Category Archives: alcohol

COVID-19 Sweden vs Other Countries

5/21/2020 deaths/ million 7 day running average doubling time
cumulative deaths/million/day days
SWEDEN 379 3.3 46
Norway 43.6 0.13 241
Finland 54.9 0.52 138
Denmark 95.6 0.49 120
USA 282 4.02 49
NZ 4.3 0 598
stay home test-trace leadership
isolate example
SWEDEN no yes ?
Norway yes yes good
Finland yes yes good
Denmark yes yes good
USA late/variable POOR poor
New Zealand yes excellent excellent

Sweden was a source of controversy for the choice against instituting a stay-home policy. As you compare Sweden with other Scandinavian countries above you will see a dramatic difference in deaths per million (cumulative), running 7 day average deaths per million per day, and doubling time. The higher the doubling time (in days) the more a country has slowed the spread. New Zealand is the obvious winner. Early and aggressive action, effective test/trace/isolate, excellent leadership and example by the president are the hallmarks of success in New Zealand. Of course New Zealand is a small island with minimal international business and tourism so the comparison is not fair. HOWEVER, their success and strategy are obvious.

The US failed (and continues to fail) on test/trace/isolate despite the bluster and misrepresentations from the Whitehouse. California and Washington instituted early measures with respect to stay-home but without adequate test kits all of US states have been unable to execute the test/trace/isolate strategy proven effective in other countries. President Trump promised California 100,000 nasal swabs per week three weeks ago. They have not arrived. (California Department of Public Health)

Thus comparing USA to Sweden we see that with adequate social distancing, test/trace/isolate, Sweden did almost as well (or as poorly) as the US where stay at home was employed on a variable time line and to different degrees between the states.

You can review worldwide data, download spreadsheets, choose countries for comparison here.

Test/Trace/Isolate + Social distance + Masks4all + cooperation = SUCCESS

Had the US responded early and effectively, stay-home could have ended very quickly and safely with much less economic disruption.

Poor Management = inadequate Test/Trace/Isolate and other measures.

The New England Journal of Medicine published an article discussing the failure of the
USA relative to Test/Trace/Isolate.

Failing the Test — The Tragic Data Gap Undermining the U.S. Pandemic Response

 

The importance of  Reviving the US CDC after annual cuts by the Trump Administration is discussed here.

On March 25 the NEJM published an editorial on responding to the pandemic.

We did not follow the recommendations.

The AMERICAN ENTERPRISE INSTITUTE, a conservative think-tank, published a comprehensive Roadmap to Reopening.

Unfortunately we have not followed that roadmap.

So boost your immune system and meet the challenge with your personal behavior. Be smart.

  1. Avoid alcohol consumption (alcohol wreaks havoc with your immunity)
  2. Get plenty of sleep (without adequate sleep your immune system does not work well )
  3. You must follow good sleep habits
  4. Exercise, especially out of doors in a green space, supports the immune system
  5. Get some sunshine and make sure you have adequate Vitamin D levels.
  6. Eat an anti-inflammatory diet rich in micronutrients.
  7. Practice stress reduction like meditation and yoga which improves the immune system
  8. Eliminate sugar-added foods and beverages from your diet. These increase inflammation, cause metabolic dysfunction, and suppress immunity.

THIS WEBSITE PROVIDES INFORMATION FOR EDUCATIONAL PURPOSES ONLY. CONSULT YOUR HEALTH CARE PROVIDER FOR MEDICAL ADVICE.

Eat clean, drink filtered water, love, laugh, exercise outdoors in a greenspace, get some morning sunlight, block the blue light before bed, engage in meaningful work, find a sense of purpose, spend time with those you love, AND sleep well tonight.

Doctor Bob

 

COVID-19: ARDS, CYTOKINE STORM, and GLUTATHIONE

My good friend Dr. Deborah Gordon recently sent me a terrific article on an Integrative Medicine Approach to Covid-19. It confirmed much of what I have discussed about COVID-19 and provides 383 scientific references (many of which were cited in my previous posts). Thank you Dr. Deborah!

In my last post I promised to write about glutathione and cytokine storm.

Cytokines are proteins made by our immune system. When our body suffers an infection, cytokines act as essential signaling proteins that produce a defensive inflammatory response. In a cytokine storm the usual regulatory process that helps resolve inflammation becomes disturbed and self destruction can occur.

With COVID-19 this can happen in any organ of the body but frequently starts in the lungs, resulting in ARDS (Acute Respiratory Distress Syndrome).

In most clinical contexts the mortality rate of ARDS is 40-45%. In the context of COVID-19 it is 80-90 % lethal in most clinical reports (twice the usual mortality rate for ARDS). However, the ICU doctors in the Northwell Hospital system in NYC have been using NAC (n-Acetylcysteine).

While using NAC as part of their treatment protocol of COVID-19 associated ARDS, they are getting 50% of patients off the ventilator with a significant reduction in mortality rates compared to previous reports (personal communication with a Northwell physician and also mentioned in the Review Article cited above.)

This drug (also available as a dietary supplement) has been used for decades to treat acetaminophen (APAP) overdose (Tylenol brand name, also called paracetamol in Europe). If not treated early APAP overdose commonly causes death from liver failure.

Chronic acetaminophen toxicity is the most common cause of liver failure leading to liver transplant in the US.

How does this treatment  with NAC work in the setting of APAP overdose?

“When paracetamol is taken in large quantities, a minor metabolite called N-acetyl-p-benzoquinone imine (NAPQI) accumulates within the body. It is normally conjugated by glutathione, but when taken in excess, the body’s glutathione reserves are not sufficient to deactivate the toxic NAPQI. This metabolite is then free to react with key hepatic enzymes, thereby damaging liver cells. This may lead to severe liver damage and even death by acute liver failure.”

NAC (n-acetylcysteine) provides cysteine, one of the three amino acids that make up glutathione.

“glutathione synthesis is primarily controlled by the cellular level of the amino acid cysteine, the availability of which is the rate-limiting step.”

So by providing a source of cysteine, the body produces more glutathione which can detoxify the liver damaging metabolites of APAP.

Glutathione is our MASTER ANTI-OXIDANT. Since a cytokine storm involves an overwhelming amount of oxidative stress, glutathione is obviously important.

Clinical research in the 1990s established that the lungs of patients with ARDS are very deficient in glutathione.

A profound 20 fold reduction was confirmed in this study.

“Glutathione is a tripeptide that is able to react with and effectively neutralize oxidants, such as hydrogen peroxide. The present study found that the alveolar epithelial lining fluid of patients with ARDS was deficient in total glutathione compared with that of normal subjects (31.5 ± 8.4 versus 651.0 ± 103.1 µM, p = 0.0001) and patients with cardiogenic pulmonary edema (31.5 ± 8.4 versus 154.1 ± 52.4 µM, p = 0.001). In addition, a greater percentage of total glutathione was in the oxidized form in patients with ARDS compared with normal subjects (30.6 ± 6.1 versus 6.4 ± 2.9%, p = 0.03). This deficiency of reduced glutathione in the alveolar fluid may predispose these patients to enhanced lung cell injury.

Subsequent studies of humans with ARDS on ventilators showed clinical benefit by increasing glutathione levels with NAC.

“In our controlled clinical trials with NAC we found that patients with ARDS have depressed plasma and red cell glutathione concentrations, that these levels are substantially increased by therapy with intravenous NAC and there are measurable clinical responses to treatment with regard to increased oxygen delivery, improved lung compliance and resolution of pulmonary edema.”

Despite these findings decades ago, the use of NAC for ARDS has not been widely adopted. But it would make sense to employ this inexpensive medication, widely used for APAP overdose, for ARDS and in particular for cytokine storm caused by COVID-19.

Oxidative stress decreases glutathione levels and if these levels reach a critically  low level in tissues, organ damage can ensue rapidly. Cytokine storm is the extreme example.

Chronic alcohol abuse also decreases protective glutathione levels in the lung.

In my recent posts on COVID-19 I have pointed out that alcohol (even 2 drinks) suppresses the immune system for at least a few days. Alcohol consumption is a double hit, first as an immune suppressant, then as a major source of oxidative stress and reduction in protective glutathione levels. Two glasses of wine tonight followed by a COVID-19 sneeze in your face the next day could be the difference between an effective immune response (mild symptoms) versus an overwhelming life threatening infection!

Likewise, one night of inadequate sleep (which immediately suppresses immunity) followed by a COVID sneeze in your face the next day could have the same deleterious effect.

Below is a chart from the review article mentioned at the start of this post. Notice the top line states “ADDRESS SLEEP, STRESS, DIET, SUGAR, ALCOHOL

If you have been reading my posts on COVID-19, you have heard this before.

integrative medicine chart

Notice the second row in the chart with escalating doses of NAC as intensity of disease increases. When cytokine storm hits NAC dose recommendations peak and glutathione (available for IV administration) is recommended. IV glutathione surprisingly is not part of most hospital formularies and I have never seen it used in a hospital setting. Functional medicine physicians sometimes use it outside of the hospital setting. IV glutathione has become a sexy and lucrative office procedure in some functional medicine practices.

NAC has high bioavailability, meaning it is absorbed well in our gut. So oral supplementation can rapidly and effectively increase levels of glutathione in the body. IN FACT, treatment of acetaminophen overdose in the ER typically begins with oral NAC (often administered through a naso-gastric feeding tube, passed through the nose and into the stomach) Doses are often calculated by the regional poison control center (available by phone 24/7/365) and subsequent doses follow a standard protocol based on weight.

I would encourage you to read through this COVID-19 INTEGRATIVE MEDICINE review article.

It is thick with science but you might be surprised by how much you understand and learn.

In the chart above there is specific mention of Vitamin C supplementation in escalating doses as degree of illness increases. Vitamin C is an important anti-oxidant and in that sense is a glutathione sparing agent helping to mitigate glutathione depletion.

Other important factors mentioned in the article and the chart above include items mentioned here in previous posts: ZINC, ZINC IONOPHORES, phytochemicals (quercitin, EGCg, curcumin), Vitamin D, exercise, sleep, stress reduction, sunshine.

So I will close this post the way I have closed on many posts related to COVID-19.

Support your immune system.

  1. Avoid alcohol consumption (alcohol wreaks havoc with your immunity)
  2. Get plenty of sleep (without adequate sleep your immune system does not work well )
  3. Follow good sleep habits
  4. Exercise, especially out of doors in a green space, supports the immune system
  5. Get some sunshine and make sure you have adequate Vitamin D levels.
  6. Eat an anti-inflammatory diet rich in micronutrients.
  7. Practice stress reduction like meditation and yoga which improves the immune system
  8.  Eliminate sugar-added foods and beverages from your diet, sugar increases inflammation, contributes to metabolic dysfunction and impairs immunity.

In a future post I will describe my PERSONAL approach to dietary supplements in the context of COVID-19. I will also discuss the issue of an ADVANCED DIRECTIVE, in case you are hospitalized.

THIS WEBSITE PROVIDES INFORMATION FOR EDUCATIONAL PURPOSES ONLY. CONSULT YOUR HEALTH CARE PROVIDER FOR MEDICAL ADVICE.

Eat clean, drink filtered water, love, laugh, exercise outdoors in a greenspace, get some morning sunlight, block the blue light before bed, engage in meaningful work, find a sense of purpose, spend time with those you love, AND sleep well tonight.

Doctor Bob

Glutathione review links are below:

Glutathione!

Mitochondrial Glutathione, a key survival antioxidant

Glutathione: overview of its protective roles, measurement, and biosynthesis

 

 

 

Sleep! You can’t live without it.

Circadian rhythm refers to the cycling of hormones according to the time of day. Every hormone cycles with daylight and darkness, each in it’s own way. Our brain has a master clock, called the circadian clock, controlled by specialized cells deep in the brain. There is a direct connection from our retina (in the back of the eyes) to the circadian clock in the brain. Blue light (part of the normal outdoor spectrum of light) stimulates very specific receptor cells in the retina which in turn communicates directly with the circadian clock telling the brain whether it is day or night. To synchronize our hormones and achieve restorative sleep, we must get outdoor light exposure to our eyes (without sunglasses, early in the day) and limit light exposure in the evening.

Artificial light, especially from cell phones and other devices that emit intense blue light, shift work, late night social activity, poor eating habits, sedentary lifestyle and at the opposite extreme, late evening workouts,  can all disrupt our circadian rhythm preventing adequate restorative sleep. A rare genetic illness called fatal insomnia that strikes adults at middle age prevents sleep and results in death within a few months, highlighting the importance of sleep. Sleep deprivation can kill a human quicker than starvation! Adequate amounts of deep non-REM sleep are required for tissue regeneration, healing, DNA repair and immune function. REM sleep with dreaming provides great benefit by organizing our memory, discharging the emotional content of traumatic events, and facilitating creative brain activity. One night of short-sleep produces a state of inattention and slow reflexes as dangerous as driving under the influence of alcohol intoxication. Chronic  short sleep and disrupted circadian rhythm results in increased risk of depression, cancer, hypertension, diabetes, dementia, obesity, metabolic syndrome, insulin resistance, heart attack and stroke, to name a few. Sleep interruption immediately halts weight loss during a calorie restricted diet (likely the result of hormonal disruption). So getting an adequate amount of restorative sleep every night is essential to good health. Here a few tips to help achieve a good night’s sleep each and every night.

  1. GET OUTDOOR LIGHT EXPOSURE ON YOUR EYES WITHOUT SUNGLASSES EVERY DAY, EARLY IN THE DAY. This helps set your biologic/circadian clock. Even on a cloudy day, outdoor light is much stronger and natural than indoor light. It is essential for setting your biologic/circadian clock. If you cannot get outside, stand or sit in front of a large window for 20-30 minutes in the morning, looking outside. Take a lunch break outside without sunglasses. Wear a shade hat instead of sunglasses. Your brain needs to experience natural outdoor light during the day.
  2. Avoid bright light in the evening, especially the light from TV, computer screens, cell phones, which all emit intense blue light and trick your brain into thinking it is daytime. Wear blue light blocking glasses/goggles for 2-3 hours before bed. (Amber tinted glasses which block blue light can be purchased on-line and can be worn over reading glasses) There is also software available that will decrease the blue light intensity of computer screens and cell phones in the evening.
  3. Practice time restricted eating. Limit all eating to an eight hour period, thus providing for an over-night fast of 16 hours. If that does not seem possible try to limit eating to a 10-hour period which provides a 14-hour overnight fast. This improves sleep, circadian rhythm, blood pressure, blood sugar and reduces stress hormones. NO SNACKS BETWEEN MEALS. NO FOOD FOR 2 HOURS BEFORE BED. For every hour decrease in eating time period from 12 hours to 8 hours you get health benefit.
  4. Eat an anti-inflammatory diet.
  5. If you snore, are overweight/obese, fall asleep during the day, or do not feel refreshed in the morning ask your doctor to order a sleep study. Obstructive Sleep Apnea makes restorative sleep impossible and increases risk of heart attack, stroke and most chronic diseases.
  6. Avoid alcohol altogether and avoid caffeine after late morning.  Alcohol in the evening may help you fall asleep but it results in a withdrawal from alcohol during the night. This disrupts normal sleep patterns.
  7. Sleep in a cold, dark, quiet room. Use black-out curtains, no night lights, no phone charger lights, no lights of any kind should be on in the room. Any amount of light in the room impairs the production of melatonin which facilitates sleep onset.
  8. Have a winddown time every evening. Develop habits of non-stressful activities, soft music, dim light, casual conversation, enjoyable reading. Do not spend evening time dealing with finances, conflict, or emotional activity.
  9. Try a magnesium supplement before bedtime. Magnesium glycinate, magnesium citrate, magnesium gluconate, are absorbed much better than cheaper supplements such as magnesium oxide. Magnesium L-Threonate is expensive, but it crosses the blood brain barrier into the brain with the greatest brain penetration of all magnesium supplements.
  10. Manage stress with yoga, meditation, regular exercise (but no intense exercise in the evening.) Perform most of your exercise outdoors in a green space. This provides much more health benefit than the equivalent exercise indoors.
  11. Regular contact with supportive family and friends is essential to health and reduces stress. The greatest predictor of health vs disease is the amount of social connectedness an individual experiences.
  12. Establish regular wake-up times and go-to-bed times. Regular sleep habits are essential. If you must rely on alarm clocks you do not have good sleep habits.

A few words about alcohol, caffeine and sleeping pills.

A drink or two in the evening may help you relax but it disrupts your sleep by causing a mild episode of alcohol withdrawal as your liver metabolizes the alcohol and your blood levels drop. Even this slight degree of alcohol withdrawal will impair a good night’s sleep.

Caffeine impairs sleep by blocking adenosine receptors in the brain. Adenosine is the neurotransmitter that increases gradually during the day creating a sate referred to as sleep pressure. Some people metabolize caffeine quickly, others slowly. The slower you metabolize caffeine the longer it takes to clear it from your adenosine receptors. Without adequate sleep pressure (adenosine receptors filled with adenosine in the brain) you cannot fall asleep. Many sleep experts recommend complete abstinence from caffeine and suggest that if you need caffeine to get started in the morning you are regularly sleep deprived.

Sleeping pills of all kinds interfere with normal sleep architecture. While they facilitate falling asleep, they impair your ability to achieve deep restorative stages of sleep and can produce many undesirable side effects including addiction, withdrawal symptoms, sleep walking, sleep driving, worsening of asthma and COPD, constipation, diarrhea, daytime drowsiness, burning and tingling sensations, unusual dreams, weakness, heartburn, etc…. Most importantly they all interfere with cycling through the various stages of sleep in a normal, restorative pattern!

If you want to explore these concepts in depth here are two excellent books that discuss sleep and circadian rhythm.

Why We Sleep, by Matthew Walker Ph.D.

The Circadian Code, by Satchin Panda Ph.D.

Eat clean, sleep well, spend time exercising out of doors, love one another.

Bob Hansen MD

A Paleo physician’s journey through major surgery

At age 46 I had a total hip arthroplasty (THA). Metal and plastic components replaced my hip joint (the stem, ball and socket of the hip). I am convinced that if I had adopted a Paleo lifestyle at age twenty instead of age 58 I would have not needed that surgery. But more about that another time.

On Monday I underwent a revision of that surgery to replace some components, scrape out bad bone, remove inflamed joint lining, flush out plastic debris, and place some bone grafts into areas where bone cysts had formed. The surgery was necessary because the plastic debris from my first artificial joint had stimulated my immune system in a way that caused my macrophages (white blood cells) and osteoclasts (a special kind of bone cell) to start destroying the bone around my hip socket. This process is called osteolysis.

Our immune cells evolved to destroy and consume bacteria and viruses, not plastic powder. So as the plastic liner of my hip prosthesis wore down, the plastic debris provided a constant source of inflammation, stimulating my immune system to get rid of a foreign invader. The bone around my prosthesis got caught in friendly fire. This problem does not seem to occur since a newer form of plastic, having only 10% the wear rate of the old plastic has been introduced. Time will tell if that proves to be true.

To prepare for surgery I reviewed my Paleo behavior with respect to diet, sleep, exercise, stress reduction and outdoor time. My exercise routine was already very reasonable. I had been strictly avoiding grains (except for occasional white rice) and legumes but did include some fermented dairy (kefir and cheese) and wine. So I eliminated all dairy and all alcohol. Sleep has always been an issue because as a physician I take call and sometimes work through the night with emergency cases.

My last call night was 3 weeks before surgery and I was up all night. The next day I flew to NJ for two important events (a reunion and a wedding) both of which were definitely not Paleo environments. A flight cancelation required more sleep deprivation in order to reach my first event on time. That sleep deprivation in combination with the changes in time zone disrupted my circadian rhythm so upon returning home two weeks before surgery I knew I had to play catch-up to be ready for surgery. I avoided alcohol except for a few drinks at my brother’s wedding and violated the wheat prohibition once with a piece of wedding cake.

When I returned to California I was 6 pounds heavier and jet lagged. I promptly got an upper respiratory infection (probably acquired on my flight home) which started in my throat and nose and went to my lungs.

So now I am jet-lagged and infected just two weeks from surgery. Not a good situation.

Thereafter I was strictly Paleo in diet, sleep, and stress reduction (yoga and meditation) but had to limit exercise to yoga and walking in order to fight the infection and prepare for surgery. I spent as much time walking outdoors as was feasible and focused on eight hours sleep each night. After one week I was beating the URI so I decided to do two 30 minute sessions of resistance training during the last week before surgery.

By the day of surgery the URI was completely cleared and I was down 6 pounds to my baseline.

I self administered my own pre-operative medication protocol (designed to mitigate post operative pain) and received a spinal anesthetic from my friend and colleague using a combination of local anesthetic and a small dose of spinal morphine. The latter can provide pain reduction for up to 24 hours after surgery.

So here is the amazing result.

5 hours after surgery I walked without pain using a walker bearing full weight on the surgical leg. I walked again that evening without pain. I knew this was the honeymoon period because the spinal morphine was still protecting me.

The next morning the honeymoon was over but I was still able to walk with full weight bearing without any pain medications and subsequently walked several times up and down the hospital halls during the first three post operative days. Although I had pain with movement I had no pain at rest.

On the day after surgery my CRP (C reactive protein) was 0.2 mg/dl. CRP is a measure of inflammation in the body. Normal range is zero to 0.5. I was elated. One day after a major traumatic event which typically initiates an inflammatory cascade, I did not have excess inflammation throughout my body as measured by CRP. My WBC (white blood cell count) was also normal.

A paleo lifestyle will not prevent pain after surgery but being in a low inflammatory state before surgery certainly helped with recovery.

My walking ability immediately after surgery and during the next three days astounded the physical therapists and nurses. They all stated I had set records.

My colleagues in the Anesthesia Department could not believe that I received no opiate or NSAID pain medications during my recovery. It is now five days since surgery. I have taken no opiate pain killers or NSAIDs except for low dose aspirin (starting yesterday) to help prevent blood clots

I avoided NSAIDs because NSAIDs increase intestinal permeability (which leads to an inflammatory response) and also because NSAIDs increase risk of cardiovascular events (heart attack, stroke, blood clots in the legs which can travel to the lungs and cause death in severe cases)

I can attribute my success to many factors including an excellent anesthetic, a great surgeon, an optimal pre-operative medication protocol, the superb nursing and therapy staffs and the Paleo lifestyle. In preparing for surgery I was able to make an effective come back from a stressful travel week, two successive nights of sleep deprivation and an upper respiratory infection only because of the Paleo approach.

As I walked my laps around the orthopedic unit I noticed that most patients spent the entire day in bed except for a few laps each day with PT. Many factors contribute to that problem. Our PT department is very aggressive but post operative pain, obesity, inflammatory diets and sedentary lifestyles all contribute to slow recovery. The hospital menu is highly inflammatory thick with processed-carbohydrates, pro-inflammatory grains, legumes, and refined vegetable oils, and yes,  even some trans fats. A strictly Paleo menu would be very helpful. But most of those patients have been living the Standard American Lifestyle (inflammatory diet, chronic sleep deprivation, inadequate exercise, poor stress management, etc.)  for a lifetime prior to surgery and it can take months to years of a Paleo lifestyle to mitigate a lifetime of self abuse. Even then some damage is permanent (like my hip).

I ate the hospital’s fresh fruit, vegetables and wild seafood, the rest was delivered from home by my loving spouse. Kathie is my anchor in the storm and my guiding light when I become lost. The importance of love and human physical contact is well recognized by the Paleo community so it is appropriate that I end with an expression of gratitude to Kathie and the host of friends who visited me during recovery. Hugs and kisses are as important as an anti-inflammatory diet.

Live clean and prosper.

Bob Hansen MD

The bacteria in your gut are essential to your health Part II, obesity, metabolic syndrome and dysbiosis

I have discussed the evidence linking the mix of bacteria in your gut (gut flora) to health and disease in Part I. The Bacteria in your Gut are essential to your health Part I | Practical Evolutionary Health

Today I will discuss the evidence related specifically to  obesity and metabolic syndrome (the constellation of obesity, insulin resistance, high blood pressure, and abnormal blood lipids). My discussion will follow closely the evidence and theory presented in research and review papers authored by Dr. Cani and colleagues. The first one is titled:

Gut microbiota controls adipose tissue expansion, gut barrier and glucose metabolism: novel insights into molecular targets and interventions using prebiotics.”

You can find the full text of this article here .

I have had the pleasure of corresponding with Dr. Cani by e-mail regarding her many publications investigating the relationship between gut flora, obesity, and metabolic syndrome.

“Recently, we and others have identified several mechanisms linking the gut microbiota with the development of obesity and associated disorders (e.g. insulin resistance, type 2 diabetes, hepatic steatosis).”

Explanation: The gut microbiota are the bacteria, viruses and other “bugs” that reside in our intestines. Insulin resistance can occur in various parts of the body, wherever insulin has an effect including fat cells, liver, muscle, brain. When higher amounts of insulin are required to achieve an effect this is called insulin resistance. In Type 2 diabetes, the pancreas is still able to make insulin but insulin is less effective in controlling blood sugar. In Type I diabetes the pancreas no longer produces insulin. Hepatic Steatosis means fatty liver disease. The liver accumulates fat and this can lead to cirrhosis, liver failure and death. Alcohol consumption can cause this but when alcohol is not involved this is called Non-Alcoholic-Fatty-Liver Disease (NAFLD). Our nation presently has an epidemic of not just obesity but also NAFLD. Evidence points to  excess carbohydrate consumption and excess consumption of vegetable oils (linoleic acid)  as contributing factors in NAFLD.  Carbohydrate restriction and consumption of saturated fat, particularly medium chain fats (as found in coconut) can protect against NAFLD. But the gut flora also play a role. The mechanisms involved are many.

“Among these, we described the concept of metabolic endotoxaemia (increase in plasma lipopolysaccharide levels) as one of the triggering factors leading to the development of metabolic inflammation and insulin resistance.”

Endotoxemia occurs when a toxin from certain kinds of bacteria circulates in the blood. This endotoxin enters our blood through our intestines under conditions in which the protective barrier of the intestines is compromised. The compromise of the intestinal barrier is variously referred to as ” leaky gut” or “increased intestinal permeability”. Wheat gluten-gliadin  causes increased intestinal permeability (especially in celiac disease) as can other plant lectins. In this discussion, the gut bacteria also contribute in the setting of “dysbiosis” (the beneficial effects of helpful bacteria are overwhelmed by the harm-causing bacteria when a healthy balance is not present)

Lipopolysaccharide (LPS) comes from the outer wall membrane of certain bacteria. Blood plasma is the liquid part of blood in which the blood cells circulate. So an “increase in plasma lipopolysaccharide” simply means that there is more LPS circulating in the blood. That is a bad thing. Depending on how much is circulating this alone can cause organ failure and death and is a major part of the physiologic changes involved in septic shock. But lower levels of LPS circulating in the blood can cause chronic low grade inflammation and insulin resistance. Obesity is associated with chronic inflammation and increased LPS circulating in the blood and being distributed to various organs where it wreaks havoc.

“Growing evidence suggests that gut microbes contribute to the onset of low-grade inflammation characterizing these metabolic disorders via mechanisms associated with gut barrier dysfunctions.”

“We have demonstrated that enteroendocrine cells (producing glucagon-like peptide-1, peptide YY and glucagon-like peptide-2) and the endocannabinoid system control gut permeability and metabolic endotoxaemia.”

That is a mouth-full. Over thirty different kinds of hormone producing cells have been found in the human intestine. These cells are called enteroendocrine cells. The hormones produced by these cells have many effects. You can find a great review of these cells and their effects here .

In Dr. Cani’s review article she describes how some of these hormones produced in the gut can increase intestinal permeability and allow more of the toxic, inflammation producing LPS to enter the bloodstream. But these hormonal effects are just part of the picture. Another part relates to endocannabinoids.

The  Endocannabinoid system in humans is complex and relates to hunger, satiety, energy metabolism, and yes gut permeability. Endocannabinoid refers to our internal (endo) production of cannabis like substances. Pot smoking people get the munchies because of the appetite stimulating effects of marijuana. But endocannabinoids have many other physiologic effects including the modulation of pain, mood, immune function and memory.

Dr. Cani describes in great detail the evidence supporting the roles that the gut flora play in influencing intestinal permeability mediated through the effects of various hormones and endocannabinoids. In animal and human studies changing the gut flora produces changes in these hormones and endocannabinoids which in turn can increase or decrease intestinal permeability and increase or decrease circulating LPS.

It turns out that specific  Prebiotics can produce growth of beneficial gut bacteria and through the series of steps outlined above, reduce inflammation in the body, improve blood sugar, improve insulin sensitivity, and decrease fat,

Oh, and similar to the endocannabinoid system, there is an “apelinergic system” in our bodies that also plays a role. If you want to read more about these systems you should read the original article and the other links below to related articles.

I have discussed in the past that fecal transplants have been used to treat the specific dysbiosis that occurs with C Difficile colitis. But fecal transplants have many potential beneficial uses.

The Fatlose 2 trial is presently studying the effects of fecal transplants on insulin resistance and related problems in human volunteers. I will let you know when the results are published, Studies conducted in rodents have demonstrated significant weight loss and improved insulin sensitivity when obese rodents receive fecal transplants from lean rodents.

In summary: dysbiosis represents an unhealthy mix of bacteria in the gut

  • dysbiosis causes increased intestinal permeability (leaky gut)
  • increased intestinal permeability leads to increased circulating LPS, which is bad
  • elevated levels of circulating LPS create a chronic state of inflammation which contributes to obesity and metabolic syndrome
  • the mechanisms that link dysbiosis to intestinal permeability include hormonal disruption (enteroendocrine cells) and the endocannabinoid system. Other mechanisms are also likely in play.
  • prebiotics and probiotics can mitigate dysbiosis, reduce intestinal permeability, reduce inflammation, and offer potential therapy for obesity and metabolic syndrome
  • fecal transplantation offers a potential for treatment for obesity and metabolic syndrome, research is underway

Our ancestors lived and evolved for a few million years prior to the relatively brief ten thousand years of agriculture and one hundred years of industrialization. The overuse of antibiotics in medicine and animal husbandry have contributed to dysbiosis. Other factors include stress, disruption of circadian rhythm, sleep deprivation. Cesarean delivery and avoidance of breast feeding conspire to dysbiosis. Processed foods feed unfriendly bacteria in our guts at the expense of beneficial bugs. Agricultural foods have introduced dietary lectins which also increase intestinal permeability and thereby contribute to chronic inflammation. The further we stray from our evolutionary niche, the more problems we experience.

This discussion just touches the surface of gut flora, dysbiosis, health and disease. We have yet to explore the gut-brain axis. Our gut and microflora communicate with and effect the function of our brain and other organs as well.

We will continue to explore health and disease from an evolutionary perspective.

Below are links to articles related to our discussion.

Peace, health and happiness.

BOB

Gut microbiota controls adipose tissue expans… [Benef Microbes. 2014] – PubMed – NCBI

Glucose metabolism: Focus on gut microbiota, … [Diabetes Metab. 2014] – PubMed – NCBI

Probiotics, prebiotics, and the host microb… [Ann N Y Acad Sci. 2013] – PubMed – NCBI

Crosstalk between the gut microbiota a… [Clin Microbiol Infect. 2012] – PubMed – NCBI

Gut microbiota and its possible relationship … [Mayo Clin Proc. 2008] – PubMed – NCBI

Enteroendocrine Cells: Neglected Players in Gastrointestinal Disorders?

Intestinal Permeability, Food and Disease

In medical school I learned some fundamental concepts about nutrition and digestion that turn out to be wrong. For example, we were taught that proteins in our diet are completely broken down into single amino acids in the gut, then absorbed through the wall of the intestine as individual amino acids. Turns out that not all proteins are completely digested in this manner and that fragments of proteins that are several amino acids long can be absorbed through the gut and enter our blood. Examples of such proteins include wheat gluten and bovine serum albumin (found in cows milk and whey protein) to name a few. The problem with absorbing such nutrients into our bloodstream is that these protein fragments are “foreign” and can be recognized by our immune systems as foreign, triggering an immune (inflammatory) response.

Some peptides (short chains of amino acids) in bovine serum albumin have structural similarity to peptides in human tissues. This foreign protein has been implicated in autoimmune diseases such as Multiple Sclerosis, Rheumatoid Arthritis and Type 1 Diabetes.

Other substances such as bacterial endotoxin similarly can be absorbed into the blood and cause trouble. Endotoxin, also called LPS or  Lipopolysaccharide, is a major component of the outer membranes of certain kinds of bacteria (gram negative bacteria such as E-coli) that live in the  Lumen of our gut. High levels of endotoxin circulating in the blood occur during septicemia and can result in death from septic shock. Lower levels of circulating endotoxin have been demonstrated to contribute to alcoholic and non-alcoholic liver disease, both of which can cause liver failure and death.

Intestinal wall permeability is governed by many factors. There are regulatory proteins that open and close the gaps (tight junctions) between the cells that line the walls of our intestines, thereby allowing more and larger foreign substances to enter our blood. This mode of entry is referred to as “paracellular” since it does not involve the usual absorption mechanism through the walls of the cells that line the intestines.

Substances regularly consumed by Americans known to increase intestinal permeability include gluten (the sticky protein found in wheat, barely, rye, oats), alcohol, non-steroidal anti-inflammatory drugs  like ibuprofen (Motrin, Advil), naprosyn (Alleve), and aspirin.  Refined “vegetable oils” that are high in a specific Polyunsaturated fatty acid called linoleic acid (examples of these vegetable oils include corn oil, soy oil, cottonseed oil) have also been demonstrated to increase intestinal permeability.

Vegetable oils have also been found to enhance the liver inflammation and destruction caused by  alcohol which is at least in part mediated by absorption of endotoxin and ultimately also caused by oxidative stress.

The same applies to non-alcoholic liver fatty liver disease. (Progression of alcoholic and non-al… [Drug Metab Pharmacokinet. 2011] – PubMed – NCBI)

Interestingly, consumption of saturated fat (as found in beef tallow, coconut oil, butter and cocoa butter-the oil of dark chocolate) protects the liver from inflammation and destruction caused by alcohol, while polyunsaturated fat consumption (vegetable oils)  do the opposite. (References above and below)

There is growing evidence for a link between auto-immune disease and Alterations in intestinal permeability. Increased intestinal permeability (IP) has been observed in a substantial percentage of individuals with Type I diabetes. It is commonly observed in populations at high risk of developing Crohn’s disease and has been observed in patients who subsequently develop Crohn’s disease. Patients with ankylosing spondylitis have increased IP and although these patients are typically treated with NSAIDs which increase IP, the effects of NSAIDS have been isolated from a primary defect in IP which is shared by relatives without the disease.

“increased intestinal permeability is observed in association with several autoimmune diseases. It is observed prior to disease and appears to be involved in disease pathogenesis.”

A paleolithic diet avoids all sources of gluten (paleo is grain-free) and it also avoids refined “vegetable oils”. These food items present a double hit relative to inflammation. First, they increase IP which increases circulating levels of various “foreign” proteins and other foreign macromolecules which can stimulate the immune system. The second hit from these food items represents their direct inflammatory effects once absorbed into the body. I have previously discussed the  inflammatory response to excess omega six fats here.

An excellent review of the importance of the ratio of omega six fats found in “vegetable oil”  to omega three fats found in fish oil can also be found here ,  here   and  here.

The potential inflammatory response and anti-nutrient effects of cereal grains and in particular the gliadin portion of wheat gluten has been discussed and reviewed in multiple papers including:

Do dietary lectins cause disease?

Non-Celiac Gluten Sensitivity: The New Frontier of Gluten Related Disorders

BMC Medicine | Full text | Spectrum of gluten-related disorders: consensus on new nomenclature and classification

BMC Medicine | Abstract | Divergence of gut permeability and mucosal immune gene expression in two gluten-associated conditions: celiac disease and gluten sensitivity

Bioactive antinutritional peptides derived from cere… [Nahrung. 1999] – PubMed – NCBI

Antinutritive effects of wheat-germ agglutinin and… [Br J Nutr. 1993] – PubMed – NCBI

This discussion just scratches the surface of the effects of intestinal permeability and health. Future discussion will address how the micro-flora (bacteria and viruses that live in our GI system) affect intestinal permeability, our brains, our immune system and our health.

Avoiding foods that we have not evolved to eat will result in decreased inflammation and will often reduce the symptoms of auto-immune and other inflammatory diseases. Many present day diseases are considered by evolutionary biologists to represent a mismatch between our culture, food, and our evolutionary biochemistry. These diseases were likely rare or non-existent  before the advent of agriculture and the subsequent industrialization of society with highly processed foods.

Eat only pastured meat, free range poultry and eggs, wild seafood, fresh vegetables, fruit and nuts and you will avoid the problems discussed above as well as a host of other problems to be discussed in future posts.

Peace,

Bob Hansen MD