Aging Gut Flora

Diet selects for the bacteria that grow in the GI track and control the development of the immune system.  Diet-based inflammation produces aging symptoms.

Returning to the Subject of Aging

I want to return to the subject of aging.  A year and a half ago I wrote, “You don’t wear out, you flame out.”  I still think that is true, but I need to update that idea of inflammation and aging to include diet, gut flora and immune system development.  So here is my old article with a new focus on the gut.

Wearing Out Only Happens with Inflammation

I don’t think that aging happens -- most symptoms associated with aging are just medically mismanaged chronic inflammation.  The major observations are that older people have more degenerative/autoimmune diseases and they suffer from fewer infectious diseases.  The typical explanation is that the bodies of older people have figured out infections with an experienced immune system and that mechanical damage takes its toll over time -- joints wear out.  I think that there may be a minor amount of truth in this cultural perspective, but there is something more profound at work, sarcopenia combined with a compromised gut flora.

Replacing Muscle with Visceral Fat Is Inflammatory

Sarcopenia (muscle loss) is the gradual loss of muscle and replacement by fat.  Thus, by age fifty most people are physically less active and even if they appear to have the same weight and shape as in their active youth, the muscle of their abdomens and limbs has been partially replaced with fat.  This fat, as in those who are obese, releases inflammatory cytokines into the circulation and the body reacts as if it has a low grade infection.

Chronic Inflammation Taxes Immune System

Senior citizens are constantly expending energy and taxing their immune system by chronic inflammation.  As a result they get fewer infections, but the chronic inflammation provides the foundation for cancer and autoimmune diseases.  Their bodies aren’t mechanically wearing out, but they are wearing out by over use of the immune system.  

Aging Symptoms Are Inflammation Symptoms

Those seniors who are physically active and eat an anti-inflammatory diet, do not appear to age as fast as those who are sedentary, obese and display the typical symptoms of chronic inflammation, the metabolic syndrome.  Most of the characteristics associated with advancing years are merely symptoms of poorly managed chronic inflammation that can be reversed by an anti-inflammatory diet and exercise.

Diet Determines Gut Flora

Diet also contributes to aging, because diet controls development of gut flora and gut flora control development of the immune system.  The gut flora of an individual reflect the bacteria that have entered the GI tract, nutrients available to the bacteria in previous meals, bacterial growth regulators released by the gut, exposure to antibiotics, exposure to phytochemicals and gut transit time.

Gut Flora Is Diverse and Adaptable

Gut flora appears to be amazingly diverse from individual to individual with thousands of bacterial species inhabiting humans worldwide and about 150 species in each individual.  The same species remain in an individual for long periods of time regardless of diet.  The dominance of particular species depends on recent diet.  Major changes can result from antibiotics or gut diseases, e.g. Crohn’s.

Constipation Means Dysfunctional Gut Flora

Bowel stools are made up predominantly of bacteria and not undigested plant parts, i.e. fiber.  Fiber is made up of plant polysaccharides that are not digested by salivary, stomach or pancreatic enzymes, e.g. proteases and amylases that degrade proteins and starch.  Fiber polysaccharides pass into the colon where they are digested by gut flora.  People with constipation usually have disrupted gut flora, e.g. wiped out by antibiotics, and so the minimal volume of remaining undigested fiber is all that passes out in compact, dehydrated lumps.  If gut flora have been exposed to a particular type of fiber and bacteria having the needed enzymes have been brought into the gut previously, then the fiber is digested to sugars that feed the gut bacteria.  The increased population of bacteria is what makes up normal, hydrated bowel stools.

Gut Flora Changes Slowly to New Foods (Polysaccharides)

Bacteria grow quickly and with ample nutrients gut bacteria can double in number in about an hour.  Bacterial species are usually defined by the ability to utilize various carbohydrates or polysaccharides as nutrients.  Depending on the food eaten, nutrients favor the growth of particular bacterial species and the gut flora population changes dynamically.  New species are incorporated into the gut flora only if they find their way into the gut on food, e.g. riding on fresh, uncooked vegetables, and food provides nutrients that can permit the new bacteria to grow.  It will take several meals for new bacteria to reach appreciable numbers.  In the mean time the new fiber may be partially degraded and produce chemicals that disrupt other gut flora and cause bloating symptoms of food intolerance.  This is not an allergic reaction of the immune system.  It just takes time and persistence to permit the gut flora to adapt.  Most people systematically make themselves intolerant to particular foods by over-reacting to initial maladaption of their gut flora to the new food.  If they persisted with progressive exposure to diverse foods, their gut flora would adapt.

Simplified Aging Gut Flora Contributes to Inflammation

People of increasing age who maintain a diverse, anti-inflammatory diet and maintain muscle mass by weight-bearing exercise, avoid age-related inflammation and disease, i.e. they age more slowly.  Conversely, those who simplify their diets by eating processed foods high in starch and vegetable oils, show symptoms normally associated with advanced age, even when young.  The aging diet is inflammatory and it also produces a gut flora which is different from the youthful.

Aging Gut Flora Contributes to Disease

Constipation is an extreme example of dysfunctional gut flora and since gut bacteria are needed for the normal development of the immune system that is located in the lining of the small intestines, constipation is also an indicator of a compromised immune system.  Aging is frequently accompanied by digestive problems with one extreme being constipation.  It should not be surprising that individuals with compromised immune systems also develop numerous degenerative diseases indicative of a lack in the immunological tolerance systems that develop in the gut in response to normal gut flora.  Constipation and digestive problems are not normal signs of aging.

Eliminate Symptoms of Aging by Cultivating Gut Flora

A healthy diet, healthy gut flora, and a competent immune system are all tightly connected.  The typical symptoms of aging merely reflect an unhealthy diet and lifestyle that leads to chronic inflammation, a compromised immune system and disease.  The process of aging can be slowed by attention to the next meal.  Most people who fail to be healthy and active well into their 80’s are simply victims of bad choices (or of bad medical advice.)

Antibiotics, Gut Flora, Food Intolerance and Disease

Cattle Are Finished by Selective Killing of Gut Flora.  The Sickened Animals Store Fat that Grills Great.  People Get Metabolic Syndrome.

The likening of modern humans to potatoes sacked out on a couch is misleading.  The obesity epidemic linked to diets of processed foods more closely resembles the stumbling progression of cattle to abattoir.  Antibiotics and diet systematically lead in both feedlot and food court to gut dysbiosis, immune system failure, hormone disruption, rampant fat accumulation, physical inactivity, depression and the modern suite of chronic diseases.  Healthcare costs escalate, but vet bills, in contrast, are forestalled by a captive bolt pistol.

Background Observations

• Antibiotics kill bacteria and not humans, because the bacteria have different machinery for making proteins, nucleic acids and cell walls.
• Antibiotics kill bacterial pathogens and not viruses or fungi.
• Antibiotics kill helpful bacteria in the gut (gut flora) even more readily than pathogens.
• Antibiotics are used in meat production to alter gut flora to change animal metabolism;  e.g. cattle treated with antibiotics gain fat.  Protection from disease is secondary.
• Simple diet means simple gut flora.  Processed foods are simplified foods that simplify gut flora.
• Probiotics can replace only a small fraction of the gut flora diversity.
• Gut bacteria control the immune system development in the lining of the gut.
• Chronic antibiotic use permanently simplifies gut flora and compromises the immune system.
• The appendix stores gut bacteria as a reserve to replenish gut flora following diarrhea.
• Diseases based on inflammation and immune system intolerance result from gut dysbiosis (inadequate gut bacteria).

Antibiotics Kill Good Bacteria

This is a rant about antibiotics, not about humane actions.  Humane actions are not the point here, since I am talking about health care and not treatment of agricultural animals.  I am pleading for the rights of gut flora everywhere and antibiotics are the casual killers.  Compromised gut flora is collateral damage in attempting to eliminate bacteria characterized as pathogens.  Every time the pediatrician treats the mother by acceding to her pleas for an antibiotic prescription to silence a howling ear ache and get a good night’s sleep, or the dermatologist treats teen acne with antibiotics, billions and billions of domesticated bacteria die.

Constipation Is a Sign

Countless hours are wasted waiting, because antibiotic-depleted gut flora cannot hydrate and form normal stools.  Probiotics are gulped down, but they supply only a handful of the hundreds of bacterial species that are needed for health.  Yeasts and other fungi that are naturally resistant to antibiotics quickly replace the lost beneficial bacteria in the gut, vagina and on other body surfaces.  Surcease for simple sorrows leads to lingering and lasting laminations.  Don’t mess with mother nurture.

Damage of Antibiotic Use Is Slow

Most of the impact of antibiotic annihilation of bacteria normally present in humans is unobserved, because the deleterious effects lag months behind the initial treatment.  After all, cattle treated with antibiotics to restructure their gut flora to induce bovine obesity, appear to thrive as they rapidly gain weight and avoid symptoms of infectious diseases.  Humans on antibiotics also display fewer dental and incidental infections.  Constipation is not a high price to pay for a better mirror image.  

Antibiotics Compromise the Immune System

Unfortunately, allergies, autoimmune diseases, degenerative diseases and cancers are not usually linked to prior use of antibiotics.  There is no evidence that gut flora recovers  after antibiotic treatment, but constipation as a consequence of chronic antibiotic use is a common indicator of gut dysbiosis, collapse of normal gut flora bacterial communities.  The harbingers of inflammatory and degenerative diseases are present, but are usually discounted, because they are a common consequence of the Western diet.

Food Intolerance Reveals Inadequacies in Gut Flora

Food intolerance is a sign of depleted gut flora diversity.  Gut flora have hundreds of genes that can break down a huge diversity of polysaccharides derived from plant cell walls.  Gut flora of Japanese who routinely consume kelp have specialized enzymes to hydrolyze unusual algal sulfated polysaccharides.  Essentially all of the polysaccharides in plant fiber can be consumed by bacteria in the anaerobic environment of the colon.  Inability of individuals to digest particular food components usually results from a deficiency of the gut flora and an indication of a history of dietary simplification and antibiotic use.  Lactose intolerance, for example, results from depletion of lactose-degrading bacteria from the gut flora and can be remedied by simply eating lactose with probiotics for a couple of weeks.  Gut flora can adapt, but they need persistent exposure to diverse, i.e. non-processed, food.

Antibiotic Allergies Are Natural

Allergies develop from a combination of inflammation and compromised immunological tolerance.  Inflammation heightens processing of antigens for presentation to the immune systems, whereas loss of immunological tolerance means that aggressive immune responses are inadequately controlled.  Thus, innocuous environmental molecules are incorrectly recognized as pathogen components.  Allergies to antibiotics, such as penicillin, make sense, because the antibiotic is used to treat inflammatory infections and the antibiotic treatment eliminates the gut bacteria that are needed to develop gut lymphocytes (Tregs) to produce tolerance.  Antibiotics lay the foundation for immune system dysfunction that is central to many chronic diseases.

Healthy gut flora and a healthy immune system require:

• avoidance of antibiotics
• systematic (not simply eating yogurt) rebuilding of gut flora following diarrhea or antibiotic use; lack of an appendix means gut flora reservoir is gone
• eating a variety of vegetables; avoiding processed food
• using herbs and spices
• don’t overdo hygiene; gut flora diversity derives from bacteria that you eat and those that rub off acquaintances
• eat seasonally to increase diversity

Lateral Gene Transfer in Gut Flora

Japanese Gain Ability to Digest Algal Polysaccharides from Marine Bacteria
Gut flora adapt to the food nutrients that are prevalent in different parts of the world.  Bacteria able to digest unusual nutrients, such as the sulfated porphyrans found in seaweed eaten in Japanese cuisine, are also consumed along with algae.  Formation of bacterial biofilms triggers the exchange of genes among gut bacteria and the acquisition of new polysaccharide-degrading enzyme activities.

Gut Flora Adapts to Diet
The million or so genes of the thousands of bacterial species found in the guts of humans around the world are adapted to the diet of each of those individuals.  Each individual gut harbors a couple of hundred different bacterial species and those different types of bacteria increase or decrease in number in response to the composition of each meal. 

Diversity of Plant Polysaccharides Provides Digestion Challenge
Plants provide the greatest challenge for digestion, because plants differ the most in their carbohydrate (sugars, oligosaccharides, polysaccharides) composition.  Some of those carbs, such as sucrose, starch or the components of the plant cell walls, pectins, arabinogalactans and xyloglucans, are present in all vegetables.  Whereas other polysaccharides, such as the sulfated porphyrans from red algae of the same name (Porphyra) are restricted to particular plants.  Each different linkage and sugar requires a different digestive enzyme.

Gut Bacteria of Algae Eaters Have Algae-Degrading Enzymes
A recent report (see ref.) traced genes from marine bacteria that digest marine algae/seaweed, to gut bacteria of people who routinely eat seaweed.  Researchers studying marine bacteria identified genes coding for new enzymes, porphyranases, that hydrolyzed porphyrans.  When they checked gene databases for other porphyranase genes, they found that some gut bacteria had previously unassigned genes that were apparently, based on their nucleotide sequences, porphyranases.  Curiously, these genes were only present in gut bacteria isolated from Japanese sources, i.e. from people who traditionally ate seaweed.  In some of these bacteria there were more than 260 genes for degrading a huge variety of different plant polysaccharides.

Marine Bacteria on Seaweed Release DNA Incorporated into Gut Bacteria
Bacteria recognize that other bacteria are around by a process called quorum sensing.  This signaling system triggers the production of matrix polysaccharides produced by the bacteria to hold the bacteria together in complex communities.  Quorum sensing also mobilizes the release of copies of the bacterium’s genes, which is coordinated with uptake of DNA from the surrounding environment.  [Note that the proteins that take in foreign DNA have basic amino acids arranged in the same heparin-binding domains that are also used by growth factors and their receptors or the numerous proteins that bind to nucleic acids in the nucleus or in ribosomes.]  Thus, biofilm formation is accompanied by enhanced lateral gene exchange that would also enhance the incorporation of porphyranase genes from ingested marine bacteria.

Gut Bacteria Are Made in Guts and Shaped by Diet
Species of gut bacteria are defined in the micro lab by their ability to grow in Petri dishes of agar containing particular combinations of sugar, polysaccharides, etc.  The sugars that different bacteria are able to metabolize for growth reflect sugars available as niches in different parts of the gut.  Thus species are defined in part by the sugars and polysaccharides they can metabolize, i.e. by the enzymes they can produce. 

In each human gut, however, bacteria of the species filling a particular niche will have many other additional genes than those that define the species.  These atypical genes are present as a consequence of serendipitous encounters with genes from other bacteria (lateral gene transfer) and may reflect peculiarities of individual diets.  Different regional cuisines also shape the regional gut flora.  Persistent diet components would be expected to provide selective advantage for bacteria with genes capable of metabolizing new nutrients.  Access to a rich diversity of bacterial genes to augment typical gut flora genomes will facilitate adaptation.  Food processing to refine and simplify nutrient diversity, and hygiene to eliminate bacterial diversity in food, will reduce diversity in gut flora and minimize adaptation to novel foods.  Antibiotics, especially persistent use, can permanently disrupt gut flora.  Decreased diversity in gut flora may eliminate species of gut bacteria that are essential for normal physiological functioning of the gut and associated immune system, and may be major contributors to degenerative and autoimmune disease.

Sources of Personal Gut Flora:

• Exposure to Mother, Breast Milk
• Pathogens from Others
• Pets, Farm Animals
• Environmental Sources
• Ingested with Food
• Appendix Reservoir of Gut Flora

Selection Pressures on Gut Flora:

• Breast Milk Normalizes Flora Development
• Formula Disrupts Flora
• Food Nutrients
• Food Phytochemicals (herbs and spices)
• Antibiotics
• Gut Secretions
• Secretory Antibodies
• Bacteriophages, Bacteriocins
• Lateral Gene Transfer

reference:
Hehemann JH, Correc G, Barbeyron T, Helbert W, Czjzek M, Michel G.  Transfer of carbohydrate-active enzymes from marine bacteria to Japanese gut microbiota.  Nature. 2010 Apr 8;464(7290):908-12.

Helminths, Oligosaccharides and Immunotolerance

Parasitic worms reverse allergies and autoimmune diseases using oligosaccharides to mimic self and silence immune over-responsiveness.

Helminth therapy, i.e. infection with parasitic intestinal worms to provide remission from allergies, inflammatory bowel and other autoimmune diseases, has been examined as a potential therapeutic model to rehabilitate immunological dysfunction.  The surface oligosaccharides of these worms have been found to mimic human oligosaccharides and alter immune responses by binding to carbohydrate-binding, i.e. lectin, receptors.

Immune Tolerance
The essence of allergic and autoimmune diseases is a defect in distinguishing between pathogen, innocuous and self molecules.  Heightened immune reactions as a result of inflammation move the immune system toward production of antibody and T cell receptors specific for antigens.  Those antigens respond to unique receptors on the surface of each B and T lymphocyte.  The lymphocyte population has been previously depleted of cells that can produce receptors that will bind to most self antigens.  This depletion makes the lymphocyte population generally non-responsive, or tolerant to self antigens.  Thus, the immune system is blind to the body.

Regulatory T Cells and Tolerance
Most of the immune cells of the body are present in the lining of the gut.  It is in the gut that various immune cells continue to develop for their various roles, including controlling immune reactions to self antigens and to common food molecules.  Immune cells in the gut are exposed to some food molecules and bacteria that leak through the cells of the intestinal villi.  Responding to these common antigens by inflammation can lead to inflammatory bowel disease.  This pathological over-responsiveness is normally avoided by development of regulatory T cells, Tregs, that suppress immune responses to common food molecules and to surface antigens of common bacteria.

Treg Development Depends on Gut Flora
Gut bacteria are needed for the normal function of the immune system.  Oddly, Helicobacter pylori, Hp, the cause of stomach ulcers and cancer, also stimulates the development of Tregs.  Thus, the pathology of Hp may result not from its presence, but rather from how it is growing.  Since Hp uses hydrogen gas produced by Klebsiella in the lower bowel and hydrogen production is dependent on dietary starch, then it follows that the pathological behavior of Hp may be dependent on dietary starch.  A low starch diet may actually result in Treg stimulation from Hp and a reduction in allergies and autoimmune diseases.

Tregs Enhanced by Heliminths
Immunological tolerance is also stimulated by parasitic worms, Helminths.  Helminth infestations, therefore, reduce allergies and autoimmune diseases and may contribute to the hygiene hypothesis to explain the prevalence of allergies, autoimmune and other inflammation-based degenerative diseases in modern societies.  Examination of worms to find the molecules responsible for inducing immunological tolerance has identified complex surface and secreted oligosaccharides (small sugar chains) as the active molecules.  Helminth oligosaccharides mimic human cell surface oligosaccharides and bind to carbohydrate-binding, lectin, receptors on immune cells to stimulate Treg development.

Lectin Receptors Control Tolerance
There are many implications of the modulation of the immune system via oligosaccharides.  Note that related oligosaccharides are components of human milk and prepare the gut and develop the immune system.  This explains why formula, which lacks these unique oligosaccharides, results in aberrant gut flora, contributes to neonatal necrotizing colitis and supports the development of allergies and autoimmune diseases.  In contrast, judicious use of self or Helminth oligosaccharides may provide a means of restoring the function of damaged immune systems and therapy for allergies and autoimmune diseases.  Also note that the critical use of lectins, which have oligosaccharide-binding sites rich in aromatic amino acids to bind the hydrophobic faces of the sugars, will also bind and provide entry into immune cells for allergens and autoantigens that have triplets of basic amino acids.  The binding sites of lectins should also bind many aromatic phytochemicals.  Immunomodulation by phytochemicals may result from interference with or mimicking the binding of oligosaccharides to lectin receptors.

reference:
van Die I, Cummings RD.  Glycans modulate immune responses in helminth infections and allergy.  Chem Immunol Allergy. 2006;90:91-112.