Making Monsters, Renegade C. butyricum and E. coli

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Clostridium

It is common knowledge that our gut is teeming with good bacteria that we feed with prebiotic fiber to keep us healthy.  But a sick gut, caused by antibiotics or fiber deficient processed food, can make us susceptible to infection with pathogens, such as the notorious, toxin-producing strains of E. coli that cause food poisoning or Clostridium difficile, a.k.a. C. diff. of hospital infections.  What prompted me to write this post, was reading that premature babies in neonatal intensive care units are dying from gut infections caused by a pathogenic strain of C. butyricum, known as a probiotic that provides protection from C. diff.

Healthy Gut Microbiota

New Toxin-Producing, Antibiotic Superbugs are Manmade

Closer examination of the report revealed that the new strain of C. butyricum is a toxin producer.  This made a lot of sense to me.  When I started working with E. coli in the early 70’s, it was known as the safe ubiquitous lab bacterium that everyone cultivated in their colons.  Similarly, C. butyricum is present in commercial probiotics and is a hero for producing butyric acid from resistant starch, promoting immune system development and reducing inflammation.  How did these beneficial gut bacteria become converted into pathogens?

Source of Antibiotic Resistant Superbugs

Antibiotic and Drug Use in Hospitals and Farms Select for Antibiotic Resistance

C. butyricum and E. coli have been converted into toxin-producing, antibiotic resistant pathogens by common procedures of meat production and hospital treatments.  These bacteria do not normally produce toxins nor are they resistant to antibiotics.  They have been systematically selected for those pathogenic properties.

Formula Contributes to NEC

Common Practices in Neonatal Intensive Care Units Lead to NEC

Chronic inflammation is one of the common contributing factors to premature births, because labor is stimulated by a spike of inflammation, normally occurring at 40 weeks of gestation.  Chronic inflammation from autoimmune disease, infection, or obesity, can cause labor to be early and a newborn to be unprepared for life without some special care.  Unfortunately, there is not uniform enlightenment about the development of newborn gut flora, and immature newborns are exposed to antibiotics and formula, which prevent normal gut flora development.  C. butyricum is not present in low birth weight babies exclusively fed breast milk, but the combination of antibiotics and formula select for colonization by antibiotic resistant hospital strains of C. butyricum.  This sets the stage for necrotizing enterocolitis, NEC, which is as nasty and lethal as the name suggests.

Toxin Producing E. Coli are Manmade

Antibiotics Used to Make Fat Cattle Select for Toxin Production

The development of toxin producing E. coli in cattle suggests how pathogenic C. butyricum was produced in the hospital environment.  E. coli was a healthy component of the digestive system of cattle, until the gut flora community was reengineered by antibiotics, so that short chain fatty acids that were normally converted into more gut bacteria and more steer manure, were instead absorbed by the gut to produce a fatter steak.  Unfortunately, this newly designed gut flora community left no place for E. coli.  Some of the E. coli spontaneously mutated to antibiotic resistance and/or picked up multi-drug resistant plasmids from other bacteria, but that still didn’t provide a niche in the new community.  Picking up a toxin-producing gene solved that problem, because the toxin releases needed nutrients from host cells.  Thus, antibiotic use in cattle directly selected for the evolution of toxin-producing, antibiotic resistant E. coli.

Antibiotics and Formula Use Lead to NEC Bacteria

Toxin-producing C. butyricum would be expected to develop in the hospital environment, because high antibiotic use will select for multiple drug resistant C. butyricum, and the disrupted gut flora produced in the presence of antibiotics will also favor toxin producing strains.  Thus, the hospital environment selects for toxin-producing, multiple drug resistant C. butyricum.  The gut flora of newborns in a neonatal intensive care unit are acquired from the staff and relatives that handle the babies.  Since the babies are routinely treated with antibiotics and drugs, multiple drug resistant bacteria, including C. butyricum, are common in fecal samples of neonates and persist for at least two years. 

Breastmilk Prevents NEC in Newborns

Breastfeeding or Donor Bank Milk Avoids NEC Caused by Formula

Exclusive use of breastmilk from mothers, donor banks or breastmilk products, eliminates NEC.   Some hospitals respond to the scientific evidence and use only breastmilk for newborns.  Other hospitals simply stick to old practices until law suits force them to change.  They continue to use formula and cow’s milk products,  even though breastmilk is available, and as a consequence NEC is still a problem. Prejudice against breastmilk persists and there is intense promotion of commercial alternatives that contribute to NEC.  None of the alternatives containing probiotics and prebiotics have been found to be adequate.   Hospitals are slow to change, because patients are uninformed and low birthweight babies continue to die.

Bacteria Migrating to Breast May Cause Cancer

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The readers of this blog are probably aware of my interest in the causes and related cures of diseases.  Juxtaposition of recent research findings has made me reconsider the role of bacteria in breast cancer.

The Findings

• Lactation/breastfeeding lowers risk of breast cancer (improves path of normal mammary duct micro biome from nipple.)
• Tubal ligation lowers risk of ovarian cancer (eliminates path for bacteria from vagina.)
• Aspirin reduces pancreatic cancer (by reducing inflammation involved in the transition from bacterial infection to cancer.)
• Pancreatic and breast cancer risks are both dramatically increased by BRCA (tumor suppressor genes involved in 5% of breast cancer.)
• Bacteria are transported from gut to blood to breast to milk to infants.  (Google entero-mammary bacterial circulation involving intestinal M cells and dendrocytes.)

Bacteria Have Access to Organs with Common Cancers

Serum or fluid flows from organs outward; liver to gall bladder to intestines, pancreas to intestines, prostate to urethra, ovary to fallopian tube to uterus to vagina.  In each case there is also an related infection and inflammation associated with the backward path to the organ.  Urinary tract infections can lead to prostatitis.  Vaginitis can lead to pelvic inflammation, gastritis to stomach cancer, and intestinal infection/inflammation can result in pancreatitis.  The theme seems to be that bacterial infections can cause inflammation that leads to cancer.

Bacterial Path to the Breast

Lactating women occasionally have bacteria that migrate back up milk ducts to cause mastitis, but this is not quite parallel to my other examples of bacterial movement, because women are not continually producing milk.  There is, however, another path of bacteria to mammary tissue.  Prior to birth, bacteria move from the maternal gut, through the blood (presumably in lymphocytes) and into mammary tissue.  Subsequent nursing transports the bacteria to the infant to initiate the milk controlled gut flora unique to exclusively breastfed infants.

Monthly Transport of Bacteria to Breast

The menstrual cycle is an abbreviated ovulation, conception, gestation and birth, which suggests that just as in the normal prelude to lactation, there may also be monthly transport of gut bacteria to mammary tissue.  These bacteria may also cause infection and inflammation, though they may not be sufficient to cause more than transient breast tenderness.

Healthy Gut Flora Means Healthy Breasts

I expect that many diseases in infants may be associated with the wrong bacteria being transported from maternal gut to breast to infant.  Clearly, if the mother suffers from dysbiosis, which is very common, it may be difficult for the correct Lactobacilli and Bifidobacteria to be transported to mammary tissue.  Transport of other bacteria may cause problems.  Those problems may be severe as a consequence of menstrual cycles that don’t end in pregnancy, but rather end in infection, inflammation and breast cancer.  It may all come down to gut flora.  The difference between women who develop breast cancer and those that remain healthy may be the health of their gut flora.  Breastfeeding, of course, reduces the risk of breast cancer, as well as improving infant gut flora.  Formula is always a risk factor for infant health, because it attacks normal infant gut flora and promotes inflammation. Since many breast cancers naturally resolve, it may also be the case that a healthy immune system can reverse breast cancer and the health of the immune system is determined by the gut flora.

Breast Is Still Best, but Second Best is Donor Milk Banks

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Milk is a baby's first prebiotic and a major function of mother's milk is to prevent adult gut bacteria from inflaming a newborn's gut, before the gut is sealed up and a new immune system is developed. Formula companies scurry to get parents hooked on their expensive substitutes that promise ease of use and nutritional equivalence, but the sad truth is that these artificial milk substitutes undermine baby gut flora with tragic results.  Even in the rare cases where mothers are not able to breastfeed their babies, there is a safe alternative, donor milk banks.  This post is a plea for new parents to wise up and smell the poop.  You may need to tell hospital staff that you will be checking diapers and taking names to make sure that your baby only gets your breast milk.

Background: Up Close and Personal Birth and Breastfeeding

I have been personally and professionally concerned about the care and nurturing of babies for the past three decades.  I was introduced to breastfeeding, milk and babies by my wife.  My first faculty position was teaching premed students at Harvard and my wife was a nurse at the Harvard Medical School affiliate, Brigham and Women's Hospital.  We honeymooned near a well baby clinic in Malawi.  My three daughters were all born at home and never used formula -- they started to eat some mashed up food at about six months and continued to nurse for more than two years.  My wife worked evening shifts, she provided some pumped milk and I drove the girls back and forth, so she could nurse during her break.  She was also a La Leche League leader for more than 25 years, was co-founder of the Singapore branch of LLL and has been an International Board Certified Lactation Consultant for 20 years.  Because of our applied discussions of lactation, I also spent several years studying passive immunity and tolerance of the mucosal immune system of the gut.

First Flora

Breast milk is nutritive for the newborn, but it also establishes the baby's gut flora.  It is the quality of the gut flora, which species of bacteria, that determines if a newborn will thrive or die.  If the baby is delivered by Caesarian, then her first gut flora will resemble the nursery staff.  If she forces her way out the old fashioned way, her first flora will resemble her mother's vaginal flora.  Interestingly, as birth approaches, the mother's vaginal flora shifts toward that found in fermented dairy products, i.e. dairy probiotics.  As soon as milk starts to reach the mother's nipples prior to birth, it is colonized by lactic acid bacteria, the only bacteria that can survive in the harsh milk environment.  Thus, breast milk is the source of both food and flora, and it is not surprising that breastfed baby poop looks and smells like curds and whey.

Breast Milk Kills Adult Gut Flora

I used to enjoy watching the student perplexity when E. coli in lab experiments progressively died in contact with raw milk.  All of the ingredients in milk conspire against normal adult gut bacteria to withhold essential vitamins, minerals and macronutrients.  The baby' stomach enzymes also convert milk proteins into antimicrobial peptides, e.g. lactoferrin into lactoferricin (FKCRRWQWRMKKLGAPSITCVRRAF, note the heparin-binding domains consisting of basic amino acids, K & R.)  Human milk oligosaccharides (HMOs, bifidus factor) are abundant in breast milk and block the attachment of pathogens to the lining of the gut to prevent infection.  At the same time, milk hormones seal the intestines to prevent leakiness.

Formula Kills Pathogens with Inflammation

Formula provides macronutrients for rapid weight gain (obesity risk), but lacks the protective components of breast milk.  The result is a rapid and irreversible shift to dominant adult gut flora and the fecal smell of E. coli.  It is not surprising that the use of formula in under developed countries results in a high rate of infant mortality.  It is, however, surprising that the gut inflammation caused by formula provides enough protection to permit its use in countries with high hygiene and good water quality.

Hospital Use of Formula and Bovine Products Increases Infant Mortality

Full term babies are pretty tough and have been known to survive major calamities in addition to formula-induced inflammation.  Tiny preterm newborns are a different story and their immature GI tracts are fragile.  Unfortunately, the first line of defense for the newborn gut, newborn gut flora, is frequently ignored in neonatal intensive care nurseries, and a major killer of preterm newborns is necrotising enterocolitis (NEC), in which bacteria common to adults overruns the immature gut.  NEC is dramatically reduced by using only breast milk, but hospital nurseries change slowly and doctors, staff and parents are unaware that formula and cow's milk products put newborns at increased risk.

Night Nurses Would Rather Feed Formula

Recent studies show that newborns designated as "breast milk only" are still given bottles of formula, because night nurses don't understand the risks of formula and enjoy feeding the babies.  The mothers are not usually told that their baby received formula and inexperienced mothers fail to recognize why their baby never had normal bowel movements.  Some hospitals continue to use bovine, cow milk, products simply because they always have and they are unaware of the damage to newborn gut flora and the cause of NEC.

Donor Milk Banks

Some mothers produce more milk than their baby needs and so they arrange to donate the extra to milk banks.  The milk banks pasteurize and distribute the milk.  Many hospitals are unfamiliar with milk banks and donations have not been energetically encouraged, so both the supply and demand for donor milk are developing.  It is important to realize that newborn and premature babies have very small stomachs of only a few ounces, and some mothers can easily produce a cup of milk at each feeding.  Thus, the cost of using only breast milk by all babies for their first few days after birth is negligible compared to the risk of disease caused by formula use. 

Demand at Least Second Best

The bottom line is that parents must demand that only breast milk be used in hospitals, even if it must be from milk banks, and all parents must be able to check diapers for the yogurty smell typical of exclusively breastfed babies.

For more information see the Human Milk Banking Association of North America

Milk, Kefir and Gut Flora

Milk is a dramatic manipulator of gut flora.  It is a baby’s first food and provides necessary nutrients, but of equal importance, it crafts a community of gut microorganisms that develop the gut and immune system of babies.  Breastfed babies receive protein, fat and sugar, but they also coat their tiny stomachs and even their respiratory system with maternal lymphocytes and bacteria.  The major carbohydrate in breast milk is lactose, but there are other prebiotic oligosaccharides (HMO, human milk oligosaccharides) and polysaccharides (GAGs, glycosaminoglycans) related to heparin and chondroitin, which carefully limit which bacteria can grow in babies.  There are firm reasons why exclusively breastfed babies have diapers that smell like yogurt and look like curds and whey.

Milk Shows an Exaggerated Interaction between Food and Flora

Evolutionary selection is extreme to favor women who can successfully birth large babies and nurture them for years on breast milk.  Fewer than 5% of women in a general population need medical intervention for gestation, labor, delivery and breastfeeding.  Essentially all women and babies are genetically predisposed to healthy childbirth and milk-based child development.  Clearly, milk is powerful and an examination of the composition of milk should yield information on the interaction between food and gut flora.

Milk is the Prebiotic for Dairy Probiotics

Traditional preservation of cow's milk produces fermented kefir, butter, yogurt, cheeses, etc.  These are all controlled fermentations that begin by converting lactose into lactic acid.  Michael Pollan devoted a major section of his book, Cooked, to the cultural ramification and biology of fermentation.  It seems magical that leaving milk to sour will reproducibly yield a common dairy beverage.  When I taught microbiology, I had students spike raw cow’s milk with E. coli and then measure the decreasing survival of these common gut bacteria that are actively excluded from dairy fermentation.  One of the lessons here is that milk stops the growth of adult gut bacteria and supports the growth of lactic acid bacteria found in baby diapers and used to make fermented dairy products.

Milk is Toxic to Most Microorganisms, until Digested
Enzymes in the stomach convert milk proteins into antimicrobial peptides.  Later in the small intestines, pancreatic proteases digest and inactivate the peptides until they are converted into amino acids and are absorbed by the intestinal microvilli.  Milk is a natural antibiotic and is used ritually for cleansing wounds and pruning hooks.  Ritual fire walking ends by walking through a pool of cow’s milk.  The spread of plant disease in orchards from tree to tree is minimized by dipping pruning tools in milk.  The proteins, fatty acids and carbohydrates in milk kill or inhibit the growth of viruses, bacteria and fungi.  Early studies of the bacteria in breastfed babies showed an exclusive group of lactic acid bacteria and an absence of adult gut bacteria.  Breast milk was shown to contain a “bifidus factor” that selected for baby gut flora and this special ingredient was later shown to consist of a complex mixture of short chains of sugars, human milk oligosaccharides.  Thus, human milk is good for babies, but bad for adult gut flora because most of the protein, fat and carbs are digested and no soluble fiber remains for colon gut flora. 

Formula Kills Baby Gut Flora

Formula made from cow's milk or soy is toxic to baby gut flora and even a single bottle of formula can permanently damage it.  The disastrous impact of formula on gut flora is readily observed in the change to smelly diapers.  Mothers trying to give the best start to their babies can tell when the night nurse got lazy and just fed her baby a bottle of formula!  Use of formula in hospitals instead of mothers nursing or using donor milk greatly increases contamination of babies with deadly strains of hospital bacteria, e.g. C. dificile, and causes necrotising enterocolitis.  The only reason that babies can survive formula and the growth of adult gut flora in the first weeks of life, is that the disrupted gut flora is highly inflammatory and the inflamed gut provides some protection from infection.  Babies are tough, but there is no reason for hospitals to continue to use formula when research clearly shows that it is a risk to the health of babies.  Health concerns are forcing hospitals to encourage exclusive breastfeeding, but more work needs to be done so that donor breast milk is the alternative.

Raw Avoids Risks of Pasteurization and Ultra Homogenization
Milk straight from the udder contains natural dairy probiotics that are fit for a calf.  Dairy probiotics are different from baby gut flora and calves are different from babies, so cow milk is not appropriate for babies.  Processing cow's milk by heat (pasteurization) or extreme mixing to make ultra small fat droplets (homogenization) changes the structure of milk to increase storage shelf life, but the restructuring also produces some health risks for gut and gut flora.  Since leaves are rich in short chain omega-3 fatty acids and seeds are rich in omega-6s, grass fed cows produce healthier (higher 3/6 ratio) milk that may not store as well.

Kefir is a Yeast and Bacteria Biofilm

Commercial dairy products are uniform, because they are made from milk using defined mixtures of pure cultures of bacteria and fungi.  These dairy probiotics can substitute but not replace gut flora, because they can't grow in a healthy gut.  Kefir is a little different, because the kefir grains are biofilms of yeast and bacteria held together by a polysaccharide called kefiran made by a bacterial enzyme that rearranges the glucose and galactose sugar residues of lactose.  The point here is that if you grow your own kefir, you may end up with many species of bacteria and some may be able to contribute to your gut flora.  Many supermarket "kefirs" are just a blend of common dairy probiotics and maybe some inulin, and have no benefits over commercial yogurt.

Dairy products are nutritious, but will not benefit the health of your gut flora (fermented vegetables are a better choice), because they lack soluble fiber and do not contain gut flora, but your gut flora may adapt to the inherently disruptive nature of raw milk.

Milk Casein, Amyloid, Pasteurization, Homogenization

Milk is a very special food for mammalian babies. It provides essential nutrients; stimulates development of the gut; promotes the growth of the unique neonate gut flora; and kills everything else. Milk is anti-bacterial, anti-fungal and anti-viral. It is used in fruit orchards as a pruning tool dip to prevent the spread of disease between trees, and it is used as a foot dip after ceremonial walking on hot coals. But is cow's milk healthy for adult humans and is milk compromised by pasteurization and homogenization?

Mother's Milk is Fierce
Milk as it is transferred from breast to baby is loaded with molecular weapons for the protection of the baby's respiratory and digestive systems. Cells from the mother are transferred along with the milk and quickly spread out on the surface of the mouth and digestive system to patrol for pathogens. The mother's immune system detects potential risks as the baby's mouth contacts the mother's lymphatic system at the breast, and the antibodies that are subsequently produced are transferred into the milk. Enzymes in the milk digest bacterial cell walls and other milk proteins are converted into anti-bacterial peptides in the baby's stomach before ultimately being digested into amino acid nutrients. Many of the fat/lipid nutrients in milk are also anti-bacterial or anti-viral. Most of the carbohydrate in milk is the simple disaccharide lactose that most bacteria can't use for food. The remaining 10% of the carbohydrates are extensions of the lactose to make galacto-oligosaccharides (GOS, a.k.a. bifidus factor) that are toxic to all but the few bacterial species that make up the highly specialized microbial community of the human baby gut flora. (Cow's milk has an entirely different composition, e.g. lacks bifidus factor, and supports a different gut flora.)

Milk is Liquid Fat
It is hard to transport fat in water, because it isn't soluble. That is true for blood or milk. We have all heard about good and bad cholesterol, LDL and HDL, and the problems of transporting blood lipids from gut to liver to tissues. Specialized carrier proteins are needed for lipid transport in blood and the same is true for milk. Caseins are the milk proteins that coat droplets of fats that make milk white and then form digestible curds in response to the baby's stomach acid and digestive enzymes. We exploit the natural curd forming response of milk proteins and lipid droplets to form yogurts and cheeses.

Pasteurization and Homogenization Put Milk in the Dairy Case
Milk behaves optimally when immediately transferred from the mother's mammary tissue to the baby's digestive tract. Bacteria that contaminate breast milk are quickly killed by cellular and molecular defenses of the milk itself. Thus, breast milk has a long storage life at room temperature, chilled or frozen. The natural defenses of milk also permit regional milk banks, where donated milk is minimally processed and screened, for subsequent use by hospitals to avoid problems, such as necrotizing colitis, associated with the use of artificial feeding substitutes. Commercial preservation of cow's milk in stores has resulted in attempts to extend the shelf-life by heat treatment (pasteurization) to provide additional protection from microbial contamination and homogenization to prevent curd formation.

Milk is for Babies
So why isn't milk the perfect food? Part of the reason may come from the highly specialized and essential role of milk for mammals like people. Millions of years of extreme selection pressure have made sure that every woman produces ample milk for all of her babies. Until very recently, if the baby could not successfully nurse, it would die. That made breast milk the perfect food for babies and milk was integral to the development of the baby gut, baby gut flora and baby immune system. But that didn't mean that cow's milk would be a healthy commercial food for human adults.

Milk Processing May Accentuate Casein Amyloid Fiber Formation
Proteins are made of a long sequence of a thousand amino acids. At each of those thousand positions there is one of twenty different amino acids. Some of the amino acids are hydrophilic and bind to water, whereas other amino acids are hydrophobic and bind only to lipids. Proteins in water fold and unfold in thousands of alternative configurations until the final shape is reached in which there is not enough energy in the molecular vibrations and movements of the water molecules to knock the protein into an alternative shape.

Heating/pasteurization and torturous mixing/homogenization can force milk casein and fats into new configurations that make the proteins stackable into fibers/amyloids. These milk protein fibers may be of interest, because protein fibers are important in many diseases, e.g. type I diabetes, Alzheimer's disease. The problem with amyloids, is that these fibers form a natural repetition of the same amino acid on each of the stacked proteins. This repetitive amino acid, e.g. positively charged lysine or arginine, can provide a binding site for a similarly spaced, oppositely charged molecule, such as heparin, which is involved in dragging molecules from the surface into cells. Beta amyloid fibers with positively charged amino acids in a band along their edges are what kills nerve cells in Alzheimer's disease.

Research has recently demonstrated that milk casein forms amyloid fibers in response to pasteurization and homogenization. It would be interesting to know if these fibers bind to heparin and if these fibers are toxic to intestinal cells.

I have raw cream from grass fed cows in my morning coffee and my three daughters never tasted formula.

Udder Nonsense

Recent articles in the popular press have heralded the genetic engineering of cows with some human milk proteins.  Milk produced by these transgenic cows is advertised as being similar or the same as human  breast milk.

This is like claiming that the udder in the picture is an all natural, low BPA container for fortified water.  

The breakthrough in humanized cow's milk, announced by Chinese researchers in PLoS One, actually documents replacement of cow lysozyme with the corresponding human enzyme.  That does not make the milk human anymore than adding egg white lysozyme would turn the cows into chickens. If it moos like a cow...

Cow's milk-based formula harms infants, because the carbohydrates it contains do not support the normal development of infant gut flora.  The result is gut inflammation, and not normal gut and immune system development.  Even human proteins produced in cows will have characteristic cow sugars attached.  It is these cow sugars on milk proteins that are associated with colic. The chains of sugars (milk oligosaccharides) free and/or associated with milk proteins are different in cows and humans, and cow carbs are a problem in formula.

I think that it is silly to support humanizing cow's milk formula, when the sensible solution is to support breast feeding and licensed human milk banks.  The natural approach is much cheaper and far healthier.  Only human milk and human milk-derived fortifiers should be used for infants (especially preterm) in hospitals.  It is time for the healthcare industry to realize that disruption of gut flora by antibiotics or artificial formula is a health risk.  The data are clear -- cow's milk (including transgenic cow’s milk) in the hospital may be profitable, but it is unhealthy, e. g. contributes to Clostridium difficile and necrotizing enterocolitis infections, and contributes to long term health problems, such as inflammatory and autoimmune diseases.

References:

China Genetically Modifying Cows To Produce Human Breast Milk

Characterization of Bioactive Recombinant Human Lysozyme Expressed in Milk of Cloned Transgenic Cattle