glutamate amino acid can be converted to GABA, a molecule important in calming the nervous system.

  • Synthesize Vitamin K, needed for clotting

  • Produce components of B vitamins 

  • Synthesize CLA, conjugated linoleic acid, which controls weight gain in aids the prevention of obesity and diabetes

  • Conversion of inactive bile to active forms for lipid metabolism, and then the colon recycles it.

  •  Creates molecules needed for Krebs cycle energy production in the mitochondria.

  • Transform bound dietary polyphenols to active forms to be used as antioxidants

Other beneficial or commensal microbial population can:

  • Prevents the growth of unwanted often pathologic bacteria

  • Downregulates NF-kappa B, a signaling pathway for inflammation, maintaining balance under normal circumstances, but allowing their activation of an inflammatory response when invaded by pathogens. 

  • Decreases IL6 and IL4, molecules that increase immune reactions 

  • Promotes CD4 helper immune cells to fight infectious pathogens

  • Shown to decrease neuroinflammation

  • Helps decrease damage from alcohol

  • Decreases production of glucose by the liver and improves insulin sensitivity

  • Produces signaling molecules to control of blood pressure.

The Innate and Adaptive Immune System Within the Gut

The microbiome has diverse multiple functions, part of which are to interconnect, interact and work symbiotically with the immune system. The beneficial microbiome can participate directly by signaling the immune system of a foreign intruder and the promotion of regulatory T cells to maintain balance and prevent an overactive response. Both the mucosal surface and the deeper tissues can respond with the innate or adaptive immune system.  

The innate system acts with a non-specific response and is our first line of defense. responding promptly and quickly. Using sensor cells, the macrophages, dendritic cells and mast cells these cells can recognize gut pathogens based on molecular patterns and can then activate an immune response. Then white blood cells and the complement system are enlisted to promote an acute inflammation and the resulting attraction of other immune cells, targeting pathogens for immediate attack, and helping destroy and dispose of them.

The adaptive system is a more refined aspect of the immune system. Its actions can identify distinct antigens that activate our T and/or B cell lymphocytes for a response. While the innate system is a rapid non-specific responder, the adaptive system is more strategic and responds to specific antigenic threats, and can evolve and establish an immunologic memory. When reexposure to that same antigen occurs, it can activate an accelerated response. The system is capable of responding to a variety of foreign antigens, toxins, allergens and even cancer cells and is extremely robust in destroying pathogens, viruses, bacteria and parasites. There is also T cell memory that creates a catalog, so to speak, of harmless substances that while foreign offer no threat and no immune response.

There are many lymphoid tissues associated with T and B cell immune functions within the body consist of the lymph nodes and lymphatic channels, which are channels or vessels that carry antigens to these lymph tissues and “present” them for recognition and immune actions. The spleen is our largest lymphoid organ and removes aged cells and also responds to pathogens in the circulation. 

There is also the MALT, the Mucosal Associated Lymphoid Tissue,found in the mucosal epithelial cells of the intestine, lung bladder, and urogenital tracts and the GALT, the Gut Associated Lymphoid Tissue which represents an immune response from the deeper tissues beneath the mucosal surface. 

 T and B cells are the actors of the Adaptive Immune System in the MALT or GALT originating in the bone marrow, and traveling to the thymus where they mature and are enzymatically modified and develop specific antigen receptors. Before being activated, they are assessed as to their ability to discriminate self, versus non self antigens, to protect from autoimmune reactions, 

T cells have the potential to differentiate into helper cells, to support the immune response, cytotoxic cells that kill infectious pathogens and cancer cells and regulatory T cells created to maintain immune balance.  B cells are also lymphocytes that require an interaction in conjunction with T cells to be activated. The B cell receptor binds to a matching receptor on an antigen and then internalizes it and presents it on its surface. They then can differentiate into plasma cells that make antigen specific antibodies.

The Mucosal Barrier in the Intestine

 The outer mucosal epithelial layer of the intestinal tract, and in the respiratory system, use the (MALT) to interface with the outer environment with its interaction in digestion, defending against exposures to foreign substances that enter through the outer portals or entryways into the body. These defenders are the initial frontline barrier acting as a safeguard. This system is composed of:

  • Epithelial cells are the surface intestinal cells that absorb nutrients and fluids. Interact with immune cells to help determine safe versus unsafe substances, produce mucous for protection, enhance the barrier to prevent foreign invasion

  • Paneth cells produce antimicrobial proteins to destroy pathogens, including bacteria, viruses, and parasites, provides barrier protection and supports the stem cells that replace old or damaged intestinal cells.

  •  Mucus cells coat the lining cells for protection, offers structure for microbial growth and assist in immune protection

M cells, interspersed between the epithelial cells are M cells which directly sample the intestinal contents in the small intestine and act as immune sensor cells on the surface that can provide surveillance and can send information to lymphoid follicles, called the Peyer’s patches located beneath the outer epithelial layer.

The GALT

The interior tissues have a combination of individually circulating l immune cells; sensor cells, T cells, B cells, antibody producers, macrophages, and monocytes as well as the GALT. This complex is considered a more global response and called (GALT) ).When the epithelial barrier is damaged, and an overwhelming number of pathogens and toxins enter the deeper tissues, the GALT is able to provide immune reinforcement by stimulating increased inflammation both in local tissues and systemically via the local circulatory system, often inducing a systemic inflammatory response.

The Intestinal Barrier 

The outer epithelial layer of the intestinal tract interfaces with the outer environment, and affords the initial line of defensive protection and defense against pathogens, pollutants and environmental toxins. Its integrity is based on a composite of interconnected adherent proteins to keep the junctions between cells impenetrable. Thus, the mucosal layer acts as a physical barrier but also provides immune surveillance and response. It also functions in immune tolerance. The mucosal layer is exposed to an enormous number of substances, specifically food antigens, thousands of species of bacteria, fungi and viruses which all of which must be discriminated against as either friend or foe. While the innate immune system is instinctually reactive to an unknown substance the more evolved adaptive immune system differentiates and stores an immune memory of which antigens especially foods, are harmless, and require no intervention. 

If it is damaged, the surface immune protection becomes inadequate and undesirable molecules and antigens can then pass into the interior tissue where they encounter the lymphatic immune system lying beneath the intestinal mucosa. While other mucosal surfaces in the genital, urologic and respiratory tracts have similar protective mechanisms, the intestinal immune system represents 70% of our total immune system. 

Damage to this mucosal layer by specific Insults are capable of damaging the gut as well as affecting the microbiome. These include:

Environmental agents:

Diesel & other hydrocarbons

Organic compounds, benzene, formaldehyde

Microplastics in the water, air and soil

Solvents 

Ozone: traffic, power plants, forest fires, industry

Detergents 

Glyphosate 

Other Sources:

Multiple Pathogens, EBV and other viruses, mycotoxins, dysbiosis alterations, SARs-Cov-2 

Food additives

Antibiotics 

Alcohol/ excessive Fat and Sugar

NSAIDs

Allergens: foods, animals, grasses/weeds

Processed foods

Leaky Gut or Gut Penetrability 

With damage to the epithelial mucosal layer of the small intestine, called Leaky Gut, the barrier and the protection it affords no longer prevents the increased amounts of different microbial pathogens, toxic substances and food molecules from penetrating the interior connective tissue layer, the lamina propria area, activating a much larger amplified immune system response to control the breach. 

Initially in the lamina propria, beneath the mucosal layer, there are sensor cells, called antigen presenting cells, (APC’s). These cells bind the antigen at receptor sites on their surfaces, move it to their interior where cytokine proteins are produced and then released to mobilize other immune responses. These cells are the white blood cell neutrophils, and lymphocytes that proliferate in number and types producing inflammatory, Th1 cells, T helper cells, Th17, and allergic T responses, TH2, and B cells that produce immunoglobulins .Generally, if the exposure is short lived the response declines and balance is restored. However if the damage is persistent and chronic these antigens, pathogens, foods and toxins can potentially enter the blood circulation and initiate similar inflammatory responses throughout the body. Other generalized symptoms of inflammation occur with fatigue, achiness, joint pain, cognitive impairment and sleep disruption, often along with mood alterations.

When intestinal damage occurs many of the symptoms are familiar digestive problems and in the media have become the focus of constant recommendations for probiotics, fiber to regulate constipation, medications for stomach over acidity or gas, and contemporary pharmaceutical therapies for immune related GI diseases like Chrohn’s disease and Ulcerative Colitis.

Symptoms that can be initiated or aggravated by leaky gut include indigestion, acid reflux and heartburn, abdominal pain, distention, gas, bloating, diarrhea, constipation, and food reactions and sensitivities, and can range from an occasional annoyance to situations that persistently interfere with daily routines. Many of these symptoms are self limited and self inflicted and can be improved with dietary and lifestyle changes and/or the addition of supplements or over the counter medications.But sometimes they provoke enough concern to seek professional advice and with the rise in intestinal cancers, often occurring at younger ages, evaluations need to be considered to allay or confirm these concerns.

Interestingly, even with lab testing, radiologic imaging and even direct visualization of areas of the intestine sometimes a definitive causative diagnosis cannot be made. Treatments offered therefore are often a prescription medication for symptom relief, due to a lack of a firm cause for the problems. 

It is frequently recognized in many chronic conditions that there is an association with intestinal barrier injury and microbial damage, dysbiosis reinforcing a recognition that measures to reduce symptoms unrelated to the gut should include dietary therapies beginning with:

Diets avoiding highly processed foods, limiting red meat, sugar, coffee and alcohol, and incorporating abundant fresh fruits and vegetables, whole grains, fermented foods, and purified water as a basic foundation for health. Yet even with the best intentions and discipline, unknown subtle minute exposures, from industrial chemicals, herbicides and pesticides, heavy metals, GMO grains, and pathogenic microbes will continue to trigger damage to the microbiome the intestine. 

Evaluating Gastrointestinal Function

The appearance of persistent GI symptoms whose causes are not detected or determined, even after a thorough western evaluation, present a quandary as to how to proceed and what to do. And while intestinal components needed for optimal digestive functioning are composed of multiple interconnected pieces, disruptions to the microbiome or barrier damage create dysfunctions that impact not only digestion but other organ systems as well. 

The ability to gain a more complete picture of specialized digestive functions is now available through gastrointestinal specific laboratories utilizing cutting edge diagnostic technology applied to stool testing. Levels of enzymes, adequacy of fat metabolism, inflammatory markers, gluten antibodies and immune function are standard tests. Microbiome measurements include beneficial bacteria or commensals, injurious pathogens; bacteria, viruses, parasites, protozoa and fungi, and their presence is determined by polymerase chain reactions (PCR testing) which calculates specific quantities of each organism's DNA. Testing also can detect damage to the protective barrier within the intestine, creating leaky gut.

With the correct data to differentiate the type of dysbiosis or barrier injury, treatment plans can be determined based on

The Principles and Areas of Need In Rebalancing the GI System

  • Healing gut integrity requires the repair of both the barrier function and the mucosal cells. An integrative model replaces needed nutrient deficiencies through diet coordinated with natural effective supplementation for cellular recovery. and rejuvenation. 

    In Chinese Medicine herbal therapies their perspective views imbalance in the gut as consisting of two components. The first is to restore the energy needed for digestion and movement in the tract to be accomplished. And while supplementation provides resources for damaged cellular pathways of function, herbal formulas actually nourish cells and help restore health using plant based combinations that work synergistically together.In the Chinese model, it has been recognized for millennia that the digestive system is the basis of the immune system, with repair being necessary both digestive and immune support. This system also evaluates the influence from other organs on digestion. Therapies always consider the role of whether an organ system is enhancing digestion or impairing it and what is needed to balance their interaction. Please see the article on Chinese medicine to better understand organ system interactions. 

    Together, combining these two paradigms offers a better opportunity for recovery and rejuvenation by approaching a problem from two perspectives that complement each other. 

  • Replacement of digestive enzymes and sometimes stomach acid and bile are needed to help break down the foods to allow absorption. Often damage to the intestinal system impacts their production secondary to the inflammatory process. So even with a good diet the nutrients the food must be broken down to access the needed nutrients.

  • Remove injurious infectious pathogens that are capable of causing gastrointestinal damage. These responsible pathogens include bacteria, parasites, viruses and fungi which can imbalance the normal microbial community’s actions, allowing the emergence of unwelcome strains, and cause injury to the intestinal structure and functions. Often this can be a process that requires not only antimicrobials but also supplements that can interrupt the formation and disperse the protective shields, the biofilms, that microbes create to avoid detection and impede immune recognition.

  • Reinoculation is necessary to restore beneficial bacteria to augment, replace and rebalance the commensal community. The merchandising and sale of probiotics is a huge business. And while we know the essential species of the needed components, understanding which bacterial species help specific problems or address the needs in the gut is still a work in progress. For example, the lactobacillus family of bacteria has dozens of different species. So choosing the combination for a specific problem still is primarily an intelligent guess. The total number of probiotics varies, and how much is needed for balance or replacement is also unknown. Serious GI illness has been shown to benefit from combined bacterial species, but your practitioner is needed for those decisions. It is also important to increase the amount slowly as too much can cause bloating and distention and with too much it is possible to over prescribe the amount needed. 

    Often, IGA and IgG immunoglobulins are deficient from extended requirements to treat pathogens in the gut, or lung. Replacement can be enhanced from pure sources of colostrum which can provide enhanced immune protection but cannot replace immune recovery. 

  • Rebalancing of lifestyle requires each person to manage their lifestyle and be proactive in their own health to support long term balance. Diet concepts are addressed later in the article, along with understanding the effect of stress from life challenges on gut and immune health, the importance of regular physical movement and adequate rest to recover.

The Microbiome and the Development of Cancer

Many people’s experience of microbial infections involves an exposure and a resulting illness. Most of the time we think of pneumonia, or a urinary or vaginal infection or food poisoning as examples. Current research has demonstrated there exist significantly different tumor microbiome communities within as many as thirty cancers. They consist of specific populations of bacteria, viruses and fungi that are unlike the balance of microbes in a healthy gut and other organs, being less diverse and more pathogenic. Evidence has also revealed that modifications to the normal microbiome and their metabolic products can also impact immune regulation affecting cancer.

Breast Cancer

  • Studies have shown that gut modification or change from dysbiosis is associated with an increased risk of breast cancer initiation based on the effects of estrogen metabolism. Specific bacteria can produce an enzyme that disconnects estrogen from a particular detoxification enzyme allowing estrogen to be recirculated increasing risk for stimulating estrogen receptor positive breast cancer.

  •  It has also been shown that specific bacterial species can induce the detoxification products that metabolize non ovarian estrogens, reducing their amounts, which are the estrogen source for postmenopausal breast cancer, which may reduce breast cancer risk.

  • A study was designed to gather data on the gut microbiota using a sterile tumor microenvironment and its looking at its effect on killing cancer cells. The study showed that dysbiosis in the gut impaired the cancer response to platinum drugs and immunotherapy. 

  • In advanced breast cancer, and other cancers by using antibiotics to kill bacteria or using germ free mice, the reduced activity of the white blood cells and their immune responses of inflammatory cytokines and Reactive Oxygen Species (ROS) showed chemotherapy to be less effective. The conclusion was that commensal bacteria are required for optimal cancer treatment responses by regulating the white blood cells driven immune responses during chemotherapy.

  • Also there is evidence that bacteria can play a protective role in preventing breast cancer. In mice that have antibiotic treatment to kill gut bacteria there is an association with the development of breast cancer that increased with continued use of the antibiotics. The theory suggests that healthy bacteria help maintain breast health by stimulating protective immune responses.

  • A recent article discussed the microbiome related to the microbial population seen in the subtypes of breast cancer microenvironments to gather information as to prognosis associated with each. It was determined that each has its own distinct subspecies that can allow predictions as to the type of breast cancer based on each specific microbiome.

  • Also a study showed an association of specific bacterial species that were capable of causing DNA cellular damage, a known cause of cancer initiation.

  • Research has shown that colonization of breast tissue by bacteria can come from trauma to the nipple or injury to the gut microbiome. Breast cancer tissue was noted to have specific species of bacteria in large amounts that were different than seen in benign disease.

  • And as shown in a separate study, out of 1440 bacterial species, 94 were associated with breast cancer and measuring a specific15 bacteria was shown to provide data that reflected prognosis.

Lung Cancer 

  • Contemporary technologies are enlightening us on the composition and effects of the gut microbiome on lung health and disease.

  • Originally the lung was considered sterile and absent of microbes.

  • It is recognized now that its microbial community is much less than the GI tract and also more changeable and fluid in its activity. However, gut dysbiosis also has a central role in the initiation of lung cancer.

  • The respiratory system is divided into an upper tract, comprising the pharynx,na sal areas, paranasal sinuses, and upper larynx, while the lower respiratory tract, the trachea, bronchi and lungs have a different microbial configuration consisting of a small number of microbes due to the thin epithelial surface needed to allow oxygen and carbon dioxide exchange.

  • An important issue associated with lung cancer initiation and progression is related to having chronic respiratory illnesses, such as COPD, cystic fibrosis, pulmonary fibrosis, asthma and bronchiectasis which results in underlying long term lung damage.

  • Lower airway damage increases the risk of chronic and recurrent infections creating persistent chronic inflammation and reactive oxidative stress which are known to result in genetic alterations contributing to oncogenesis as well as interfering with apoptosis. Also with chronic lung disease commonly steroids and often antibiotics are needed for infections which also impair the lungs' protective immune functions. In addition gut dysbiosis, which causes local inflammation and immune dysfunction which has been shown to result in systemic inflammation in the pulmonary organs.

  • Fermentation of non digestible fiber in the gut produces short chain fatty acids, SCFA’s, which protect the mucosal cells, including the lungs, from inflammation, and can inhibit binding and infection from pathogens. 

  • Treatment with checkpoint Inhibitor targeted therapies unblocks restrictions on immune activity and allows greater immune attack toward cancers that have the PD-1 receptors. These drugs are improving outcomes in positive PD-1 receptor lung cancer patients. However, resistance can develop to these drugs and appears to be related to alterations in the gut microbiome. 

  • A study in mice with lung tumors who were germ free or treated to kill intestinal bacteria with antibiotics and therefore without a substantial microbiome, were then given fecal microbiota transplantation, FMT, from patients who responded to immune checkpoint inhibitors, ICI. These mice had a positive response to their tumors, whereas FMT from patients who did not respond to ICI’s failed to affect tumor growth. It was also discovered that one bacteria in the FMT in responder patients was Akkermansia Muciniphila which can be increased by oral ingestion in humans when stool testing shows a deficiency.

Prostate Cancer

  • There is intriguing research that shows an association between the gut microbiota and prostate cancer. 

  • Also, studies have shown specific species of bacteria present in the biopsy of cancer patients that are not seen in normal controls who have been biopsied. This has encouraged more investigation to document the exact subspecies of the bacteria found especially to determine the potential for treatments.

  • In prostate cancer, there is an association with the excessive production of male hormones, androgens and prostate cancer growth. Treatments are available that are able to block androgen production and inhibit tumor growth. However, over time many men no longer respond to hormone blocking, allowing hormone cancer growth. This is called castration resistant prostate cancer.

  • Studies, in mice, have revealed information that the gut microbiota can produce androgens that contribute to this resistance by providing increased androgens. Research has shown that when mice were castrated, tumor volume diminished, but they did progress to castration resistance, but when given antibiotics to decrease specific gut bacteria again tumor size decreased.

  • Fecal microbiota transplantation (FMT) from mice and patients that were castration resistant made those mice with prostate cancer also castration resistant, while tumor growth was controlled when FMT from patients that were hormone sensitive were given to mice which showed that gut microbiota contribute to resistance to endocrine therapies by providing a secondary source of androgens.

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