Anti-Inflammatory Diet

All health care starts with diet. My recommendations for a healthy diet are here:
Anti-Inflammatory Diet and Lifestyle.
There are over 190 articles on diet, inflammation and disease on this blog
(find topics using search [upper left] or index [lower right]), and
more articles by Prof. Ayers on Suite101 .

Showing posts with label biofilm. Show all posts
Showing posts with label biofilm. Show all posts

Wednesday, June 25, 2014

Antibiotic Resistance, Superbugs and Drugs

Antibiotic resistance results, because spontaneous mutations occur so frequently that all bacteria are different.  It is just a matter of exposing enough bacteria to an antibiotic to find one that is insensitive to a particular antibiotic.  More bacteria mean a greater chance of mutations to antibiotic resistance.  The gut contains a lot of bacteria and sewage treatment plants are loaded with gut flora.

Antibiotics are Ubiquitous
All organisms, plants, fungi and animals/humans produce chemicals that kill bacteria, i.e. antibiotics.  I have written many articles about the natural antibiotics of plants, a.k.a. phytoalexins or “antioxidant” polyphenolics, and the human defensins that are peptides with heparin binding domains.  Bacteria also produce viruses, called bacteriophages, that kill other bacteria.  All of these natural antibiotics are small molecules that interact with many different human proteins, and it is these side effects that permit their exploitation as pharmaceuticals.  Thus, statins were selected from fungal antibiotics that inhibited an enzyme needed for human synthesis of cholesterol, metformin was a phytoalexin found to reduce blood sugar and resveratrol is a grape phytoalexin.

Plant Antibiotics are Natural
The flavoring chemicals in herbs and spices have a far more important use in food preparation than titillation of taste buds, since those chemicals kill common food pathogens.  More profoundly, it is important to realize that the selective advantage of phytochemicals/polyphenols/alkaloids/essential oils to the plants that make them, is as natural antibiotics.  Plants kill bacteria, as well as fungi and insects, for a living.

Plant Chemicals Attack all Aspects of Bacteria
Most of the thousand genes that are present in a bacterium code for proteins/enzymes and most antibiotics target those enzymes.  Penicillin binds to an enzyme needed to make bacterial cell walls, streptomycin target protein synthesis, rifampicin blocks RNA synthesis, actinomycin D inhibits DNA synthesis, etc.

Mutation to Antibiotic Resistance is Automatic in Bacteria
Each time a cell replicates, mistakes are made and the new DNA molecule of each chromosome is slightly different than the original.  There are about a thousand genes on the single chromosome of a bacterium and about the same number on each of the 23 human chromosomes.  About a dozen mistakes, mutations, are made each time bacteria replicate.  The mutations that alter the gene target of an antibiotic and produce a bacterial enzyme that is unaffected by the antibiotic, yield an antibiotic resistant bacterium.  The mutant gene now codes for antibiotic resistance and the presence of several resistance genes in the same bacterium produces multiple antibiotic resistant "superbugs."

Mutations are Random, but Antibiotics Select for Resistance
Each cellular replication produces random mutations throughout the bacterial DNA, but of the billion sites along the DNA that can mutate, only a few will produce a modified enzyme that will no longer interact with a particular antibiotic and thus be resistant.  Antibiotic resistance mutants are rare, less than one in a million, but a million bacteria can grow from a single cell in a day and occupy a volume less than a crystal of salt.  Ten hours later, after ten more doublings of the million bacteria, there will be a billion, and there will be a good chance that among those will be a mutant that is resistant to a particular antibiotic.  In the pound of bacteria in the human gut, there are mutants that are resistant to most antibiotics, including the antibiotics that have not yet been developed.  Of course, most of those antibiotic resistant bacteria are just flushed down the toilet.  Treatment with antibiotics kills all of the sensitive bacteria and leaves only the resistant.  Thus, antibiotic treatments select for antibiotic resistant bacteria.

Common Use of Antibiotics Selects for Resistance on Plasmids
Genes are transferred between bacteria by bacteriophages, conjugation (a kind of bacterial sex) and transformation, which is the release of DNA from one bacterium with subsequent uptake by another.  Biofilms, which are communities of many different species of bacteria, stimulate transformation and exploit bacterial DNA as a matrix material to hold the communities together.  The human gut is lined with biofilms and the biofilm bacteria secrete vitamins as the quorum sensing signals that coordinate community activity.  Thus, some vitamins must stimulate transformation, the exchange of DNA among members of the different species of bacteria in the biofilms with evolution of new and novel species.  Rapid change in the gut environment selects for a shift in genes that provide for adaptation to the new environment to small DNA fragments, plasmids, that move most readily between bacteria.  Antibiotic treatment results in antibiotic resistance genes on plasmids.

Use of Multiple Antibiotics Selects for Multiple Antibiotic Resistance Plasmids
Persistent use of an antibiotic will spread resistance to a particular antibiotic through the gut flora, facilitated by antibiotic resistant plasmids.  Replacement of a second antibiotic will result in a new plasmid with both antibiotic resistance genes.  Hospitalization and exposure to a plethora of bacteria with multiple antibiotic resistance plasmids will result in rapid conversion of gut flora to multiple antibiotic resistance upon exposure to any antibiotics.  Hospital staff would be expected to be natural repositories for multiple resistance genes, especially if they are exposed to any antibiotic (or pharmaceutical.)

Most Pharmaceuticals Select for Multiple Antibiotic Resistance Plasmids and Superbugs

The frightening rise of superbugs resistant to all known antibiotics has been attributed to the accelerated use of antibiotics in medicine and agriculture.  Mixing megatons of bacteria in the guts of billions of people with tons of antibiotics, and still more in sewage treatment plants and agriculture, is bound to produce bacteria with every type of multiple antibiotic resistance plasmid imaginable.  But that is not the biggest problem, since fingering the commercial use and misuse of antibiotics ignores biggest exposure of bacteria to antibiotics.  It ignores the fact that most popular pharmaceuticals, NSAIDs, statins, anti-depressants, anti-diabetics, etc., also have substantial antibiotic activity.  Most of these pharmaceuticals started out as phytoalexins and then were found to also have pharmaceutical activity.  Pharmaceuticals are just repurposed natural antibiotics.  When you take an aspirin or Metformin or a statin, you are taking an antibiotic.  When you take a pharmaceutical, you are selecting for multiple antibiotic resistance plasmids in your gut flora and you may be making the next superbug.

Wednesday, March 12, 2014

Health in Diagrams I — Gut Flora and Diet

This is the first of three posts to summarize my thoughts on diet, inflammation and disease mediated by gut flora.  I decided that I needed to make my points as explicit as possible by putting them down in diagrams and making references to my other posts.  By the time I finish, I will reach my 200th blog post at Cooling Inflammation.
Everyone Leaves Out Gut Flora
I want to first explain and diagram my current understanding of the relationship between gut flora (the complex community of hundreds of different types of bacteria and fungi in the intestines) and diet.  My impression is that many people have health problems based on diet, but when they try to heal their health, they fix their diet and see only limited benefits.  Medicine provides only a temporary treatment using dairy probiotics.  The problem is that they failed to fix their gut flora, which was also damaged by their unhealthy diet.  

Health Requires a Match between Diet and Gut Flora
It is a myth that gut flora will just adjust to diet and a healthy diet leads to a healthy gut flora.  
A damaged gut flora lacks necessary species of bacteria.  Antibiotics, for example, can permanently delete dozens of particular bacterial species of gut flora that can only be replaced by reintroducing the missing bacteria by eating those bacteria again.  The missing bacteria may be needed to digest particular foods and the result is food intolerances, commonly mistaken for food allergies.  Antibiotic use frequently leads to autoimmune diseases, that are caused by deficient regulatory T cells of the immune system that develop in the lining of the intestines in response to particular gut bacteria.  The natural source of gut bacteria is eating the bacteria clinging to raw or fermented vegetables.
Diagram Showing the Interaction of Food, Gut Flora and the Immune System


Food is just Protein, Fat and Soluble Fiber
The human body produces enzymes to fully digest proteins, fats and one polysaccharide, starch.  All other parts of plants and animals are edible (fermented by gut flora) soluble fiber polysaccharides or insoluble, undigestible fiber consisting of cellulose or lignin, which together also make up the undigested organic matter, humus, of soil.  Grains are problematical for health, because their starch is readily converted to sugar, i.e. high glycemic, and their fiber is insoluble (not fermented by gut flora) and high in phytate.  Phytochemicals, plant polyphenolics, are of questionable value as antioxidants and are of unexplored importance for their antimicrobial impact on gut flora.
Polymers (Protein, Starch) are Hydrolyzed by Enzymes to Oligomers and then Monomers (Amino Acids, Glucose)
The stomach mixes protein digesting enzymes, proteases, and starch digesting amylase, with food protein and starch.  Proteases convert the long chains polypeptides, polymers of protein amino acids, into shorter fragments, oligopeptides.  The specific nature of the stomach proteases leaves groups of basic amino acids (lysine, arginine), heparin-binding domains, intact.  These peptides, similar to the defensins of the microvilli crypts, are anti-microbial and work with residual acidity to reduce bacterial growth in the first part of the small intestines.  Pancreatic enzymes then digest the peptides further and the small peptides are ultimately digested by enzymes on the surface of intestinal epithelial cells just prior to absorption.  Similarly, starch is degraded to oligosaccharide amylodextrins, which are then hydrolyzed to glucose at the intestinal surface prior to absorption.  Amino acids and glucose are not normally available to bacteria in the intestines.
Fats are Dissolved by Bile, Digested by Lipase and Absorbed
Fats are triglycerides, i.e. three fatty acids attached to the three hydroxyl groups of glycerol.  Fats are hard to digest, because they form oily droplets.  The droplets are dissolved in the intestines with bile, which is an acidic form of cholesterol, that is produced in the liver and stored in the gall bladder.  Fat in a meal triggers bile release from the gall bladder into the small intestines.  The bile represents a huge reservoir of the cholesterol that is synthesized by the body and dwarfs the cholesterol content of any meal.  Statins decrease body production of cholesterol, interfere with bile/fat digestion and lower lipid cholesterol levels.  (Unfortunately, lowering lipid cholesterol levels has minimal impact on heart disease and the only impact of statins on cardiovascular disease is through weak anti-inflammatory side effects.)  Pancreatic lipase removes two of the fatty acids from each triglyceride.  The fatty acids (a.k.a. soap) and monoglyceride are absorbed by the intestinal cells and reformed into triglycerides that make their way to lymphatic lacteals and are dumped into the blood, where they circulate as chylomicrons surrounded in lipoprotein.  Lipoprotein lipase binds to heparan sulfate on the surface of blood vessels and gradually removes fatty acids, until the diminished chylomicron is absorbed by the liver and exits as a VLDL.  (Note that this is another connection between lipid metabolism and inflammation, since inflammation decreases heparan sulfate on cell surfaces.  Heparan sulfate also mediates LDL binding to cells and amyloid stacking.)
Plant Polysaccharides are Soluble Fiber and Food for Gut Flora
All that remains of food after the protein, fat and glycemic starch (glycogen) have been removed in the small intestines are plant cell wall polysaccharides, resistant starch, storage polysaccharides, e.g. inulin, plant beta-glucan, animal glycans, e.g. chondroitin sulfate and heparan sulfate, and insoluble fiber.  The insoluble fiber passes on to be a minor contributor to the bulk of stools and the rest of the polysaccharide is potentially fermentable by gut flora into short chain fatty acids (formic, acetic, propionic, butyric acids).  Some of the polysaccharides are simple repeating units of one or two sugars in long chains, but others are made of five to ten different sugars in complex branched structures.  Simple repeating polysaccharides require just a few different enzymes for their initial synthesis and a few for their digestion.  Thus, resistant starch can be digested by a couple of enzymes into glucose that can be used by most gut flora.  Arabinogalactan, on the other hand, requires a dozen enzymes for plant synthesis and an equal number of hydrolytic enzymes to produce arabinose and galactose, which require further enzymes for metabolism in a select few of species of gut flora bacteria.  
Food Intolerance/“Allergy” Indicates Missing Bacteria
Gut flora in general can produce several hundred different enzymes for digestion of diverse soluble fiber,  but most soluble fiber polysaccharides can only be digested by certain bacteria and those bacteria increase, if the complementary fiber is present in the diet.  If a fiber is absent from the diet, bacteria that specialize in digesting that polysaccharide will be eliminated.  People living on diets limited to just a few types of soluble fiber can only digest those fibers and a shift in diet to other types of soluble fiber will lead to symptoms of dietary upset, such as bloating, gas production and food intolerance.  Food intolerances reflect inadequate diversity in gut flora and a mismatch between bacteria and food.  Food intolerances can be eliminated by repairing gut flora and the typical repair solution is eating homegrown fermented vegetables that provide the missing species of bacteria.
Immune Cells Develop in Response to Gut Bacteria
Most of the body’s immune cells are in the intestines.  Cells of the immune system are constantly dividing in bones and the thymus gland, developing in the lining of the intestines and migrating to other tissues.  Filamentous bacteria of the gut flora stimulate the development of aggressive immune cells that kill other cells that are infected with pathogens or viruses or are cancerous.  Furrows perpendicular to the flow of food cultivate the growth of Clostridium species that ferment soluble fiber, e.g. resistant starch, and release butyric acid that stimulates the development of regulatory T cells, Tregs.  It is the Tregs that control the aggressive immune cells and prevent attack on self (autoimmunity) or innocuous antigens (allergy).  It appears that merely eating resistant starch, e.g. potato starch, with probiotics that contain butyric acid producing Clostridium bacteria may provide a cure for many autoimmune diseases.
Gut Biofilms Release Vitamins as Quorum Sensing Signals
 The gut flora lines the intestines in numerous biofilm communities, which form from dozens of different species of bacteria that communicate by exchanging molecules called quorum sensing signals.  These signals from the biofilms intimately attached to the lining of the intestines are vitamins.  Thus, healthy gut flora are the major source of vitamins and other sources, such as fruits and vegetables are only needed, if the gut flora is damaged, e.g. by antibiotics.
Volume of Stools Reflects Gut Flora Fermenting Soluble Fiber
The bulk of bowel movements, stools, is bacteria, the compressed gut flora that accumulated in the colon while fermenting soluble fiber.  We always hear that we need to eat fiber for regularity, but since insoluble fiber is only a minor contributor to stool volume and it is associated with anti-nutritive attributes, such as the binding and removal of zinc and iron by phytate, the fiber that counts for regularity is soluble fiber.  Regularity results from the fermentation of soluble fiber polysaccharides producing short chain fatty acids, such as butyrate, that are the major source of energy for colon cells.  And the growing bacteria in the colon provide most of the bulk of the hydrated stools.  Inadequate dietary soluble fiber or damaged gut flora, dysbiosis, leave only dehydrated insoluble fiber and compact stools of constipation.  Constipation can result from dehydration or excessive retention, but chronic constipation, even in the presence of adequate dietary soluble fiber, is an indication of damaged gut flora and an increased risk for diseases resulting from deficiencies of Treg production:  autoimmune diseases and allergies.  Constipation and associated autoimmune diseases can be cured by repairing gut flora and supplying adequate dietary soluble fiber.

Thursday, January 23, 2014

Gut Flora Risk and Repair

….All 190 posts here….
The two most important contributors to health are diet and gut flora.  All of the other contributors, such as exercise, genetics, environmental toxins, hygiene, etc. are of minor importance.  A healthy diet, such as The Anti-Inflammatory Diet that I recommend on this blog, is simple and relatively easy to follow after weaning from the Standard American Diet.  One version of the healthy diet is just eating meat, fish, eggs, dairy and plenty of vegetables, but avoiding vegetable oils and grains.  Most people will be healthy with that general diet, but if and only if, they also have a healthy gut flora that is adapted to the food they eat.

Most people make themselves sick by not matching their gut bacteria to what they eat, so let me repeat the main point of this article:

You will get sick if the bacteria in your colon can’t digest your food.
And sick means allergies, autoimmunity, cancer, etc.
Read and Heed or Dead

What Killed American Gut Flora?
There are hundreds of different species of bacteria growing on partially digested food (soluble fiber) in your colon.  Americans are sick, not because they are too poor to buy food, but because they have the worst, i.e. least diverse, gut flora in the world.

Do:  We pick up, recruit, eat new bacteria and repair our gut flora by:
  • touching surfaces, people, pets, etc. and putting our fingers near our mouths,
  • eating live fermented food, or semi-clean vegetables,
  • not cooking/killing/sanitizing all of the bacteria around us,
  • eating probiotics and transferring some of their genes to our gut flora.

Don’t:  We wipe out or reduce the diversity of our gut flora by:
  • using inappropriate hygiene that kills the bacteria we need for health,
  • taking antibiotics that kill gut flora and compromise our immune system,
  • trying to eat a wide variety of foods, which is counterproductive and only permits a few varieties of bacteria to survive.

Hygiene Kills Beneficial Bacteria
Nothing comes from nothing…  For bacteria to come out, bacteria must go in.  You have to eat bacteria to extrude them by the pound.  Each day a single bacterium growing and dividing in your gut once per hour will produce a million daughter bacteria (24 doublings, estimate that doubling two, ten times is about a thousand, and 1000X1000= million.)  So if you mixed a milligram (about the size of the period at the end of this sentence) of gut bacteria with ample food, you would have a kilogram (pounds) of bacteria by the end of the day.  Similarly, it takes about a day for a single bacterium applied to a petri dish of nutrient agar to produce a colony weighing about 10 milligrams.  The point here, is that a single bacterium that makes it through the acid bath of the stomach can be a major player in your colon in a couple of days.  This is a very good thing.  We want to kiss babies, because babies systematically vacuum up bacteria from the darkest  of corners and with shameless generosity present them in an irresistible pucker.  We need those bacteria, and so do the babies.  Hygiene, e.g. antibacterial hand soap, bleaching surfaces or closing toilet lids isolates people from potential sources of beneficial gut bacteria. 

Traditional Food is Fermented (with Live Bacteria)
Shockey
In most cultures, extra food is mixed with something like salt or spices to kill local problem microbes and then bacteria are permitted to grow.  The result is fermentation of the sugars available in the food with production of organic acids, e.g. vinegar, that stop the growth of other bacteria that might grow on protein and cause objectionable flavors.  Homemade fermented veggies contain a wide variety of happenstantial bacteria that can adapt to productive gut growth.

Cooking Kills
We cook to dissolve and soften foods.  Meat can be eaten whole and our stomach enzymes will easily digest the protein and fat to provide all of our nutritional needs.  The only plant material that can be digested by our enzymes is starch.  The rest of the plant requires cooking to make the protein available and the remaining carbohydrates, soluble fiber, require digestion by hundreds of different enzymes produced only by microorganisms.  Cooking will release soluble fiber to feed gut flora, but it also kills bacteria, so some raw foods must be eaten to make sure that the gut is always supplied with fresh bacterial recruits.  Cooked or pasteurized foods do not contain live bacteria and are not useful as sources to repair gut flora.

Probiotics are not Gut Flora
Commercial probiotics are made from bacteria used in dairy products (dairy probiotics) or bacteria used to make enzymes in other products, such as laundry detergents.  
These bacteria can be repackaged and sold as probiotics, because they have already been tested for toxicity.  These bacteria don’t normally grow in the gut and if you swallow them, they just pass through.  These “probiotics” can temporarily provide some of the functions of gut flora, because they are bacteria, but they don’t grow in the gut.

Gut Flora are Bacteria Created in the Gut
Gut bacteria produce chemical signals that coordinate the metabolism of food by hundreds of different species of bacteria.  We call these chemical signals vitamins, because humans extract the vitamins from the bacterial biofilms that always line the gut, so humans don’t need to produce their own vitamins.  Gut flora can produce all of the vitamins that we need, so it is not surprising that multivitamins do not provide any health benefit and concentrated vitamins my be harmful by disrupting normal metabolism of gut flora.  Biofilms also promote the exchange of genes between different species of bacteria, so the concept of species does not actually apply to gut flora, where new species are rapidly being created.  A common example of this process is the curing of lactose intolerance by simply eating small amounts of live yogurt for a couple of weeks.  The cure results from the transfer of a gene that produces an enzyme to digest lactose from the yogurt probiotic bacteria to the regular gut bacteria.  The new species, a natural GMO, continues to grow in the gut, digest lactose, and cure lactose intolerance.  The yogurt probiotics just get flushed away and that is why dairy probiotics must be eaten continuously to provide some of the benefits of healthy gut flora.

Antibiotics Kill Gut Flora, Compromise the Immune System and Cause Disease
Antibiotics are a huge benefit in curing and avoiding infectious disease.  Unfortunately, antibiotics can cause lasting damage by killing beneficial species of bacteria of the gut flora.  Loss of essential bacteria is commonly seen as food intolerances (true food allergies are rare) or constipation.  Since gut flora are needed for development of both the aggressive and suppressive parts of the immune system, which occurs in the lining of the gut, then antibiotics slowly lead to loss of function of the immune system that leads to autoimmunity or allergies.  Probiotics typically administered following antibiotic treatments do not repair the gut flora and leave the immune system damaged and prone to autoimmune diseases and allergies.

Variety in Foods Leads to Loss of Diversity in Gut Flora
It may be more entertaining to eat a new cuisine at each meal, but it confuses your gut flora.  Your gut is a river that endlessly moves food from mouth portal to pottie.  Bacteria divide and eddies cast some of the bacteria back to mix with food upstream before inevitably moving with the masses down and out.  Bacteria that don’t multiply as quickly as others eventually become extinct.  Bacteria that grow well on broccoli may wither with onions.  If you continue to eat some broccoli and some onions, then your gut flora will adapt, but if the type of polysaccharides, the soluble fiber, changes continuously, then you will end up with the stunted gut flora of Americans.  Diversity of gut flora is reduced by too much variety in food.

Matching Food to Gut Flora Takes Time
All of the gut problems that people complain about, gas, bloating, diarrhea, constipation, food intolerances/allergies (except gluten and a couple of others), etc. are due to a mismatch between food and the digestive enzymes of gut flora.  Modern food processing retains protein, fat and starch and removes the polysaccharides/soluble fiber that reaches the colon, feeds gut bacteria and produces short chain fatty acids (acetic acid, butyric acid, propionic acid) that feed the colon and reduce inflammation.  It takes time for gut bacteria to adapt to new soluble fiber in new foods by recruiting or creating new bacteria, and this is only possible, if inappropriate hygiene is avoided or if homemade fermented foods are eaten.

Thursday, December 19, 2013

Antibiotics, Gluten, Hashimoto's Thyroiditis and Baldness

My impression is that Hashimoto's is caused by a combination of an initial immune attack on the thyroid and incompetent regulatory T cells.  In most cases the immune attack on the thyroid is a secondary consequence of celiac/gluten intolerance, in which anti-transglutaminase antibodies attack transglutaminase bound to gluten in the intestines.  Transglutaminase  is an enzyme that is also produced by the thyroid (and hair follicles) and attack by celiac antibodies can enhance or inhibit thyroid hormone production (or baldness.)  Both Hashimoto's and celiac do not occur if the suppressive part of the immune system, i.e. regulatory T cells, is functioning.  

Antibiotics Compromise the Immune System
The major point here is that antibiotics disrupt normal bacterial biofilms that line the intestines and these healthy gut bacteria are required for development of regulatory T cells.  Compromise of Tregs leads to autoimmune diseases, e.g. celiac, Hashimoto’s and baldness, and also allergies.

Antigens/Allergens Have Basic Amino Acid Triplets
The antigens targeted in autoimmune diseases, e.g. tTG, anti-nuclear, TPO, and allergies form an obvious pattern.  All of these antigens and allergens have simple amino acid sequences (rare patches of three basic/positively charged amino acids) that enhance their presentation to the immune system to produce antibodies.  Nuclear proteins, for example, are frequent autoantigens and most of these proteins interact with nucleic acids (negatively charged) and have predictable patches of positively charged amino acids (arginine and lysine).  Other common autoantigens have basic amino acid (arg/lys) patches, because they interact with phospholipids (also negatively charged.)  Proteins with basic patches, e.g. HIV-TAT or heparanase, are also readily transported into cells and nuclei.  Peptides with these sequences are produced by action of stomach enzymes on proteins, e.g. milk lactoferrin, and are antimicrobial.

Allergies / Autoimmune Diseases Are a Predictable Consequence of Antibiotics
Doctors treat with antibiotics, but they fail to repair damage that they cause to gut flora.  The gut flora of most patients treated with antibiotics, especially those who are most fastidiously hygienic, never fully recover.  Constipation is a common symptom of severe dysbiosis and related immunoincompetence.  Probiotics are gut flora bandaids and do not survive as components of gut flora.

Gut bacteria are also needed for development of the aggressive part of the immune system.  Thus, autoimmune diseases can be treated with even more intense use of antibiotics, that will eliminate the rest of the immune system.  Since all vitamins are produced by gut flora as quorum sensing signals, antibiotics can also produce the exotic symptoms of vitamin deficiencies.

Antibiotics are essential to many therapeutic approaches, e.g. surgical procedures or therapy for chronic Lyme disease, but they must be used responsibly and treated patients must be subsequently tested to ensure a repaired gut flora and a functional immune system have been reestablished after antibiotics.  Long term antibiotic use needs special attention, e.g. deliberate Repair of Gut Flora or a fecal transplant.


Thus, I think that it is most likely that ever increasing antibiotic exposure and processed foods, coupled with obsessive hygiene have led to crippled gut flora (as observed in the simplified gut microbiomes of Americans), a net decline in suppressive Tregs and the observed increase of autoimmunity and allergies.  The competence of the immune system may be a major determinant in the course of infection with a pathogen that can produce chronic infections.

Wednesday, July 31, 2013

Vitamin C, Guinea Pigs, Limeys and Gut Worms

Scurvy and the Need for Vitamin C
Old timey sailors got the symptoms of scurvy, defective collagen and connective tissue, presumably because they stopped eating leafy greens that contained the needed vitamin C, aka ascorbic acid.  Primates/humans and guinea pigs are among the few animals that lack the ability to make their own ascorbic acid and therefore must eat a diet with a minimum amount of the vitamin to avoid a deficiency disease.  This is the conventional wisdom partially based on observation and experiment, but also founded on conjecture.

Parasitic Gut Worms Were the Natural Source of Vitamin C
I don't believe that vitamins are essential ingredients of a healthy diet, but rather I contend that all of the necessary nutritional chemicals are produced by the microorganisms of the gut.  I have previously discussed the gut flora (bacteria and fungi) as the source of most vitamins.  I wish to expand vitamin production to include gut fauna (animals).  I think that it is likely that intestinal worms are the historically natural source of human vitamin C.

Gut Bacteria Control the Development of the Immune System
The human gut actively communicates with the biofilms of bacteria and fungi that form a lining for the healthy gut.  The aggressive cells of the immune system that attack invading pathogens, develop in response to chemical signals from filamentous gut bacteria, and the suppressive cells of the other half of the immune system, which prevents attack on innocuous food antigens (to avoid allergies) or the human body itself (autoimmunity), develop in response to Clostridium ssp.  Thus, the immune system can be highly compromised, if the gut flora bacteria are damaged, e.g. by antibiotics.

Vitamins are Signaling Chemicals of Gut Biofilms
The communities of bacteria in gut biofilms are self-regulating by exchanging chemicals called quorum sensing signaling molecules.  Different species of bacteria and fungi in the biofilms produce and detect different chemical signals.  Since the biofilms are in intimate contact with the cells that line the gut and absorb dietary nutrients, it is not surprising that the biofilm signaling molecules are also absorbed by intestine cells.  Many of these biofilm signal molecules are vitamins, e.g. the B vitamins.  Gut bacteria are the natural source of most vitamins and healthy gut flora eliminates the need for eating vitamins in food or supplements.  Vitamin deficiencies are a symptom of a damaged gut flora.  Antibiotics and vitamin supplements can damage healthy gut biofilms.

Dietary Soluble Fiber Feeds Gut Flora
The human gut flora consists of a couple of hundred different species of bacteria in each person.  Those bacteria in aggregate can produce about a hundred thousand different proteins that focus on the digestion of food molecules that the upper gut cannot digest and absorb.  Since the upper gut can only digest proteins, fats and starch/sugars, that means that the gut flora eat the rest, undigested plant/animal polysaccharides.  Soluble fiber is the plant polysaccharides, e.g. inulin and pectin, that are digested and feed the gut flora.  The undigested polysaccharides include cellulose.  Lignin and some other plant polymers also pass through the gut and are eliminated.  The undigested stuff is called insoluble fiber and it also has bound phytate, which drags some metals such as zinc out with it.  That is why insoluble fiber, such as wheat bran, is not nutritious or healthy.  Insoluble fiber is also a minor contributor to the bulk of stools, which are made up predominately of the gut bacteria that have grown on soluble fiber.

Sea Voyages Damage Gut Organisms
The hundred of different species of bacteria in the gut change in proportions to adapt to different foods in each meal.  If the diet is fairly constant, then the diversity of the population gradually increases, just as the diversity of species in a tropical rain forest is greater than in a temperate forest.  This also explains why gut flora diversity is far less in the USA than in other parts of the world.  Americans are encouraged to eat diverse diets in the search for vitamins and superfoods.  Each dramatic change in diet makes it hard for the gut flora to adapt and the remaining bacteria are those that are generalists.  It might also be expected that early sailors who changed their diets dramatically when they went to sea, ended up with a highly compromised ship-board gut flora (and fauna.)

The Perils of Hygiene
I have a fascination for stories involving the potential of rampaging tigers.  Images of a tiger attempting to drag a hunter from his seat on an elephant or the need of a colleague to employ an armed bodyguard when capturing crabs from Malaysian Mangrove roots at night, linger in my imagination.  I still think about the report of Wallace guarding his derrière while collecting beetles in Bukit Timah, Singapore, in “The Malay Archipelago.”  Humans tend to be incompatible with lions and tigers and bears, and we wipe them out.  We do the same with bacteria, fungi and worms.  We wash our hands, flush the toilet, use hand sanitizers, kill weeds, spray pesticides, grow meticulous lawns/crops, dose ourselves with antibiotics and cleanse.  We are free of the threat of tigers, but we failed to see what else was lost during their extermination.

Probiotics Don’t Fix the Damage of Antibiotics
Antibiotics ravage gut flora.  It is no surprise that a course of antibiotics frequently leads to diarrhea or constipation, since normal stools require normal gut flora.  What is surprising is that physicians, e.g. Dr. Oz, seem to think that antibiotic decimated gut flora can be fixed with probiotics.  Sure, probiotics can provide a temporary bandaid, since Lactobacilli that would normally live on milk in the gut of newborns, are able to provide most of the functions of an adult gut flora.  But probiotics don’t survive in the adult gut and probiotics to not repair damaged gut flora.

Changes to Gut Flora are Permanent, Unless....
Gut bacteria are like wolves in Idaho.  If you don’t bring in new wolves and stop hunting them, you never again have wolves in the wilderness.  If you don’t bring in new bacteria and feed them, damaged gut flora does not repair.  Antibiotic treatment that wipes out the bacteria needed for development of the suppressive immune system will lead to autoimmune disease.  However, repairing the gut flora by flushing in new bacteria (fecal transplant) or gradually reintroducing new diverse bacteria with fermented foods, can also reverse autoimmune diseases as the immune system is repaired.

Parasitic Worms Were Lost at Sea
We think that vitamin C is only provided by plants that we eat, because we didn’t notice what was lost when we cleaned out the worms that typically inhabit the human gut.  Who would have thought that those inconvenient creatures were there for our own good?  We unknowingly compensated for the lost vitamin C production of the worms by incorporating foods rich in vitamin C in our diets.  Shipboard diets that eliminated bowel worms were augmented with limes rich in ascorbic acid.

Guinea Pigs Also Need Worms
It is interesting to note that the experimental animal used to replicate human nutritional requirements for vitamin C is the guinea pig, which is one of the few animals (in addition to bats and primates) that doesn’t make its own.  It is also interesting that guinea pigs (and bats?) commonly have intestinal worms that have to be purged from their bowels before they are used in the lab. 

Gut Flora and Fauna Provide Vitamins
My bottom line is that a normal, healthy gut contains all of the bacteria, fungi and worms to supply all of the needed vitamins.  I do, however, think that dietary vitamin C is a good replacement for one function of intestinal worms, even though I will be watching for other benefits ( Helminth therapy?) that were lost with the removal of these parasites.

Some points:
  •   Many vitamins are signal molecules for gut biofilm quorum sensing.
  •   Intestinal worms are the typical source for human vitamin C.
  •   Vitamin D is a hormone produced in the skin in response to sunlight.
  •   Vitamin supplements are unnecessary (problem?), if gut flora and fauna are healthy.
  •   Modern diets and hygiene eliminate gut parasites, so food needs to supply vitamin C.
  •   Chronic inflammation consumes vitamin C and eliminates production of vitamin D.

Friday, May 4, 2012

New Antibiotics, Biofilm Inhibitors, Vitamin Deficiency

I was not expecting my recent reading of an article on femtosecond reaction kinetics to produce another discussion of quorum sensing, biofilms and vitamins. The idea behind the article was to identify new targets for drug design based on the ephemeral transition states that occur as enzymes bind substrates, stabilize transition states and yield product molecules. Drugs that mimic the transition states make good enzyme inhibitors. One of the target enzymes for the control of disease is an enzyme, MTAN, involved in the synthesis of quorum sensing molecules that orchestrate the construction of common biofilms. The idea is to inhibit MTAN and also avoid selection for antibiotic resistance. Unfortunately, targeting quorum sensing molecules also may produce vitamin deficiencies, since many of these molecules, in this case vitamin K, are also quorum sensing molecules.

Drugs have too many Side Effects
Specificity in the binding of molecules to the thousands of proteins that are coded by the ca. 20,000 human genes depends on a very tight fit between the molecular "key" and the binding site "lock" of the protein. Just as in physical world, a small key/drug molecule with limited surface detail is not as safe/specific as a larger key with many surface features, and a larger lock/enzyme active site that is harder to pick/has fewer interactions with random enzymes. Unfortunately, most drugs are small molecules with limited surface features that make them like molecular skeleton keys that produce many side effects by interacting with unintended proteins/enzymes.

Transition States are more Specific
A recent focus on drug research is to exploit molecular computation and modeling to design molecules that will bind to the part of an enzyme that actually participates in binding substrates and catalyzing chemical reactions. These designed molecules can interact with an expanded region of the enzyme and bind more strongly than the normal substrate. The designed molecules can be very effective inhibitors that will not react as nonspecifically as inhibitors identified by trial an error, e.g. statins.

Biofilm Inhibitors are Targets for Antibiotic Development
The enzymes involved in the synthetic pathways of biofilm quorum sensing signals have been identified and powerful inhibitors of some of these enzymes have now been designed and synthesized. These inhibitors are very effective in inhibiting biofilm formation by some common bacterial pathogens (and essential gut flora.)

Biofilm Inhibitors will also Block Vitamin Production in Gut Biofilms
The new biofilm inhibitor antibiotics may have enhanced specificity, but they target enzymes that also provide essential functions in biofilms that are needed for healthy gut and immune system function. Many of the vitamins that are produced by gut flora are also quorum sensing signal molecules in healthy gut biofilms. Thus, blocking MTAN to block biofilm formation of a pathogen, will also block gut synthesis of vitamin K, which is made in gut bacteria using the MTAN pathway. These inhibitors would be expected to be particularly damaging to the specialized gut flora of breastfed babies, since these gut bacteria are known producers of vitamin K.

Tuesday, June 14, 2011

Food Poisoning and Manmade E. coli

Bacteria on food is a problem for diet-compromised people.   
Gut Flora are Required for a Healthy Immune System
Healthy people don't get sick from food poisoning, because their gut flora provide protection.  Gut bacteria control the development of the human immune system by producing interesting compounds, including short chain fatty acids and vitamins.  In response to the gut bacteria, the healthy immune system produces white blood cells that can effectively attack bacteria, and also control this aggressive behavior to spare human cells and avoid unnecessary attacks on beneficial bacteria.
Disrupted Gut Flora Lead to Susceptibility to Disease/Infection
Gut flora can be compromised by what we eat and antibiotics.  Those normally affected by food poisoning are the very young (on formula), the old (constipated) and those treated with antibiotics.  Each of these groups have abnormal gut flora.  Food poisoning is rarely observed in exclusively breastfed babies being introduced to foods, because human milk contains potent antimicrobial polysaccharides (human milk oligosaccharides) that only permit the growth of a few species of Bifidobacteria.  Formula (in any amount) disrupts the normal development of the gut and immune system by stimulating an inflammatory growth of adult gut bacteria, making these babies more susceptible to intestinal and respiratory diseases, including food poisoning.
Constipation, which is more common in older people, reflects a disruption of the gut flora and decreases the effectiveness of the immune system in these individuals.  In most cases the compromised gut flora results from a long history of a restricted diet and  reduced access to environmental sources of bacteria.
Antibiotics are usually ignored as major corruptors of the immune system, even though they are known to produce diarrhea and constipation.  Doctors reluctantly suggest that people taking antibiotics should just eat some yogurt.  This is a silly oversight that severely compromises future health, because probiotics supply only a tiny fraction of the 150 different species of bacteria needed for a healthy body and immune system.
Pathogenic E. coli is Made by Antibiotic Use in Cattle
E. coli is a common and essential resident of the human gut and the best studied bacterium.  This bacterium is not normally resistant to antibiotics nor does it produce deadly toxins.  Antibiotic resistance and toxin production results from treating cattle with antibiotics to increase fat production prior to butchering.
Antibiotics Select for E. coli that Stick to Rectal Surface of Cattle
Pathogenic E. coli are not found throughout cattle fecal material, but rather they are only in the outermost surface layer.  This outer layer of material contains bacteria from the surface of the rectum just as the cow pies are deposited.  E. coli does not normally stick to this surface, because it lacks a protein, such as a hemagglutinin capable of binding to the surface polysaccharides, heparan sulfate.  Antibiotics kill off the bacteria normally residing on the surface.  As a member of the intestinal biofilm community, E. coli continually exchanges DNA/genes with other bacteria in the gut and picks up three useful genes, to become a pathogen:
  1. Antibiotic resistance
  2. Hemagglutinin for sticking to surfaces
  3. Toxin to release nutrients from the intestinal walls.
E. coli with these three genes can colonize the rectal tissue of cattle in feed lots.
Pathogenic E. coli Can be Easily Avoided
We have to work hard as a society to have problems with E. coli.  Pathogenic E. coli results from absurd use of huge quantities of antibiotics just to disrupt the normal gut flora of cattle so that they become unhealthy and store fat in their tissues, i.e. prime beef.  The same effect can also be achieved just by feeding the cattle some short chain fatty acids, or better still avoiding this step by feeding exclusively on grass.  It would also be easy to treat the few cattle that have pathogenic E. coli, so that it doesn't become a problem.  Proper treatment of manure and meat processing would also block transmission of pathogenic E. coli to agricultural crops or meat.  Finally, an Anti-inflammatory Diet and Lifestyle would provide a healthy gut flora and immune system that would make people less susceptible to the pathogen.

Friday, December 31, 2010

Honey, Hydrophobicity and Biofilms

A reader (Jay Bryant) recently pointed out a PNAS article on the structure of a bacterial enzyme that uses sucrose to make the glucan matrix of dental biofilms.  This article released a cascade of associations in my mind and illustrated why honey does not contribute to dental plaques, but is antimicrobial and aids wound healing.  People forget that sugars combine both hydrophilic and hydrophobic properties, and thereby act as soaps.
The starting point of the chemical versatility of carbohydrates is the inability of the central portion of a sugar ring structure to form hydrogen bonds.  Each sugar is made of  a linear chain of carbon atoms with each carbon linked also to a hydrogen and a hydroxyl.  Only the hydroxyl can participate in hydrogen bonds, so each carbon has a hydrophilic side (bonds with water to make hydrogen bonds) and a hydrophobic side (that makes van der Waals bonds with other hydrophobic molecules.)  The sugars circularize and the rings have faces that are predominantly hydrophobic and perimeters with hydroxyls that are hydrophilic.  Polysaccharides (long chains of sugars), such as cellulose, can sometimes form long fibers that form a hydrophobic context for hydrogen bonds between the hydroxyls of adjacent polymers.  These cellulose fibers are very resistant to chemical or biological attack and accumulate as the most abundant biological molecules on Earth.
The PNAS article provides another example of how protein enzymes interact with carbohydrates, in this case sucrose and a polymer of glucose.  Typical weak bonds between the amino acid residues of proteins and other molecules are hydrogen, ionic or van der Waals bonds with energies of a couple of kcals/mol.  In contrast, the bonding of the hydrophobic face of a sugar to the hydrophobic face of an hydrophobic amino acid, e.g. tryptophan, phenylalanine, histidine, lysine or arginine, releases more than ten kcals/mol of energy.  Thus, the structure of the bacterial enzyme that makes biofilm glucan chains from dietary sucrose, the sucrose is bound to the enzyme on the face of a prominent tryptophan.  Examination of enzymes that bind to polysaccharides will show a series of tryptophans arrayed across the surface of the enzymes with spacing appropriate to bind to the individual sugars of the polysaccharide.
Biofilms are communities of multiple species of bacteria held together by a polysaccharide matrix.  In the case of dental plaque, the polysaccharide is made of glucose links, whereas many other matrix polysaccharides are negatively charged and held together by positively charged metal ions.  The bacteria bind to the polysaccharides using protein receptors that exploit the display of hydrophobic binding sites of the polysaccharides.  It takes energy to make polysaccharides and the dental plaque bacteria use the energy already expended in the formation of sucrose to produce a polymer of glucose, an alpha-glucan, and free fructose.  Thus, sucrose is essential in forming this type of biofilm and without this sugar, the dental plaque cannot form.  Milk lactose, or glucose would be a more appropriate sweetener.  Unfortunately, high fructose corn syrup would be a poor substitute, because of the high liver toxicity of the fructose (it causes fatty liver, just like alcohol) and very high activity in forming advanced glycation end products (AGEs), which contribute to the symptoms of  diabetics.
Honey seems to be magical, because at low concentrations the sugars present in honey  (mostly glucose and fructose, and not sucrose) are nutrients for bacteria, but at high concentrations honey is anti-bacterial and useful as a wound treatment.  I think that the explanation for its antimicrobial activity is that sugars are amphipathic, that is they have both hydrophilic and hydrophobic properties, just like soap, and at high concentrations they kill bacteria, just as soaps at high concentrations kill bacteria.  In fact, the gentle soaplike properties of sugars are exploited experimentally to dissolve proteins that are normally embedded in cellular membranes.  This explanation predicts that corn syrup, which can also be used to form very stable soap bubbles, should also be useful in wound healing.

Wednesday, January 13, 2010

Rosacea, Brain Cooling and Niacin Flush

Other players include:  Cathelicidins, Prostaglandins, Cryptic Bacteria, Nerves, Gut

What does it take to make your face red?  Excessive solar exposure can lead to apoptosis of skin cells overloaded with DNA damage and trigger inflammation: vasodilation, recruitment of neutrophils, swelling, etc.  Similarly, a local infection can cause inflammation and the accumulation of neutrophils (see The Inner Life/Extravasation for slide show), lymphocytes, etc., that is observed as pus.  These are general responses that occur in skin anywhere, but the face also blushes in response to emotional cues and flushes with exercise.  Rosacea seems to involve all of these reactions to produce a variety of symptoms of wide severity.  Here I try to provide an overview of the complex physiological interactions involved in rosacea.

Rosacea is Persistent Vasodilation of the Face with Accumulation of Neutrophils

The nervous and circulatory systems of the face are unique and provide numerous triggers for inflammation.  Emotional blushing is a common trait among those who progress to rosacea, even though this type of vasodilation is not easily observed with some facial characteristics.  Thus, many rosaceans claim to have never flushed before their first outbreak, but tests of skin circulation indicate that these individuals had skin types that prohibited display of the blushing.  The face is also adapted to control brain temperature, so changes in body temperature, physical activity, etc. can also trigger flushing.

Facial Blood Circulation to Cool the Brain

The cooling of the blood as it traverses the facial skin is used to cool the brain during extensive exercise or in warm environments.  This unique adaptation also means that control of facial vasodilation can potentially be disrupted in disease and cause symptoms of pathology.  In rosacea,  the brain cooling response is disturbed (see reference below), resulting in persistent vasodilation and suggesting that the unique control of inflammation in the face is why rosacea is limited to the face.  The pattern of blood circulation in the face, however, only roughly approximates the inflammation pattern in rosacea.

Nerves to the Face

The face receives sensory branching from the trigeminal nerve.  The enervation pattern of the branches matches emotional blushing, but they also appear to approximate the pattern of reddening in rosacea.  It makes sense that rosacea involves nerve-triggered dilation of the blood vessels of the face.  One contrast between emotional blushing and rosacea is that emotional blushing does not lead to the offloading of lymphocytes, whereas rosacea produces localization of neutrophils that exacerbate and prolong inflammation.

Cathelicidin, Vitamin D Receptor, DNA Complexes, Autoinflammation

A major component of the innate immune system is the group of basic antimicrobial peptides, cathelicidins.  Cathelicidins are effective against bacteria and they are produced during inflammation and are partially controlled by the vitamin D receptor acting as a transcription factor.  Thus, part of the action of vitamin D in providing protection against disease is by enhancing cathelicidin production.  Cathelicidin action in the skin parallels the control of intestinal villi development by defensins, that are also basic antimicrobial peptides under the control of vitamin D.  Cathelicidins also form complexes with host DNA from damaged cells.  These cathelicin/DNA complexes bind to toll-like receptors (TLRs) and trigger inflammation.  This reaction has been associated with psoriasis and may explain how neutrophil damage can perpetuate inflammation in rosacea.

Niacin Flushing Implicates Arrestins

The unique circulatory system of the face also makes it susceptible to flushing with niacin, a.k.a. nicotinic acid or vitamin B3.  Niacin is cheaper and much more effective at raising HDL and lowering triglycerides and LDL than statins, but is not fully utilized because it also produces intense facial flushes.  A recent article (below) has demonstrated that the lipid benefits can be separated from the flushing and implicated beta-arrestin 1 activation by niacin binding to GPR109A (G-protein-coupled receptor) as the triggering event.  Arrestin, which is involved in clathrin-mediated endocytosis, activates phospholipase A2 that in turn releases arachidonic acid (ARA) from phospholipids.  The ARA (that got into the phospholipids as the omega-6 fatty acid in vegetable oils) is converted by COX-2 into the inflammatory prostaglandin D2.  This prostaglandin is what stimulates vasodilation.  It is possible to produce chemicals that will stimulate the lipid metabolism alterations of niacin, without producing the arrestin activation and inflammation.  Aspirin can be used to inhibit COX-2 and other parts of NFkB-mediated inflammation and eliminate the niacin flush.  It is also interesting that the modified lipid metabolism of schizophrenics also eliminates niacin flushing.  Salicylic acid, the same as the acetylsalicylic acid of Aspirin without the acetate, is also used in some topical applications to quiet the symptoms of rosacea.  Arrestin activation may be involved in rosacea.

Gut Flora, Biofilms and Cryptic Bacteria

The gut is probably involved in most cases of rosacea and bacteria are also implicated by the modification of rosacea symptoms by antibiotics.  This area has not been explored, but I suspect that gut flora controlled by diet, as well as pathogenic biofilms and cryptic bacteria, e.g. Clamydia pneumoneae, in facial tissue are involved in varying degrees in the panoply of pathologies called collectively, rosacea.  Since the bacteria in contact with the gut determine the development of the lymphocytes in the lining of the gut, e.g. Tregs vs. T cells that fight infections, pathogenic gut biofilms may disrupt the normal function of the immune system and support rosacea.  Die off and release of cell wall endotoxin from cryptic bacteria could explain the paradoxical inflammation in response to many treatments that are normally anti-inflammatory.  I have discussed in another article potential approaches to strip off biofilms.

Treatment with Anti-Inflammatory Diet

The Anti-Inflammatory Diet (AID) and Lifestyle that I advocate on this blog would seem to be a natural cure for rosacea.  It should eliminate the inflammatory background that supports rosacea and was probably essential for its development.  This diet also eliminates acne, which is directly related to the accumulation of lymphocytes to make pus.  Inflammation is also needed for the offloading of neutrophils that exacerbate inflammation in rosacea.  Vitamin D is instrumental in cathelicidin production to eliminate cryptic bacteria. 

In most cases of rosacea, the AID should be helpful.  Eliminating dietary sources of inflammation, especially vegetable oils (the source of omega-6 fatty acids that are converted into inflammatory prostaglandins), should reduce rosacea symptoms.

In advanced, severe cases, however, it appears that maintenance of the suppression of the response to cryptic bacteria is required to prevent endotoxin-based inflammation.  Thus, most treatments that decrease inflammation, e.g. omega-3 oils, vitamin D3, Vagal maneuvers, can paradoxically produce elevated inflammation.  These treatments may also inadvertantly contribute to inflammation by upsetting pathogenic interactions between bacteria and intestinal cells.  I have discussed these paradoxical ramifications in another article.

references:
Brinnel H, Friedel J, Caputa M, Cabanac M, Grosshans E.  1989.  Rosacea: disturbed defense against brain overheating.  Arch Dermatol Res. 281(1):66-72.
Walters RW, Shukla AK, Kovacs JJ, Violin JD, DeWire SM, Lam CM, Chen JR, Muehlbauer MJ, Whalen EJ, Lefkowitz RJ.  2009.  Beta-Arrestin1 mediates nicotinic acid-induced flushing, but not its antilipolytic effect, in mice.  J Clin Invest. 119(5):1312-21.

Thursday, November 5, 2009

Biofilms as Human Gut Mycorrhizals


Are Biofilms Healthy Extensions of Intestinal Villi?

If soil is the stomach of the earth, then plant roots and mycorrizal fungi must be the intestines.

Mycorrhizal fungal hyphae extend from root hairs of plants into surrounding soil and enhance the uptake of phosphate and other nutritents.  Many plants cannot colonize new soil without taking their fungal partners with them.  It would seem obvious that the highly adapted human gut flora would include bacteria and fungi that actively communicate with intestinal epithelial cells.  Perhaps that communication includes both nutrients, e.g. hydrogen, ammonia, etc., vitamins and bacterial wall components, e.g. LPS.

Plants Sit and Mine Soil, Humans Mine Nutrients Passed through Their Gut

I want to try to give a plant’s view of human digestion.  Plants elaborate roots that branch repeatedly and the final extensions sprout hairs from individual epithelial cells.  Mycorrhizal fungal hyphae further extend the reach of the plant into the soil for nutrients. 

I think that a plant would look at us and see us stuffing soil/food into our mouths and watch it come out the other end.  It would then try to figure out where are roots are, i.e. how we absorb the water and minerals from our moving internal stream of soil.  The villi of the small intestines would look like root hairs, but where are the mycorrhizal fungi?  Another problem is that the soil keeps moving past the root hairs and would break off fungal hyphae extending into the soil.  Still another problem is the constant shedding of epithelial cells from the tips of the villi.  The plant would be perplexed, but closer inspection would reveal that biofilms could solve the problems.

Biofilms Coat the Intestinal Villi

Biofilms coating and perhaps spanning the villi of the small intestines may enhance the transport of nutrients into the villi.  This may be controversial and the biofilms may be more commonly limited to the smoother surface of the colon.  The point here is that biofilms may enhance the intestinal uptake of nutrients from food.  Biofilms may, therefore, be essential for health and extend the reach of the intestinal epithelial cells.

Bacterial Community Composition May Be Determined by Diet

A biofilm is composed of some type of linear polymer, such as DNA, heparan sulfate or bacterial acidic polysaccharides, with bacteria that bind to the polymer and to the intestinal epithelium.  Diet determines the bacterial composition of the biofilm.  Thus, the newborn starts without biofilms, gut development is finished by growth hormones in milk and a single species of Bifidobacteria excludes biofilm production, until solid food or formula initiates adult biofilms.  The bacteria in the biofilm depend on diet, so the biofilms can be either beneficial or pathogenic.

Communication within Biofilms and with the Intestines

The bacteria respond to the presence of other bacteria by quorum sensing, which involves release of small molecules that alter the gene expression of other bacteria in the community.  As a consequence, genes, e.g. antibiotic resistance, are exchanged and metabolism is altered.  This is how Klebsiella nitrogenase and hydrogen production is controlled.  The biofilm bacteria also produce compounds, e.g. vitamin D (?), that alter the behavior of the intestinal epithelial cells.  The intestines can respond with inflammation to recognized pathogen components or by triggering development of cells of the immune system.  The intestines are the home of most of the body’s immune cells.

Stimulation of Tregs

Helicobacter pylori adhering to the stomach lining increases the stomach’s quota of regulatory T cells that are involved in immunological tolerance.  Presumably, the supply of Tregs in the intestines is also regulated by biofilms.  Disruption of this system by chronic inflammation can deplete Tregs and lead to unrestrained immune attack that is observed as inflammatory bowel disease.  Thus, Crohn’s disease and ulcerative colitis may be triggered by damaged biofilms.

Thursday, October 22, 2009

Erectile Dysfunction Diet

Inflammation Leads to Hypertension, Nitric Oxide Inadequacy and Impotence

Drugs for erectile dysfunction (ED), e.g. sidenafil (Viagra), compensate for inadequate nitric oxide (NO) production from arginine by inhibiting the enzyme, phosphodiesterase (PDE5), that hydrolyzes the cyclic GMP that mediates the NO-triggered process of vascular dilation.

Inflammation Is the Core of ED

Drug treatment to compensate for inadequate NO production is a multibillion dollar industry that avoids curing the underlying cause of the ED.  All of the physiological predispositions to ED result in or derive from chronic inflammation.  The major cause of ED, hypertension, frequently as a result of kidney disease, diabetes or metabolic syndrome, can be treated with diet and exercise.  Of course the typically recommended diet is essentially the Anti-Inflammatory Diet, compromised by the unenlightened persistence in the counterproductive use of grain starches, high fructose corn syrup, omega-6 polyunsaturated fatty acids and low saturated fat.

Decreasing Testosterone Results from Declining Health -- not Age

Recent studies also indicate that testosterone levels do not normally decline with age, but rather with declining health.  Healthy men have higher testosterone levels.  I would suggest that reduction in serum testosterone could be used as a measure of chronic inflammation in men.  This also suggests that many of the symptoms associated with aging in men actually reflect increasing chronic inflammation and reduced testosterone.

ED Diets Are Just the Anti-Inflammatory Diet Plus Veggies

A chronic high starch/sugar/HFCS diet with omega-6 oils in place of saturated fats, leads to chronic inflammation, high triglycerides, risk of metabolic syndrome and obesity.  Of course, diabetics have an even lower tolerance for this type of diet.  This diet, which is rather typical in many modern cultures, also provides a high risk of damage to endothelial cells lining the circulatory system and to ED.  The opposite of the inflammatory diet is the low carb, high omega-3 fish oil, no vegetable oil, meat/fish/dairy, Anti-Inflammatory Diet.  This is supplemented with exercise and high vitamin D.  Foods labeled as beneficial to ED also include specific herbs, spices and leafy vegetables, because these contain organic chemicals that inhibit components of the inflammation system or are anti-oxidants.
 
ED and Biofilms

I would suspect that men with ED suffer from chronic dietary inflammation and one of the consequences of this type of diet is the accumulation of pathogenic biofilms.  Hypertension, which is a contributor to ED and a consequence of chronic inflammation, is also associated with periodontal biofilms and kidney disease (aggravated by renal biofilms.)  I suspect that endothelial cells of capillaries are compromised by biofilm-derived endotoxins that ultimately contribute to apoptosis, decrease in capillary beds and elevation of blood pressure.  All of these assaults on endothelial cells undermine penile vasculature and contribute to ED.

Viagra Can Lead to Rosacea

Men taking Viagra or other PDE5 inhibitors typically have compromised vascular systems that are the basis for ED.  Increasing the response to NO in men with ED produces an increased risk of rosacea.  Withdrawal from PDE5 inhibitors stops the rosacea, which returns if the PDE5 inhibitor use is reinitiated.  Thus, the flush that is the goal of Viagra therapy, leaves some redfaced.

ref:
Ioannides, D. et al. (2009) Phosphodiesterase-5 inhibitors and rosacea: report of 10 cases. Br. J. Dermatol. 160: 719-20.