Showing posts with label inflammation. Show all posts
Showing posts with label inflammation. Show all posts
Monday, March 16, 2015
Gut Microbiome 2014 Diet Inflammation Disease and Repair
--- My other 200 posts here ---
The year 2014 began with my posts on damage to the gut microbiota caused by antibiotics, processed foods and excess hygiene. I lamented the inadequacy of information from the media on damage/repair of the gut bacteria and highlighted medical myths with a post on some of Dr. Oz’s own ills that are self-inflicted by his diet and hygiene recommendations. I also started to discuss how to cure autoimmune diseases by repairing damaged gut flora and by avoiding the antibiotic activity present in many common drugs.With my 200th post in March, I summarized my thoughts on the causes and cures of common diseases in a series of diagrams on:
Health Diagram I — Gut Flora and Diet,
Health Diagram III — Inflammation from Cell to Tissue
Antibiotics Contribute to Autoimmune Diseases
Some species of gut bacteria are needed for the development of the aggressive half of the immune system and other species are needed for the suppressive half. Thus, starving or poisoning gut flora leads to immune system problems and diseases. Antibiotics are a quick way of crippling the immune system. It seems that the aggressive part of the immune system is less fragile, because in most cases antibiotic treatments produce autoimmune disease due to loss of bacteria that are needed for development of immune cells that block the aggressive half of the immune system from attacking innocuous cells of the body or environment, i.e. antibiotics usually trigger deficient tolerance, and autoimmunity.
Feed the Gut Microbiome for a Healthy Immune System
Diet provides food for the body and flora. Protein and fat are the macronutrients needed for the body, while the gut microbiota lives off of plant polysaccharides (except starch) that pass through the small intestines undigested into the colon. The hundreds of plant polysaccharides are hydrolyzed by hundreds of enzymes made by gut flora and produce short chain fatty acids, e.g. acetate and butyrate, that feed colon cells. Food processing systematically removes polysaccharides that feed gut flora and compromises the components of the immune system dependent on those bacteria.Repairing the Gut Microbiome by Eating the Missing Bacteria
It is easier to see that eating a diet that lacks food for the gut microbiota will be a problem, than it is to figure out where to find replacements for lost species of gut bacteria. The only way that bacteria get into the gut is down the throat. To repair a damaged gut microbiota requires both changing diet and introducing the missing types of bacteria by eating them. Eating dairy probiotics and fermented vegetables can provide a quick, but only temporary fix. Most of the needed bacteria are more common in soil than in food.Phytochemicals Are First and Foremost Antibiotics
I was shocked that my background in phytochemicals didn’t lead more directly to a major culprit causing modern diseases. The gut microbiota is clearly a major factor in health and sickness. Antibiotics that kill bacteria, damage the gut microbiota. It is also unsurprising that processing food to reduce soluble fiber, damages gut flora, by systematically depriving gut bacteria of their major source of food. The proliferation of antimicrobial products also damages the gut flora. What I missed in this onslaught of modern lifestyles on the gut microbiota, was the major player in antibiotic resistance — phytochemicals are natural antibiotics.
I Missed the Antibiotic Activity of Common Medicines
I studied phytochemicals and wrote research articles on their toxic, antibiotic activities, but everyone else was merchandizing phytochemicals as antioxidants, essential oils and superfoods. This is a major conceptual problem. Our bodies expend a significant fraction of our energy resources to detoxicify phytochemicals and human cultures have elaborate rituals to avoid phytochemicals and domesticate plants by breeding for the least toxic. What I missed was the implication that the pharmaceutical industry was repurposing toxic, antibiotic phytochemicals as medicines and then skipping the "antibiotic" label.
Unlabelled Antibiotic Drugs Cause the Rise of Superbugs
Overuse of antibiotics is a problem, because it damages the gut microbiome and contributes to the modern increase in autoimmunity. Food processing is another culprit and so is the mania for hyperhygiene and the demonization of bacteria. Unfortunately, the major culprit in the development of multiple antibiotic resistant superbugs is the tons of commonly used pharmaceuticals that systematically attack gut bacteria, but are not labelled as antibiotics. Most modern drugs were developed from phytochemicals and were initially used in plants to kill bacteria and fungi, i.e. phytoalexins. Pharmaceutical companies acknowledge the antibiotic activities of common drugs, by sponsoring research conferences to develop existing drugs as new classes of antibiotics for treatment of superbugs.
CIDP Inflammation and Autoantigens
Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) is chronic, relapsing autoimmune disease in which the immune system attacks the insulating myelin sheaths of nerves in the limbs. The result is numbness and pain. An acute version of this myelin compromising disease is Guillain-Barre syndrome (GBS) typically initiated by Campylobacter jejuni infection. A related disease of brain tissue is multiple sclerosis (MS). In each of these cases antibodies bind to protein or glycolipid antigens unique to myelin and target the attack by lymphocytes.
Autoimmune diseases represent a disruption of the normal function of the immune system that arises from a breakdown of the self/non-self tolerance process. Immune responses by antibodies or lymphocytes is normally reserved for molecules that don’t exist in the body, i.e. self. Differentiation of lymphocytes in the thymus or bone marrow involves systematic elimination of all lymphocytes that interact with self antigens. There are, however, self antigens that are not normally encountered by the immune system, e.g. nuclear antigens, brain antigens, since these antigens are only excluded from the cytoplasm or result from specialized differentiation. Thus, you can find in mystery novels the use of letters coated with powdered brain antigen to slowly kill targets by induction of a lethal autoimmune disease.
The self antigens that are the typical targets of the CIDP, GB and MS are gangliosides, myelin glycolipid also produced by C. jejuni, and basic proteins such as peripheral myelin protein 22. The glycolipid makes sense, because the initial exposure is during a bacterial infection that also produces inflammation. The basic proteins are a different case.
I have examined numerous self or autoantigens that are the targets for antibodies produced in autoimmune diseases and allergies. In each case the same amino acid sequence or domain is present, three basic (positively charged, arginine or lysine) amino acids. This is true for the myelin autoantigens; allergens from ragweed, mites, peanut, etc.; diabetes, lupus and arthritis.
Here is the example of the CIDP autoantigen, peripheral myelin protein 22:
MLLLLLSIIVLHVAVLVLLFVSTIVSQW
IVGNGHATDLWQNCSTSSSGNVHHCF
SSSPNEWLQSVQATMILSIIFSILSLFLF
FCQLFTLTKGGRFYITGIFQILAGLCVM
SAAAIYTVRHPEWHLNSDYSYGFAYIL
AWVAFPLALLSGVIYVILRKRE
The three basic amino acids, RKR, are at the end of the protein amino acid sequence.
A dramatic instance of tissue damage caused by physical injury or infection, is superimposed on chronic dietary inflammation to provide the environment for an inappropriate response of the immune system to a self or identical foreign antigen. The only proteins that seem to be presented in this way to the immune system are those with the strong heparin-binding domain, BBB (B = basic amino acid). This indicates that perhaps the reduction in heparin production that accompanies inflammation, may be responsible for the aberrant immune response. It is also noteworthy that heparin and anti-inflammatory agents can reduce the symptoms of many autoimmune diseases.
There are many complex therapies to deal with the symptoms of these autoimmune diseases. In all of these cases, one of the most eff
ective approaches is an anti-inflammatory diet and lifestyle. A novel additional approach is helminth therapy, infection with parasites to suppress the T-lymphocyte autoimmune attack. This approach is effective with MS, and I think would be an excellent, relatively safe approach to be examined for the other myelin autoimmune diseases.
Read more »
Autoimmune diseases represent a disruption of the normal function of the immune system that arises from a breakdown of the self/non-self tolerance process. Immune responses by antibodies or lymphocytes is normally reserved for molecules that don’t exist in the body, i.e. self. Differentiation of lymphocytes in the thymus or bone marrow involves systematic elimination of all lymphocytes that interact with self antigens. There are, however, self antigens that are not normally encountered by the immune system, e.g. nuclear antigens, brain antigens, since these antigens are only excluded from the cytoplasm or result from specialized differentiation. Thus, you can find in mystery novels the use of letters coated with powdered brain antigen to slowly kill targets by induction of a lethal autoimmune disease.
The self antigens that are the typical targets of the CIDP, GB and MS are gangliosides, myelin glycolipid also produced by C. jejuni, and basic proteins such as peripheral myelin protein 22. The glycolipid makes sense, because the initial exposure is during a bacterial infection that also produces inflammation. The basic proteins are a different case.
I have examined numerous self or autoantigens that are the targets for antibodies produced in autoimmune diseases and allergies. In each case the same amino acid sequence or domain is present, three basic (positively charged, arginine or lysine) amino acids. This is true for the myelin autoantigens; allergens from ragweed, mites, peanut, etc.; diabetes, lupus and arthritis.
Here is the example of the CIDP autoantigen, peripheral myelin protein 22:
MLLLLLSIIVLHVAVLVLLFVSTIVSQW
IVGNGHATDLWQNCSTSSSGNVHHCF
SSSPNEWLQSVQATMILSIIFSILSLFLF
FCQLFTLTKGGRFYITGIFQILAGLCVM
SAAAIYTVRHPEWHLNSDYSYGFAYIL
AWVAFPLALLSGVIYVILRKRE
The three basic amino acids, RKR, are at the end of the protein amino acid sequence.
A dramatic instance of tissue damage caused by physical injury or infection, is superimposed on chronic dietary inflammation to provide the environment for an inappropriate response of the immune system to a self or identical foreign antigen. The only proteins that seem to be presented in this way to the immune system are those with the strong heparin-binding domain, BBB (B = basic amino acid). This indicates that perhaps the reduction in heparin production that accompanies inflammation, may be responsible for the aberrant immune response. It is also noteworthy that heparin and anti-inflammatory agents can reduce the symptoms of many autoimmune diseases.
There are many complex therapies to deal with the symptoms of these autoimmune diseases. In all of these cases, one of the most eff
ective approaches is an anti-inflammatory diet and lifestyle. A novel additional approach is helminth therapy, infection with parasites to suppress the T-lymphocyte autoimmune attack. This approach is effective with MS, and I think would be an excellent, relatively safe approach to be examined for the other myelin autoimmune diseases.Vagus Nerve Controls Intestinal Inflammation
Macrophages release inflammatory signals (TNF, IL-1, IL-6, IL-18) that result in tissue inflammation. Nicotine is anti-inflammatory by acting on the acetylcholine receptors normally responsive to acetylcholine released by the vagus nerve. Acupuncture is anti-inflammatory by stimulating the vagus nerve-mediated effects on macrophages.
The relationship between the nervous and immune systems has been accepted as a reality, but has been elusive. Numerous examples in alternative medicine appear to show that a variety of treatments have immunological impacts, but explanations based on cellular biology have been slow to materialize. Here I will discuss some of the recent experiments that reveal obvious connections between nerves and macrophages that may explain in medical terms at least part of the efficacy of acupuncture.
Dilation of blood vessels that causes reddening, swelling and warmth of tissue inflammation results from changes at the cellular level. If the sentinel cells of a tissue, macrophages, are exposed to a bacterium, for example, receptors on the surface of the macrophages bind fragments of the bacterial cell wall, i.e. lipopolysaccharide (LPS) or endotoxin, and signal the expression of five dozen genes. Among these genes are inflammatory mediators, TNF, IL-1, IL-6, IL-18, that are released from the macrophages and trigger behavioral changes in the surrounding cells of the tissue, which are observed as inflammation.
Expression of the inflammatory genes is controlled by a master transcription factor, NFkB. Thus, LPS will signal a macrophage, NFkB is activated, inflammatory genes are expressed, mediators are secreted and tissue inflammation is observed. Dozens of different inputs determine if NFkB will be activated or quieted. Nicotine for example has been observed to block inflammation by LPS.
It has been shown that macrophages also have receptors for the neurotransmitter acetylcholine that is released by branches of the vagus nerve in the intestines. It has also been recently shown that excitation of the vagus nerve releases acetylcholine and blocks the response of intestinal macrophages to LPS. Thus, vagus stimulation is anti-inflammatory and blocks NFkB activation through a competing transcription factor, STAT3. Nicotine acts by binding to the acetylcholine receptors of the macrophages and is similarly anti-inflammatory.
Acupuncture appears to work by needle stimulation of the vagus nerve that sends signals to the brain. Returning nerve impulses via the vagus nerve subsequently release acetylcholine back into the surrounding tissue and block inflammation. In this context, acupuncture would be exploiting an existing inflammation dampening system, that would serve to localize spreading inflammatory signaling and emphasize the source of inflammation for action by the circulating elements of the immune system.
Read more »
The relationship between the nervous and immune systems has been accepted as a reality, but has been elusive. Numerous examples in alternative medicine appear to show that a variety of treatments have immunological impacts, but explanations based on cellular biology have been slow to materialize. Here I will discuss some of the recent experiments that reveal obvious connections between nerves and macrophages that may explain in medical terms at least part of the efficacy of acupuncture.
Dilation of blood vessels that causes reddening, swelling and warmth of tissue inflammation results from changes at the cellular level. If the sentinel cells of a tissue, macrophages, are exposed to a bacterium, for example, receptors on the surface of the macrophages bind fragments of the bacterial cell wall, i.e. lipopolysaccharide (LPS) or endotoxin, and signal the expression of five dozen genes. Among these genes are inflammatory mediators, TNF, IL-1, IL-6, IL-18, that are released from the macrophages and trigger behavioral changes in the surrounding cells of the tissue, which are observed as inflammation.
Expression of the inflammatory genes is controlled by a master transcription factor, NFkB. Thus, LPS will signal a macrophage, NFkB is activated, inflammatory genes are expressed, mediators are secreted and tissue inflammation is observed. Dozens of different inputs determine if NFkB will be activated or quieted. Nicotine for example has been observed to block inflammation by LPS.
It has been shown that macrophages also have receptors for the neurotransmitter acetylcholine that is released by branches of the vagus nerve in the intestines. It has also been recently shown that excitation of the vagus nerve releases acetylcholine and blocks the response of intestinal macrophages to LPS. Thus, vagus stimulation is anti-inflammatory and blocks NFkB activation through a competing transcription factor, STAT3. Nicotine acts by binding to the acetylcholine receptors of the macrophages and is similarly anti-inflammatory.
Acupuncture appears to work by needle stimulation of the vagus nerve that sends signals to the brain. Returning nerve impulses via the vagus nerve subsequently release acetylcholine back into the surrounding tissue and block inflammation. In this context, acupuncture would be exploiting an existing inflammation dampening system, that would serve to localize spreading inflammatory signaling and emphasize the source of inflammation for action by the circulating elements of the immune system.
Molecular Inflammation
Much of the physiology of inflammation is the response of tissue to injury. At the cellular level, inflamed tissues express a particular set of five dozen inflammatory genes. Several different inputs can trigger inflammation, but a single transcription factor, NFkB, turns on the inflammatory gene program.
Each tissue has unique structures and functions as a result of different proteins, yet essentially all cells have the same genes. The differences are due to the expression of subsets of the total 20,000 or so genes -- each different type of cell produces different amounts of protein from each of the available genes. The history of each cell, its cellular neighbors and the biochemical signals that it has received, determines how genes are expressed by the presence or absence of the master molecular controls, the transcription factors. These control proteins interact by sticking to the control sequences at the end of the DNA sequences that are the genes along the very long DNA molecules called chromosomes. Humans have 64 chromosomes -- 23 pairs and on average each chromosome has about a thousand genes interspersed among long stretches of other DNA. The point here is that a particular protein can bind to part of a group of genes, the control region, and the designated genes will be turned on to produce the proteins of inflammation.
The transcription factor that controls inflammation is nuclear factor kappa B, NFkB. Its name reflects its initial characterization in B lymphocytes that were stimulated to produce the heavy chain of immunoglobulins, the kappa chain. NFkB was ultimately implicated in the control of the expression of many genes integral to immunity and that included the suite of genes characteristic of inflammation.
Transcription factors, such as NFkB, physically stick to particular sequences of the four DNA bases, ATG or C, and this means that the NFkB protein has positively charged (basic, i.e. arginine or lysine) amino acids that hydrogen bond with the negatively charged phosphate groups of the DNA. This general interaction is similar to the binding of extracellular proteins to heparin. Moreover, the proteins that interact with DNA or RNA are all found in the nucleus, so it is not surprising that all of the nuclear proteins have a nuclear localization signal, NLS, that in most cases consists of groups of basic amino acids (BBBB or BBxxxx...xxxBB) that are also classes of heparin binding domains. Proteins with these NLSs exposed will be transported from the cytoplasm to the nucleus and if present extracellularly, they will be endocytosed by binding to heparan sulfate proteoglycans and then transported to the nucleus. I think that these unusual properties are the basis for why extreme autoimmune diseases, such as lupus, result in the production of antibodies against nuclear proteins.
The genes turned on for expression by NFkB when inflammation is triggered yield the inflammatory cytokines, IL-1, IL-6 and TNF; the enzyme that makes omega-3 and omega-6 fatty acids into the corresponding anti-inflammatory and inflammatory prostaglandins, COX-2; and the enzyme producing nitric oxide, iNOS. You may notice that many of these protein products can in turn also stimulate inflammation and they can in fact cause the spread of inflammation in a radiating wave from the point of initiation. As this wave encounters the dendrites of neurons, pain can result, but additional signals are transmitted to the brain and the response down the vagus nerve produces the regional production of anti-inflammatory cytokines that control the continued spread of inflammation.
Many plant products bind to proteins involved in the signaling of inflammation. Aspirin for example binds to COX-2 and stops the production of prostaglandins. The inflammatory prostaglandins are needed for the proper development of stomach lining, so aspirin in high local concentrations can damage the gut. Since COX-2 is needed for anti-inflammatory prostaglanding production it also has this negative result. Aspirin also binds directly to NFkB and in so doing blocks inflammation directly. The turmeric compound, curcumin, is even more effective at blocking inflammation by interacting with NFkB. Unfortunately curcumin is “detoxified” by enzymes in the intestines and its inflammatory actions are thereby diminished. The cultural practice of including black pepper with turmeric compensates for the gut effects, because the piperine in black pepper inactivates the defensive enzymes and temporarily permits serum levels of curcumin to become therapeutic.
Read more »
Each tissue has unique structures and functions as a result of different proteins, yet essentially all cells have the same genes. The differences are due to the expression of subsets of the total 20,000 or so genes -- each different type of cell produces different amounts of protein from each of the available genes. The history of each cell, its cellular neighbors and the biochemical signals that it has received, determines how genes are expressed by the presence or absence of the master molecular controls, the transcription factors. These control proteins interact by sticking to the control sequences at the end of the DNA sequences that are the genes along the very long DNA molecules called chromosomes. Humans have 64 chromosomes -- 23 pairs and on average each chromosome has about a thousand genes interspersed among long stretches of other DNA. The point here is that a particular protein can bind to part of a group of genes, the control region, and the designated genes will be turned on to produce the proteins of inflammation.
The transcription factor that controls inflammation is nuclear factor kappa B, NFkB. Its name reflects its initial characterization in B lymphocytes that were stimulated to produce the heavy chain of immunoglobulins, the kappa chain. NFkB was ultimately implicated in the control of the expression of many genes integral to immunity and that included the suite of genes characteristic of inflammation.
Transcription factors, such as NFkB, physically stick to particular sequences of the four DNA bases, ATG or C, and this means that the NFkB protein has positively charged (basic, i.e. arginine or lysine) amino acids that hydrogen bond with the negatively charged phosphate groups of the DNA. This general interaction is similar to the binding of extracellular proteins to heparin. Moreover, the proteins that interact with DNA or RNA are all found in the nucleus, so it is not surprising that all of the nuclear proteins have a nuclear localization signal, NLS, that in most cases consists of groups of basic amino acids (BBBB or BBxxxx...xxxBB) that are also classes of heparin binding domains. Proteins with these NLSs exposed will be transported from the cytoplasm to the nucleus and if present extracellularly, they will be endocytosed by binding to heparan sulfate proteoglycans and then transported to the nucleus. I think that these unusual properties are the basis for why extreme autoimmune diseases, such as lupus, result in the production of antibodies against nuclear proteins.
The genes turned on for expression by NFkB when inflammation is triggered yield the inflammatory cytokines, IL-1, IL-6 and TNF; the enzyme that makes omega-3 and omega-6 fatty acids into the corresponding anti-inflammatory and inflammatory prostaglandins, COX-2; and the enzyme producing nitric oxide, iNOS. You may notice that many of these protein products can in turn also stimulate inflammation and they can in fact cause the spread of inflammation in a radiating wave from the point of initiation. As this wave encounters the dendrites of neurons, pain can result, but additional signals are transmitted to the brain and the response down the vagus nerve produces the regional production of anti-inflammatory cytokines that control the continued spread of inflammation.
Many plant products bind to proteins involved in the signaling of inflammation. Aspirin for example binds to COX-2 and stops the production of prostaglandins. The inflammatory prostaglandins are needed for the proper development of stomach lining, so aspirin in high local concentrations can damage the gut. Since COX-2 is needed for anti-inflammatory prostaglanding production it also has this negative result. Aspirin also binds directly to NFkB and in so doing blocks inflammation directly. The turmeric compound, curcumin, is even more effective at blocking inflammation by interacting with NFkB. Unfortunately curcumin is “detoxified” by enzymes in the intestines and its inflammatory actions are thereby diminished. The cultural practice of including black pepper with turmeric compensates for the gut effects, because the piperine in black pepper inactivates the defensive enzymes and temporarily permits serum levels of curcumin to become therapeutic.
Inflammation Score
Most people need some feedback to monitor the impact of their diet and exercise on their health. I tried to point out some of the major contributors to chronic inflammation with a little check list. See how you score (choose one of the list for each category) and give me your feedback on the how you think each part contributes to inflammatory diseases.
Fat Content ____
lean 0
extra abdominal fat 4
obese 8
Carbs ____
small meals, no cereal for breakfast 0
fistful of starch with each meal 2
pasta/rice/potato as a meal 4
HFCS ____
high fructose corn syrup banned from your diet 0
don’t avoid HFCS, but avoid soft drinks 2
have replaced sucrose with HFCS, enjoy soft drinks 4
Unsaturated Fats ____
have removed vegetable oils (except olive oil) from your kitchen 0
use canola oil 2
have replaced saturated fats with corn oil 4
Trans fats ____
eat no trans fats 0
avoid trans fats on your chips 2
don’t know what trans fats are 4
Fish oil ____
supplement with two or more fish oil (DHA/EPA) capsules per day 0
eat at least two helpings of oily fish per week 2
avoid all fish products 4
Antioxidants ____
know that coffee, tea and chocolate are good sources of vegetable antioxidants 0
eat five servings of fruits and veggies 0
take vitamin C supplement, because you avoid veggies 2
avoid veggies; meat and potatoes type 4
Exercise ____
take a stroll after meals and maintain your muscle mass 0
run when you feel guilty 2
couch potato 4
If you smoke, add an extra 15 points
Add ‘em up. How much are you stoking the inflammation furnace?
0-5 Cool! You will never look your age.
6-10 You are getting warm. Hope that you dont have any genetic predispositions to disease.
11-15 You may postpone inflammatory illness until middle age. The flame is lit. Pick your disease.
16-25 If you aren’t showing a chronic disease, you will soon.
26+ You can reverse your disease symptoms with the inflammatory diet and exercise.
Read more »
Fat Content ____
lean 0
extra abdominal fat 4
obese 8
Carbs ____
small meals, no cereal for breakfast 0
fistful of starch with each meal 2
pasta/rice/potato as a meal 4
HFCS ____
high fructose corn syrup banned from your diet 0
don’t avoid HFCS, but avoid soft drinks 2
have replaced sucrose with HFCS, enjoy soft drinks 4
Unsaturated Fats ____
have removed vegetable oils (except olive oil) from your kitchen 0
use canola oil 2
have replaced saturated fats with corn oil 4
Trans fats ____
eat no trans fats 0
avoid trans fats on your chips 2
don’t know what trans fats are 4
Fish oil ____
supplement with two or more fish oil (DHA/EPA) capsules per day 0
eat at least two helpings of oily fish per week 2
avoid all fish products 4
Antioxidants ____
know that coffee, tea and chocolate are good sources of vegetable antioxidants 0
eat five servings of fruits and veggies 0
take vitamin C supplement, because you avoid veggies 2
avoid veggies; meat and potatoes type 4
Exercise ____
take a stroll after meals and maintain your muscle mass 0
run when you feel guilty 2
couch potato 4
If you smoke, add an extra 15 points
Add ‘em up. How much are you stoking the inflammation furnace?
0-5 Cool! You will never look your age.
6-10 You are getting warm. Hope that you dont have any genetic predispositions to disease.
11-15 You may postpone inflammatory illness until middle age. The flame is lit. Pick your disease.
16-25 If you aren’t showing a chronic disease, you will soon.
26+ You can reverse your disease symptoms with the inflammatory diet and exercise.
Why Discuss Mother’s Milk on an Inflammation Blog
Milk Is Perfectly Adapted for Infant Nutrition/Development
I think that I should explain, if it is not obvious, why I keep bringing up breastfeeding/infant nutrition on this blog about diet, inflammation and disease. The starting point is that infants need nutrition, protection from disease and continued normal development or they won’t be able to reproduce. That means that milk is the focal point of a lot of natural selection and absence of the natural functions of milk, e.g. use of formula, would be expected to lead to inflammation and disease, which it does. Analysis of milk and how formula makes infants susceptible to disease and alters normal development, provides an extreme example of the interactions of diet, gut flora and the immune system.
Since this is World Breastfeeding Week and my wife is an Internationally Board Certified Lactation Consultant, I think that writing a few articles on milk is good for my health.
Milk Provides Complete Nutrition, Controls Gut Flora, Promotes Gut Development -- Formula Doesn’t
I find it amazing that supplements are encouraged for exclusively breastfeeding infants. It doesn’t make sense to suspect that breast milk is inadequate and why is formula fortified with ingredients at ten to a hundred times the levels in breast milk? The answer is in the infant gut flora and perhaps in poor maternal nutrition/gut flora.
Mother’s Milk Promotes Normal Infant Gut Flora -- Bifidobacteria
The normal infant gut flora is very simple, Bifidobacteria. Adults have gut flora composed of hundreds of different species of bacteria and infants have just Bifidobacteria. The name of the infant bacterium should be familiar if you read labels on yogurt. Bifidobacteria are common probiotics. That also explains why the diapers of exclusively breast fed babies smell like yogurt. Formula Promotes Adult Gut Flora
One bottle of formula kills the Bifidobacteria and replaces it with adult gut bacteria. The diapers are forever changed, because the adult gut flora is very persistent. The presence of the adult gut flora also explains why formula has the high levels of supplements. The adult gut flora consumes the supplements and leaves only tiny amounts for the infant. All of the breast milk nutrients go to the baby if only Bifidobacteria is present, but after the adult gut flora are established much higher levels are needed and the infant may still be deficient. Adult, formula-supported gut flora also digest antibodies and other protective factors in mother’s milk.
Supplement Mothers to Improve Infant Nutrition
Modern mothers are also eating modern diets that produce deficiencies. Chronic diet-based inflammation leads to a compromised ability to produce vitamin D in sunlight. Nursing mothers with poor diets may not be transferring enough vitamin D to their nursing babies. Since formula and the adult gut flora that it stimulates, causes gut inflammation, I suspect that formula fed infants are also compromised in their ability to produce their own vitamin D in sunlight. It makes more sense to supplement mothers than babies.
Formula Is not Breast Milk, It’s Not Even Close
Formula is cheap to produce, but expensive to buy. Formula is promoted as the next best substitute for milk from a baby’s own mother, but that isn’t true either. The next best alternative is mother’s milk from a certified human milk bank. It is available at a reasonable cost. Hospitals should know better and provide the only appropriate alternative. Early formula use dramatically increases healthcare costs.
Formula Lacks the Oligosaccharides Needed to Support only Bifidobacter
Fructose oligosaccharides (FOS) and other short chains of sugars are being promoted to support the growth of beneficial gut flora. These oligosaccharides do promote the growth of adult gut flora, but not just infant Bifidobacteria. Formula plus FOS and/or other prebiotic oligosaccharides other than those present in human milk support the growth of bacteria that rob nutrients from and degrade the protective components of breast milk. If the diaper smells like adult gut flora, then the baby was not fed mother’s milk.
Development of Gut and Brain
The newborn gut and brain are only partially developed. Mother’s milk is needed to supply growth factors to close and differentiate the gut epithelium, and long chain omega-3 fatty acids for brain growth. Formula may eventually be supplemented with the needed fatty acids, but the growth factors/hormones present in mother’s milk will not be provided in formula. Recent studies have shown that hundreds of different genes are activated in gut cells from infants fed either breast milk or formula. Formula leaves the gut leaky and fails to stimulate the development of the immune system that is dependent on interaction with normal infant gut flora. These dysfunctions partially explain the increased (10X to 100X) gut and respiratory infections resulting from formula use. The reduced brain development with formula explains the five point reduction in IQ of formula fed infants.
It’s worldwide breastfeeding week. Support healthy, non-inflammatory gut flora (infant Bifidobacteria) around the globe!
Cancer Stem Cells Require Inflammation
Spread of cancer requires stem cells and inflammation. A tumor provides support for development of cancer stem cells and the inflammation transcription factor, NFkB is needed for the expression of the stem cell phenotype.
A recent research article shows that inflammation is the basis for prostate cancer and in particular for the division of cancer stem cells, i.e. proliferation. The stem cells of prostate cancer are a rare form of epithelial (surface layer) cells that produce a particular protein on the surface of their cell membrane that is different from the other cells in a prostate tumor. The researchers examined the genes that were expressed in the presumptive prostate cancer stem cells using DNA array technology
that measures gene expression by the amount of mRNA transcribed from each gene. Thus, the total mRNA from the cell sample is extracted, attached to fluorescent dyes, hybridized to each of the 20,000 human genes displayed in tiny drops on a microscope slide and examined by a fluorescence microscope. The amount of fluorescent mRNA attached to each gene is a measure of the expression of that gene. Control cell mRNA extracts can be used for comparison.
The major finding of the research was that the suite of inflammatory genes controlled by the inflammatory transcription factor NFkB were characteristic of the prostate cancer stem cells.
If NFkB was inhibited by the active ingredient in feverfew, parthenolide, the cancer stem cells died by programmed cell death, apoptosis. Parthenolide is used to treat inflammation, e.g. in arthritis. NFkB is also inhibited by aspirin and curcumin, the active component in turmeric. These and other anti-inflammatory plant products have been implicated in reducing cancer.
Read more »
A recent research article shows that inflammation is the basis for prostate cancer and in particular for the division of cancer stem cells, i.e. proliferation. The stem cells of prostate cancer are a rare form of epithelial (surface layer) cells that produce a particular protein on the surface of their cell membrane that is different from the other cells in a prostate tumor. The researchers examined the genes that were expressed in the presumptive prostate cancer stem cells using DNA array technology
that measures gene expression by the amount of mRNA transcribed from each gene. Thus, the total mRNA from the cell sample is extracted, attached to fluorescent dyes, hybridized to each of the 20,000 human genes displayed in tiny drops on a microscope slide and examined by a fluorescence microscope. The amount of fluorescent mRNA attached to each gene is a measure of the expression of that gene. Control cell mRNA extracts can be used for comparison.The major finding of the research was that the suite of inflammatory genes controlled by the inflammatory transcription factor NFkB were characteristic of the prostate cancer stem cells.
If NFkB was inhibited by the active ingredient in feverfew, parthenolide, the cancer stem cells died by programmed cell death, apoptosis. Parthenolide is used to treat inflammation, e.g. in arthritis. NFkB is also inhibited by aspirin and curcumin, the active component in turmeric. These and other anti-inflammatory plant products have been implicated in reducing cancer.Vagus Nerve Controls Gut Inflammation II
Inflammatory Mast Cells Silenced
In a previous article, I outlined the role of the vagus nerve in responding to infection/damage signals by producing signals that inhibit inflammation. In a recent article (ref. below), the role of the vagus nerve in gut inflammation was examined using real-time biophotonic labeling. Basically that means that a video camera sensitive to infrared can be used to detect infrared dyes produced when NFkB is activated -- the camera is able to visualize regions of inflammation in living mice. Using this technique, researchers were able to demonstrate that cutting the vagus nerve produced heightened inflammation in gut treated with an irritant. The vagus nerve appears to stimulate regulatory T cells that lower the activity of inflammatory cells.
Inflammation/NFkB Activation Visualized in Live Mice
The studies were performed in a mouse line constructed to express an infrared fluorescent protein in cells in which the inflammation transcription factor, NFkB, is activated. Mice of this strain were prepared with and without the vagus nerve intact leading to the intestines. The mice were then exposed to sodium dextran sulfate (DSS) to simulate inflammatory bowel disease symptoms.
Cutting the Vagus Nerve Permits Inflammation
Mice with intact vagus nerves exhibited much less inflammation in their gut than those without vagus innervation. The cut vagus experiments demonstrated that the vagus nerve was responsible for suppressing inflammation. Further experiments were performed to determine if the inflammatory and anti-inflammatory reactions could be transferred to other mice by transferring cells from the treated mice.
Regulatory T Cells (CD4+, CD25+) Block Inflammation
Transfer experiments showed that inflammatory T cells (CD4+, CD25-) from cut vagus, DSS mice would cause bowel inflammation in other mice, but that did not happen with the same type of cells from mice with intact vagus nerves. Further tests showed that either cutting the vagus or adding inflammatory T cells from a mouse with a cut vagus, reduced the population of regulatory T cells (CD4+, CD25+) in control mice treated with DSS. So, without the vagus stimulation, the regulatory T cell population declined in the presence of inflammatory signals.
Absence of Regulatory T Cells Can Explain Many Inflammatory Diseases
In many inflammatory diseases, e.g. celiac, Crohn’s disease, rosacea, there appears to be a deficiency of regulatory T cells. In the absence regulatory T cells, signals from vagus nerves will no longer produce anti-inflammatory suppression. In fact the same nerve signals may become inflammatory. This would explain why rosaceans will become inflamed by hot or cold stimulation that would normally lead to anti-inflammatory stimulation of regulatory T cells. Similarly, capsaicin, castor oil and menthol, which normally produce an anti-inflammatory response, produce inflammation in rosaceans.
[Vagal stimulation exercise links: here and here.]
reference:
OMahony C, van der Kleij HP, Bienenstock J, Shanahan F, OMahony L. 2009. Loss of vagal anti-inflammatory effect - in vivo visualization and adoptive transfer. Am J Physiol Regul Integr Comp Physiol. Aug 12. [Epub ahead of print]
Read more »
In a previous article, I outlined the role of the vagus nerve in responding to infection/damage signals by producing signals that inhibit inflammation. In a recent article (ref. below), the role of the vagus nerve in gut inflammation was examined using real-time biophotonic labeling. Basically that means that a video camera sensitive to infrared can be used to detect infrared dyes produced when NFkB is activated -- the camera is able to visualize regions of inflammation in living mice. Using this technique, researchers were able to demonstrate that cutting the vagus nerve produced heightened inflammation in gut treated with an irritant. The vagus nerve appears to stimulate regulatory T cells that lower the activity of inflammatory cells.
Inflammation/NFkB Activation Visualized in Live Mice
The studies were performed in a mouse line constructed to express an infrared fluorescent protein in cells in which the inflammation transcription factor, NFkB, is activated. Mice of this strain were prepared with and without the vagus nerve intact leading to the intestines. The mice were then exposed to sodium dextran sulfate (DSS) to simulate inflammatory bowel disease symptoms.Cutting the Vagus Nerve Permits Inflammation
Mice with intact vagus nerves exhibited much less inflammation in their gut than those without vagus innervation. The cut vagus experiments demonstrated that the vagus nerve was responsible for suppressing inflammation. Further experiments were performed to determine if the inflammatory and anti-inflammatory reactions could be transferred to other mice by transferring cells from the treated mice.
Regulatory T Cells (CD4+, CD25+) Block Inflammation
Transfer experiments showed that inflammatory T cells (CD4+, CD25-) from cut vagus, DSS mice would cause bowel inflammation in other mice, but that did not happen with the same type of cells from mice with intact vagus nerves. Further tests showed that either cutting the vagus or adding inflammatory T cells from a mouse with a cut vagus, reduced the population of regulatory T cells (CD4+, CD25+) in control mice treated with DSS. So, without the vagus stimulation, the regulatory T cell population declined in the presence of inflammatory signals.Absence of Regulatory T Cells Can Explain Many Inflammatory Diseases
In many inflammatory diseases, e.g. celiac, Crohn’s disease, rosacea, there appears to be a deficiency of regulatory T cells. In the absence regulatory T cells, signals from vagus nerves will no longer produce anti-inflammatory suppression. In fact the same nerve signals may become inflammatory. This would explain why rosaceans will become inflamed by hot or cold stimulation that would normally lead to anti-inflammatory stimulation of regulatory T cells. Similarly, capsaicin, castor oil and menthol, which normally produce an anti-inflammatory response, produce inflammation in rosaceans.
[Vagal stimulation exercise links: here and here.]
reference:
OMahony C, van der Kleij HP, Bienenstock J, Shanahan F, OMahony L. 2009. Loss of vagal anti-inflammatory effect - in vivo visualization and adoptive transfer. Am J Physiol Regul Integr Comp Physiol. Aug 12. [Epub ahead of print]
Sunday, March 15, 2015
Health Diagrams III — Inflammation from Cell to Tissue
---All 200 Posts---
I have explained my perspective in diagrams of the relationship between diet, gut flora and disease:
Health Diagrams I — Gut Flora and Diet
and of the interaction between gut flora, the immune system and autoimmunity:
Health Diagrams II — Curing Autoimmunity and Allergies
Now I am discussing how inflammation, the foundation of most chronic diseases, begins at the cellular level and results in the classic symptoms of tissue inflammation: redness, heat, swelling and pain.
NF-kB is the Transcription Factor that Controls Inflammation Genes
Of the 23,000 human genes, about 1,000 on each of 23 chromosomes, five dozen, e.g. enzymes involved in nitric oxide (vasodilation and erection hormone), synthesis of heparin sulfate and prostaglandin synthesis from omega-6 fatty acids or cytokines (IL-1, IL-6, TNFa), are associated with inflammation. These inflammatory genes are turned on or expressed in individual cells, when the inflammation transcription factor, NF-kB, is activated by any of numerous external signals, including inflammatory cytokines, bacterial or fungal cell wall materials (LPS or beta-glucan), advanced glycation end products (AGE, e.g. HgA1C, resulting from high blood sugar) or reactive oxygen species (ROS, e.g. super oxide, from insulin resistance).
NF-kB and Inflammation
Superoxid Causes Insulin Resistance
Superoxid Causes Insulin Resistance
Inflammation is the Foundation of Growth, Birth, Cancer and Pain
We think of inflammation as the sum of physical symptoms, and our purpose in responding to inflammation is typically to limit its impact. We try to stop swelling by applying cold or hot, and we take aspirin to lower fevers and stop pain. We fail to realize that inflammation is essential to the growth and development of many different tissues, and that inflammation is a cycle that leads back to normal function.
Body tissues, such as the lining of the intestines or the uterus, continually produce new cells to replace the old that are sloughed off. NF-kB must be turned on for these growth and attrition cycles. Taking aspirin blocks NF-kB in the gut and stops local development of the lining, resulting in weak areas that bleed. That is why doctors encourage patients to drink a half glass of water before and after swallowing aspirin tablets.
Another more dramatic example of control of inflammation is conception, gestation and birth. Conception and gestation require inhibition of inflammation, to permit growth of a foreign organism (a fetus is half sperm genes) in the uterus. Chronic inflammation limits the ability of the uterus to suppress immune attack and can produce infertility, which is treated by aspirin and heparin, which suppress chronic inflammation. The return of inflammation at the end of gestation precipitates labor and birth. Excess Inflammation produces high levels of circulating inflammatory cytokines, which causes postpartum depression. Depression and chronic inflammation have the same cytokine profiles, i.e. depression is a symptom of chronic inflammation.
Birth and Inflammation
Proliferation, or enhanced cell division, is another aspect of inflammation and is also the foundation for cancer. That is the reason that some doctors recommend low dose aspirin to reduce colon cancer. Similarly, since inflammation is the basis for coronary artery disease, doctors sometimes recommend low dose aspirin, although this is controversial. Doctors also use aspirin as a so called blood thinner, since it blocks inflammatory signaling in platelets and discourages clotting. Inflammation of nerve cells is experienced by the brain as pain.
When it is understood that inflammation is an essential feature of many normal, healthy cell and tissue functions, then “inflammation," with its negative connotations, becomes a misnomer.
NSAIDs Inhibit Inflammatory Prostaglandin Production
Aspirin directly inhibits NF-kB activation inside the cell, but it also chemically modifies COX, the enzyme that converts omega-6 polyunsaturated fatty acids (common in polyunsaturated vegetable oils) into inflammatory prostaglandins. Other NSAIDS (Non-Steroidal Anti-Inflammatory Drugs) just inhibit COX, but Aspirin transfers its acetyl group to make acetyl-COX, which has a new activity that converts omega-6 fatty acids into anti-inflammatory prostaglandins. The high omega-6 fatty acid content of vegetable/seed oils, such as corn, soy, canola, etc. is why these oils, in contrast to olive oil or butter, are inflammatory. Omega-3 fish oil is anti-inflammatory, because it is converted to anti-inflammatory prostaglandins. Plant omega-3 fatty acids are shorter and are not converted to prostaglandins, but inhibit omega-6 conversion.
Aspirin
Nitric Oxide, Vasodilation and Viagra
Swelling is caused by vasodilation, the relaxation of blood vessels, and accumulation of serum in the tissue. This vasodilation also makes the tissue red and warm from the increased amount of warm blood in the capillaries. Vasodilation is caused by nitric oxide, NO, that is produced by an enzyme under the control of NF-kB, which takes the nitrogen from arginine (or nitroglycerine). The NO diffuses easily and binds to receptors that produce an amplified signal, cyclic GMP, that relaxes the muscle cells surrounding blood vessels. [Viagra is potentially dangerous, because it just exaggerates the amplified signal and obscures the underlying vascular damage, e.g. hypertension, that causes erectile dysfunction by blocking normal vasodilation.]
Nitric Oxide and Erectile Dysfunction
Hot/Cold and Endorphins
The dilemma of whether to use hot or cold therapy to block inflammation is based on a misunderstanding of what the temperature changes are actually doing. Changing the temperature of the skin alters the structure of sensory proteins in nerves of the skin and triggers signals to the brain that register as hot or cold. Chemicals, e.g. capsaicin or menthol, can have the same effect without changing skin temperature. The important response for inflammation control, is return signals from the brain that release neurohormones, e.g. endorphins, from different nerves that reach not only some of the skin that was hot or cold, but also deeper tissue. The endorphins block inflammation and all of its symptoms. That is why chemically treated pads are more effective than icing or changing from hot to cold, because "hot" and "cold" signaling chemicals can be applied simultaneously. None of the treatments is more than skin deep. Actually chilling or heating tissue below the skin is damaging and causes more inflammation. Low dose Naltrexone may be effective in some cases of chronic inflammation, by stimulating systemic rebound endorphin production.
Dr. Oz, Pain, Hot/Cold Receptors
Lymphocyte Offloading, Mast Cells, Heparin
Rosacea is a group of diseases that involve inflammation of the face in an exaggerated blush. Any of the signals that would lead to blushing cause intense vasodilation. A blush is fleeting, but rosacea is made chronic by another aspect of inflammation, offloading of lymphocytes. Large numbers of lymphocytes accumulating in response to a local infection would produce pus. In the case of rosacea, the distributed leucocytes, including neutrophils, respond to the blushing signals by producing inflammatory signals, such as P protein. The result is cycles of inflammation, autoinflammation.
Mast cells can also be offloaded from blood vessels and provide a link between the immune system and inflammation. Mast cells display IgE receptors on their surfaces, which bind antigens and trigger release of histamine, heparin and protease. Histamine is a neurotransmitter that binds to receptors on blood vessels and nerve cells. In the gut, histamine mediates many digestive processes. Heparin released along with histamine, coats the gut and prevents attachment of pathogens by competing for binding to the heparan sulfate proteoglycans (HSPGs) that form the surface of cells that line the gut. [Heparin is the most common drug used in hospitals and is produced from intestines of cattle and hogs in the meat industry.] Heparin also binds and inactivates the proteases released from mast cells. Upon release, the now active proteases attack and activate receptors on nerves and immune cells.
Mast Cells and Heparin
Heparin is Anti-Inflammatory
Heparin is the most negatively charged polysaccharide, mediates most of the receptor/hormone interactions at cell surfaces; facilitates amyloid plaque formation, e.g. in Alzheimers, atherosclerosis, diabetes, dementia; and controls numerous protease reactions in the complement system and clotting, etc. There are hundreds of heparin-binding proteins. Heparin is produced in secretory granules of mast cells by the action of heparanase on heparan sulfate proteoglycans. Heparin is a mixture of small fragments, oligosaccharides of heparan sulfate polysaccharides. Heparin is anti-inflammatory and is administered to facilitate conception and gestation. Inflammation also inhibits the genes involved in heparan sulfate proteoglycan production and since HSPGs are a major component of basement membranes of tissues and provide the barrier function of blood vessels in kidneys and brain, inflammation leads to proteinuria and loss of the blood brain barrier. Since HSPGs have a short half life of six hours and are rapidly recycled, heparin added to the blood is rapidly absorbed by vessels, and heparin taken orally is absorbed by intestinal cells, but does not reach the blood. HSPGs and heparin are central components of immunity and inflammation.
Heparin and Inflammation
Inflammation Blocks Skin Synthesis of Vitamin D from Cholesterol
Inflammation blocks solar synthesis of vitamin D in the skin and is more important than skin pigmentation, use of sunblock or latitude in producing vitamin D deficiency. The vitamin D content of food is negligible compared to solar production in the skin. It is not surprising that rising chronic inflammation is also accompanied by rising vitamin D deficiency. Vitamin D supplementation is usually ineffective in curing vitamin D deficiency, because the supplements are too low and very high levels of supplemental vitamin D are required to reverse underlying chronic inflammation. Statins are very effective at blocking cholesterol synthesis and although reducing cholesterol has minimal impact on the target, cardiovascular disease, it dramatically reduces vitamin D causing muscle pain, etc.
Most vitamins are enzyme cofactors synthesized by gut bacteria and used as quorum sensing signals during formation of biofilms. Vitamin D, in contrast, is a steroid hormone and receptors for vitamin D are inside cells. The receptor/vitamin D complex is transported into the nucleus where it acts as a transcription factor to control the expression of genes. Vitamin D controls the expression of defensins in the crypts of the villi of the small intestines. The antimicrobial activity of defensins is based on the basic amino acids (arginine and lysine) of its heparin binding domains. Vitamin D also interacts with NF-kB in the nucleus and modulates inflammation.
Inflammation and Vitamin D
Bacteria and LPS
Lipopolysaccharide is a wall component that is indicative of bacteria, just as beta-glucan is indicative of fungi, and both are intense activators of NF-kB and inflammation. LPS is released from damaged bacteria, e.g. by antibiotic treatment, binds to receptors on the surface of intestines and stimulates inflammation with release of NO, which produces diarrhea. Food intolerances, which are based on incomplete digestion of food components, because of an incomplete gut flora (immunological responses/food allergies are rare) are probably also the result of LPS release from gut flora and inflammation.
Innate Immunity is also Triggered by LPS
The basic defenses of humans against microorganisms are mediated at the cellular level by triggering molecules common to all microorganisms, e.g. LPS for bacteria. The responses are equally general: lysozyme to digest bacterial wall peptidylglycan, lactoferrin that binds iron and yields antibacterial peptides. LPS (and inflammatory cytokines) also stimulates the liver to produce CRP (C Reactive Protein) that binds to choline on bacteria as the first step in phagocytosis and DNAse I that digests NETs (neutrophil extracellular traps) that are the DNA and histones released by triggered neutrophil cells that enmesh bacteria for engulfment by phagocytic cells. [NETS plug peripheral catheters and can be cleared with probiotics that stimulate DNAse I release from the liver.] NETs are also present at sites of inflammation and the accompanying nuclear proteins have the basic triplets that stimulate immune presentation and act as autoantigens, i. e. produce anti-nuclear antibodies, in the absence of adequate Tregs.
Diet and Inflammation
The diagram outlines the interactions that produce the tissue symptoms of inflammation. Many components of modern diet can trigger inflammation:
Sugars and high glycemic starches raise blood sugar and enhance AGE/HgA1C.
Vegetable oils high in omega-6 oils are converted into inflammatory prostaglandins.
Wheat and other grains have high glycemic starch and insoluble fiber that is inflammatory. Gluten is inflammatory.
Antibiotics damage the gut flora and produce vitamin deficiencies, autoimmunity and allergies.
Food intolerances result from damaged gut flora and produce gut inflammation.
Fish high in omega-3 EPA and DHA are anti-inflammatory.
The Anti-Inflammatory Diet
Health Results from a Balance of:
Diet (meat, fish, eggs, dairy, vegetables), containing macronutrients of protein, starch 30-100 g/d and fat (low omega 6/3 and saturated fat for most calories), and micronutrients
Soluble Fiber, e.g. resistant starch (consult Free the Animal), inulin, pectin, (plant polysaccharides, animal GAGs)
Gut Flora, diverse and adapted to dietary soluble fiber,
Exercise
Resistant Starch, Panacea, but Why?
Mark’s Daily Apple provides an authoritative diet guide (except for the gut flora).
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