The Microbiome and Immunity

Billions of years ago, in the primordial sea of single-celled organisms, these beings figured out how to produce signal molecules and to decode those made by other organisms. Thus chemical communication was born. The earliest multicellular organisms had a digestive tube containing microbes and with neurons wrapped around it to facilitate motion of food in one direction. Now interspecies cooperation within a larger organism was possible. The process of evolution together (increasingly complex beings of the animal kindom and the microbes in and on our bodies) created a great deal of interdependence between microbe and host. Our human ancestors couldn’t see the microbial realm, but they did recognize the principle of ‘as above, so below’ and that the digestive tract seemed to have an important impact on our health overall.

Now that we have the technology to study our physiology in amazing detail, and to identify the incredible diversity of microbes (bacteria, fungi, viruses, archaea and even some eukaryotes) especially within our digestive tract but also on our surfaces by genetic sequencing, everything has changed about how we view the gut. We now recognize that the enormous surface area of our digestive tracts is our largest and most constant interface with our environment through what we take in. It’s not only our digestive functions, especially secretion and motility, that are important aspects of this interface, but also our immunity, metabolism and more. About 70% of our immune system is actually located in our gut, and there are many ways that our microbiota interface with it. Indeed, all of our immune system components are directly or indirectly regulated by the microbiota.

Partnership between our microbes and us

The very first line of defense of the human body is our epithelial barrier, both our external skin and our internal mucous membranes. As we evolved within the context of the greater natural ecology, these borders have always been in dynamic interrelationship with the microbes that are present in water and soil, on the surfaces of plants . . . basically everywhere. In fact, no borders in nature are actually stark or well-defined. All involve complex interaction between a wide variety of living beings, for example permaculturists understand that edges of ponds, of forests, of seacoasts are where much of the action in the ecology takes place. For the human immune system, these potent edges of activity are especially located in key areas of interface between us and our environment – our mouths, throats and sinuses, urethras and vaginas, and especially our lower intestines.

Our epithelial surfaces are the first key part of our innate immunity, that part of our defensive system that is genetically hardwired to respond to all threats in similar ways. That is, the innate, or cellular immune system includes our physical and mechanical barrier defenses and initiates basic biochemical and inflammatory strategies that are relatively non-specific to any particular pathogen.

In a healthy organism, epithelial cells are tightly joined to each other with both cell juncture structures and with rubber-cement-like proteoglycans of the extracellular matrix. Permeability of epithelial surfaces, between and through cell membranes, is tightly controlled by these structures and other factors. In addition to the tight cell junctures, these cells typically turn over frequently, make mucus or express cilia, all of which help prevent pathogens from adhering to them, the necessary first step of infection. We can sneeze, cough, vomit, urinate or accelerate our gut motility to the point of diarrhea in order to dislodge pathogens and we also secrete antimicrobial substances and enzymes in our sweat, earwax, saliva, mucus, tears, sebaceous secretions etc to help protect us. Immunoglobulins of the acquired immune system also block pathogens from adhering to epithelial cells and initiating infection as well as tag them so they’re easier for white blood cells to find and eat them.

There are several ways that our microbial friends assist in our epithelial integrity and these very direct ways of preventing infection:

• First of all, our gut microbes feed our intestinal epithelial cells (enterocytes) with the metabolites of resistant starches, complex carbohydrates made with bonds that we don’t have the endogenous enzymes to break, especially short chain fatty acids called butyrate. Butyrate not only provides energy and supports nutrient uptake for colonic cells, but it also plays a role in regulating epithelial proliferation and differentiation – repair of damaged cells and promotion of reversion of abnormal cells back to normal. It’s thought that lack of butyrate contributes to the development of gut permeability, inflammation and colon cancer.

  
  

• By their very presence, they take up the ecological niches of our body, forming a physical barrier that keeps pathogens away from our epithelial surfaces. Resident microbes are also using any resources present, like sloughed off cells, that may support proliferation of pathogens.

  
  

• Our commensal microbes also produce several types of chemicals, from ammonia, indoles, and lactic acid to outright toxins that also protect our barriers, for example vaginal Lactobaccilli produce lactic acid and other secretions that prevent infection.

Lactobacillus (a Firmicute) in particular seems to help self-regulate the balance of organisms and inhibit pathogens like diarrhea-causing bacteria (i.e. shigella, salmonella, pathogenic E. coli) from affecting us. Gut microbes increase other bacteriostatic substances that help protect us from infection as well. For example, anaerobes produce volatile fatty acids from bile products that inhibit pathogenic bacteria.

The gut flora also helps support healthy mucosal secretions - large amounts of lubricating liquid secretions and mucus, from saliva in the mouth to colonic secretion in the large intestine. These secretions also contain substances that contribute to immune defense inside the gut, especially immunoglobulins, and our secretory functions are very sensitive to foreign chemicals like medications (why so many drugs have GI side effects). Their presence also supports tight junctions between epithelial cells, preventing pathogens from gaining access to our tissues.

And, what’s happening in the gut is postulated to also be linked to other mucosal tissues such as the respiratory tract through a process of ‘common mucosal response’. This theory suggests that antigen presentation (acquired arm of the system) at one mucosal site stimulates lymphoid cell migration to other mucosal sites, thus influencing the immune responses of remote sites.

The second line of immune defense, still basically within the innate immune system, is the inflammatory response. Truly, there is quite a bit of overlap between inflammation and the acquired or adaptive immune system, they are really just arms of the same function. Inflammation involves the activation of our plasma protein systems – complement, clotting, and kinin and our leukocytes – neutrophils, eosinophils, basophils, monocytes, mast cells, etc. Endothelial cells in the blood vessels get the message that danger or injury is present, initiate vasodilation, and the classic symptoms of swelling, redness, tenderness and heat develop from the increased blood flow that is enabling the leukocytes (white blood cells) to make their way to the scene of the trouble and phagocytize or otherwise do in the offending pathogen.

When we have normal colonic ecology and mucosal integrity, we have reduced uptake of antigens. This prevents triggering of immune response and the initiation of inflammation. If the bowel becomes permeable from damage, proteins and other substances leak out of the gut and become antigens. Our commensal microbes also escape the confines of the mucus layer and lumen of the gut and can find their way into tissues and bloodstream. All this leaking out can lead to immune cross-reactivity and the development of autoimmune conditions.

Cytokines like interleukins are signal molecules that can either promote inflammation or dampen it down. They are secreted by T cells, which are some of our key immune players. By helping regulate and differentiate the various kinds of T cells, a healthy microbiome influences upregulation of anti-inflammatory mediators such as IL-10 and IL-22, and downregulates pro-inflammatory mediators such as IL-17. Commensal flora like Bacteroides fragilis and non-pathogenic Clostridium have been shown to enhance T regulatory (Treg) cells’ activity and differentiation respectively, suppressing inflammation. This balance of immune homeostasis is especially important in the gut environment with it’s enormous population of microbes, but it sets the stage for immune balance in the whole body.

Our third layer of defense is known as the acquired or adaptive immune system, the part that learns and remembers the pathogens we’ve encountered in our personal experience that makes it possible for us to mount a much more targeted, efficient and effective response if we contact it again. In the process of phagocytosis, the pathogen or other antigen is digested and processed for presentation of fragments of key structures like viral spikes, bacterial flagellin, nucleic acids, peptidoglycans and other proteins so they can be recognized and remembered. These bits of pathogens become antigens, along with non-infectious antigens like pollen, food, venom, drugs, vaccines and transplanted tissue, all things that our immune system can react to.

Essentially, all blood cells, red, white and platelets, originally come from stem cells in the bone marrow. The T-cells make their way to the thymus gland, where they are ‘educated’ and emerge as immunocompetent T cells, where B-cells are develop immunocompetency in the bone marrow. Immunocompetent refers to their ability to interact with antigens, and once the T and B cells gain this ability, they migrate to secondary lymphatic organs where they anticipate further antigen exposure. These secondary lymphatic organs, such as Peyer’s patches in the jejunum, are located just underneath our mucous membranes linings, especially in the gut but also respiratory system etc. These lymphatic zones, gut- or mucosal- associated lymphoid tissues, or GALT etc., are key sites of antigen presentation and immune co-ordination. They are very rich in dendritic cells and macrophages, which are also phagocytes, but function as antigen presenting cells in concert with T-helper cells and T and B cells themselves. When an antigen is presented properly, B cells differentiate into active antibody-producing cells (plasma cells), and T cells differentiate into effector cells like cytotoxic T cells, or direct warriors for our cause. Activated dendritic cells also generate T regulatory cells, which are critical for intestinal homeostasis and tolerance.

Perhaps the most interesting role of microbes involves the ways our immune system learns what is our own self, who are our microbial friends, and who or what is a threat to our wellbeing. Evolution conserved pattern recognition receptors (PRR), for example toll-like receptors or TLR, that have the ability to identify those protein bits and other fragments or appendages of cells. These pattern recognition receptors are located on human epithelial cells as well as on macrophages and dendritic cells. TLRs are a key bridge from innate to acquired immunity--they increase induction of cytokines to increase response of the lymphocytes to foreign antigens. PRRs also make tolerance of our commensal microbes possible. Essentially, pathogens’ bits and fragments become PAMPs, or pathogen-associated molecular patterns, our commensal microbes’ molecular bits like LPS and peptidoglycans are recognized as MAMPs, or microbe-associated molecular patterns and damaged cells (again bits of proteins) from our own body are DAMPs, or damage-associated molecular patterns. These are all understood by the pattern recognition receptors, and that helps educate both innate and acquired immune system to develop and maintain tolerance to benign organisms as well as accurate response to real threats. For example, Bacteroides fragilis is recognized by a polysaccharide (PSA) on it’s surface, and promotes induction of Treg cells to produce the anti-inflammatory IL-10.

Another fascinating type of receptor in our guts that checks out what’s happening in the lumen is the M cell. M cells are attached to secondary lymphatic organs (GALT) and function by taking in microbes by endocytosis and examining them whole. The information is received by the immune cells within the lymphatic zone. In the “other direction,” segmented filamentous bacteria (SFB) are the only commensal microbe thought to actually be embedded in the gut epithelium. The rest of our microbes are mostly in the mucus layers or floating around in the lumen of the gut. These segmented filamentous bacteria function to support maturation of T cells, especially Th17, which increase antimicrobial defenses in the gut, and also potently induce production of IgA, the key antibody of the intestinal barrier.

These mechanisms rely on direct recognition of microbes by receptors. The immune system is also regulated by metabolic products produced by commensal microbes from the soluble fiber and other nutrients we consume. Especially those short chain fatty acids (SCFA), but other metabolites as well play many roles in our gut immunity, from the differentiation of T cells to the integrity of our epithelial barriers. SCFA have even been found to support healthy immune response in other body tissues besides the gut.

So what science is finding is that there are many possible interactions – chemical, nutritional, modulatory, inductive -- made possible by the microbiota that have both singular and combination effects on multiple aspects of both innate and adaptive immunity. Communication is definitely a two-way street, with microbes influencing host and vice versa.

So many changes in modern life

Many developments have led to changes in the ecology of modern humans over the last twelve thousand or so years, vastly accelerated in the most recent hundred years. For most of human existence, we lived in intimate proximity to nature and all the microorganisms that are part of the natural ecology. We foraged, scavenged and hunted for food, which we dried, cached or later fermented to help even out food’s availability to us. Our ancestors didn’t know that microbes helped preserve foods like vegetables or dairy products, but they employed tools and processes that made the magic happen.

Industrial agriculture, the corporate food distribution system, and the germ theory (at least) have conspired to sanitize our food, our surroundings, and our very bodies in the name of safety and luxury, but these have come at a great price. In some places traditional food cultures-- both the organisms and the social fabric-- have been lost, and many of us are far removed from the origins of our foods, which are processed for us in sterile factories. Our medical system has been diligently fighting against germs (pathogens), without realizing that most of the microbes in our environment are important allies, to us humans as well as the rest of nature, including our crops.

Increasing urbanization has displaced people from nature. Living in cities with dense population, people are more likely exposed to pollution and anti-microbial substances rather than soil, plants or animals besides pets. This lack impairs the development of our immune systems, leading to increased reactivity to benign substances – allergies.

Diverse fresh whole foods support a diverse functional ecology, and provide important substrates for microbes’ metabolism like resistant starch, and often beneficial microbes from the soil. Many people no longer eat a variety of cultured, fermented, and otherwise microbially preserved foods that ancestors depended on. Instead, the introduction of a diet with abundant refined carbohydrates, especially combined with a lot of animal protein dramatically changed our digestion and our microbiome. Lack of fiber reduces intestinal transit time, reduces prebiotic starches that feed our microbes, and can reverse the detoxifying conjugation the liver performs on toxins, enabling their reabsorption. This type of diet can encourage the growth of less beneficial species of microbes and also increase intestinal permeability.

There are also specific food additives and pesticide residues that can disrupt normal biochemistry in the gut. For example sulfates or sulfites can break down into hydrogen sulfide which can be quite toxic-- inhibiting oxidation of butyrate, and so increasing mucosal permeability. Glyphosate was originally developed as an antibiotic, and it is much more toxic to our microbes than it is to our human cells, a factor that is overlooked in evaluations of its toxic effects on us.

The biochemical picture that’s created when either physical or psychological stress sends us into sympathetic nervous mode initiates several mechanisms that harm the microbiome. Catecholamines, especially norepinephrine, spill over into the gut lumen and dramatically affect microbial organisms, specifically enhancing the growth of potential pathogens like E. coli, and causing beneficial bacteria like Lactobacilli to be pooped out. Stress can also decrease mucus and immunoglobulin A production in the gut, damaging our defenses and causing increased intestinal permeability which in turn triggers local immune activation. Bacterial metabolism changes in ways that can be harmful as well.

High C-section rates, around 30% in the US and higher in some other countries, have also contributed, especially to impaired immune and other system development that are dependent on our microbes. When babies are not born vaginally they miss exposure to the vaginal microbiome, which literally seeds their microbial population. Babies born by C-section collect their initial microbes from hospital workers and environment, which are more likely to be antibiotic resistant. If not nursed, they also miss exposure to skin microbes or the Bifidobacterium that migrates to the nipples to be ingested by the newborn. Human milk naturally has pre-biotics in it, and is the perfect food to nourish both baby and microbiome. Recently obstetric care has increasingly used vaginal swabs to ‘inoculate’ the newborn with vaginal microbes. Some of the newest research demonstrates that there is a microbiome in the placenta, the species of which are closest to the birth parent’s mouth, further elaborating our understanding of the microbiome at birth.

Antibiotics have varying effects depending on their administration, activity on pathogens, dosage, time and pharmacokinetics. For example, if the drug is taken orally and is well absorbed in the small intestine, it won’t affect the colonic flora too much. But conversely, an injected antibiotic that is then secreted by the body into saliva or bile in an active form will have an effect. Even one course of antibiotic administration can change the microbial balance for a long period of time, and the longer they are administered the more change can occur. Medications other than antibiotics can harm our microbes and their ecology too, including anti-fungal, anti-viral and anti-parasitics, but also other kinds of drugs. PPIs, which suppress HCl production, NSAIDs which reduce pain and inflammation are key culprits because they change the ecological environment of the gut, but other drugs that don’t even target the GI tract can have an impact.

We have gone too far with the germ theory and keeping ourselves safe. Substances that were originally thought to be safe, or safely protect us from hazards like fire, such as asbestos, pesticides, flame retardant chemicals and phthalates are being found to not only be toxic to us, but even more so to our microbes who, being unicellular, are more susceptible to them.

How these changes have impacted our health

Many of our most challenging modern conditions, from autoimmune disease to metabolic and cognitive disorders involve miscommunication--links of our hologram are missing. For many years, medical science has made dramatic breakthroughs in the treatment of pathogenic infections, from antibiotics to protease inhibitors. But what we’re seeing over the last few decades is an equally dramatic increase in conditions that aren’t communicable because they’re not caused by pathogens. Especially the combination of allergies, eczema and asthma, the atopic three, but also all sorts of chronic inflammatory conditions are increasingly recognized as dysregulation of immune system homeostasis and function due to aberrations of the microbiome. The other big issue is damage and permeability of the gut lining, where commensal microbes end up in places the immune system doesn’t expect and can become antigens. Typically it’s a paucity of abundance and diversity of microbial species, bacteria, fungi, archaea, bacteriophages, viruses and others, that has led to confusion in the immune system. Who are my friends, who are threats?

Another observation from my experience is increased susceptibility to recurrent infections. As we saw above with the innate immune system, without our microbes’ protection and population of our mucous membranes, pathogens gain easier access to these surfaces. Infections keep returning, or morphing from fungal to bacterial, especially in mucosa like vaginas. Without the resiliency conferred by a stable microbiome, our surfaces become vulnerable to opportunistic pathogens.

Allergies, especially serious, life-threatening allergies, have also dramatically increased, as have autoimmune conditions.

We are also finding that degeneration in elders’ structures and functions is accelerated with loss of their microbiome, from cognitive decline to increased risk of colorectal cancer, atherosclerosis, vulvovaginal atrophy and overall frailty.

Building a healthier ecology

First of all, we must recognize that we are part of nature, and nature is part of us. Connection with the natural environment, which recent science is finding has all sorts of benefits, really is important to our wellbeing. We may also need to let go of our fears of pathogens, “buggies,” dirty colons and other outdated ideas and myths.

Herbs can help restore the important qualities that make up the ecological niches where most of our microbial friends live:

• Vulneraries and mild astringents like plantain, calendula, comfrey, meadowsweet, lady’s mantle or yarrow help heal the gut mucosal lining, reducing permeability.

• Demulcents help encourage production of mucus, especially when regularly over time - plantain, comfrey, marshmallow, flax seeds, chia seeds, oats, violet leaf, etc.

• Carminatives help optimize intestinal transit time, which our microbes prefers to be not too fast, not too slow. There are lots of delicious carminatives, best taken in tea, like fennel, mint, chamomile, catnip, caraway, coriander, lemon balm, etc.

• Bitters increase secretions in the digestive system, and higher Hcl will help kill pathogens in our food, and the increased bile will also support good gut motility – artichoke leaf, dandelion, yellowdock root, etc.

• Antimicrobials may be useful if we believe there to be an overabundance of pathogenic or other species causing trouble, like fresh garlic or barberry, but I tend to prefer to invite in the friendly microbes and trust them to balance out the ecology.

Exposure to nature can be tricky for folks that live in cities or other areas where it’s less accessible, and allergies can also make being outdoors uncomfortable. But any activity that connects us with the invisible microbes of the natural world is helpful, including pets, other humans and produce from a farmer’s market. If someone can get their hands into garden soil, hug trees, pick berries, swim in clean wild water, forage wild edibles, lie on mossy ground, smell flowers . . . . any of these and many more examples will help introduce a wider variety of microbial species into our personal ecology.

Foods that support good microbial population of the intestines include:

Polyphenol sources - plants rich in flavonoids and other polyphenols are colorful fruits and vegetables esp. berries; also green tea and chocolate

Demulcent foods - oatmeal, other whole grain porridges, hemp seed powder, cinnamon, vegetables like okra

Fiber-rich foods - whole grains, legumes, vegetables, fruits

Prebiotic foods contain oligosaccharides - sunchokes, chicory, burdock, onions, leeks, asparagus, and other starchy vegetables.

Cultured and fermented foods are some of the best sources of beneficial organisms and should be consumed regularly (without being cooked). Examples include cultured dairy (yogurt, kefir, sour cream, buttermilk, etc.) lacto fermented vegetables (sauerkraut, kimchi, beet kvass, pickles, all others), miso, natto, raw apple cider vinegar, tamari, naturally cured meats like salami, unpasteurized and unsulfited beer, cider or mead, kombucha, etc. I typically suggest that people consume two different fermented foods each day, at least sometimes on an empty stomach such as for a snack or first course. Some microbes in foods will make it past the stomach all the way to the lower intestines. I have also suggested clients collect ferments from a bunch of their friends, that way they benefit from the microbes from many different kitchens too!

Probiotic administration should be used at least during times of stress and after antibiotic or other microbiota-damaging illness or therapy. Most products on the marketplace include several of the most well-studied microbial strains. I have suggested the targeted ones to clients as well, like those intended for mood or urinary health.

Babies - need Bifidus and Bacteroides fragilis (most key for immune development), not too much acidophilus under two years old. Supplement 1-5 billion organisms.

Children - 5-10 billion organisms

Pregnancy - 40-100 billion organisms

With antibiotic therapy - take probiotic 1 hour before antibiotic or 2 hours afterward; minimum of 3 months past the end of the round of medication. This is one of the key opportunities to really affect the microbiome.

Many probiotic labels recommend taking them with meals, but by an informal poll of herbalists it seems that between meals or at bedtime, all with water, will make it more likely the microbes will get past the stomach to the lower gut. There are also enteric-coated probiotics available.

Resources:

Arnolds and Lozupone - Striking a Balance with Help from our Little Friends – How the Gut Microbiota Contributes to Immune Homeostasis

Lei, Nair, and Alegre - The Interplay between the Intestinal Microbiota and the Immune System

Okumura and Takeda – Review - Maintenance of gut homeostasis by the mucosal immune system

Rodney Deitert – The Human Superorganism

McCance – Pathophysiology – The Biologic Basis for Disease in Adults and Children

classes with Mary Bove, ND

honestly, others that I have read over years and forgotten . . .