Dr. Sarah Myhill, MD, is a UK-based fatigue specialist focused on nutrition and preventive medicine, and a co-author of the recent trailblazing article, “Chronic Fatigue Syndrome and Mitochondrial Dysfunction.” 
With small bowel overgrowth, Dr. Myhill explains, foods are fermented instead of being digested, producing toxins that can spill over into the circulation, triggering excessive free radical production and inhibiting mitochondrial energy production. She suggests tests, natural & other remedies, and underlying causes.
Mitochondrial Failure Results in Fatigue
There is good evidence that the central pathological lesion (abnormal change) in CFS is mitochondrial failure. What is critical to mitochondrial function is good redox state – that is to say, the balance between free radical stress and our ability to cope with those free radicals (the body’s antioxidant status).
Free radicals damage mitochondria so they go slow, but we have a system of antioxidants in place to protect us against this free radical stress. (See “Antioxidants”  and “CFS – The Methylation Cycle.” ]
Free Radicals Partly Control Mitochondrial Activity
Excessive free radical production, which cannot be dealt with by antioxidant reserves, will damage and switch off mitochondria.
One would think that the largest source of free radicals comes from mitochondria themselves, since here we have large amounts of glucose being oxidized in the presence of oxygen to produce energy, with a large potential to produce free radicals, such as superoxide. While this is undoubtedly a major source, even greater than this is the liver P450 cytochrome system.
Humans are able to eat a wider variety of foods than any other mammal because of this amazing detoxification system of enzymes. It has resulted in humans becoming the most successful mammal because we can occupy almost any ecological niche.
• When the P450 detox system is working well, this has enormous evolutionary advantages.
• However, if things start to go wrong, excessive amounts of free radicals are produced with the potential to switch on a chronic fatigue syndrome.
At this point it must be emphasized that a chronic fatigue syndrome is a protective adaptive response.
If a person [with poor P450 detox function] did not become acutely fatigued, and succeeded in pushing on physically or mentally, then the excessive free radicals so generated would have the potential to cause enormous pathological damage. This is probably why we do not see wild animals with chronic fatigue syndromes: They simply push themselves to destruction, or starve to death.
The Liver P450 Detoxification System is a Major Source of Free Radicals
There are two stages to liver detox. Stage one is an oxidation reaction to make molecules a bit more active in order that stage two can take place, in which another molecule is stuck on. This tacking on allows the toxin to become less active and more water soluble so it can be excreted in urine. The tacking on could be of a sugar (glucuronidation), amino acid, glutathione, sulphate group, and so on.
There are many possible ways the liver P450 cytochrome system could be overwhelmed.
1. Genetic. Some people simply have genetically poor detox ability. One example of this of course is Gilbert’s syndrome  [involves tendency to jaundice and affects perhaps 5% of the population], where conjugation with glucuronide (stage 2 detox) is lacking.
And the first stage of detoxification – the oxidation reaction – may make some toxins more toxic! Many CFS sufferers have fast stage one and slow stage two metabolism, which means they have a P450 system which initially produces more rather than less toxic stress! So for example over 80% of Gilbert’s sufferers complain of fatigue.
One example [of fast stage one & slow stage two effects] involves alcohol metabolism. This is metabolized initially into acetaldehyde – a nasty toxic compound which is responsible for hangovers! Alcohol intolerance is almost universal in CFS.
2. An acquired metabolic lesion as a result of deficiency. For example, many of these P450 cytochrome enzymes are highly dependent on metal co-factors such as zinc, magnesium, or selenium.
3. Toxins produced from normal metabolism. For example, detoxifying neurotransmitters, products from immune activity, breakdown products from damaged tissues, etc.
4. Overwhelming toxins from the outside world. Such as persistent organic pollutants, or of course prescribed drug medication or social drugs of addiction (caffeine, alcohol).
5. Intoxicants arising as a result of fermentation from the upper gut.
Tests for Liver Detox Ability
We can do genetic tests (such as single nucleotide polymorphisms or SNIPs) through Genova laboratories. Genova also offers functional tests to look at stage one and stage two detoxification. (Genova, formerly Great Smokies Diagnostic Laboratories, based in Asheville, North Carolina , expanded to include Genova Europe in the UK  via acquisition in 2007.)
Fermentation in the Upper Gut – and Resulting Toxins
Foods should be quickly and efficiently digested and absorbed in the stomach, duodenum and small bowel, and these departments should be sterile.
• It is only fiber getting down into the large bowel which should be fermented. Digestion proceeds with no gas formation.
• High fiber foods will be fermented in the large bowel, as anyone who eats pulses (the bean family) can testify to!
With small bowel overgrowth, we see bacteria, yeasts and possibly other parasites existing in the small bowel, which means that foods are fermented there instead of being digested. (See last section, listing “Causes of Upper Gut Fermentation.”) When foods get fermented they produce all sorts of unwanted products which have to be detoxified by the liver cytochrome P450 detox system.
These unwanted products include:
• Alcohols – Such as ethyl alcohol, propyl alcohol, butyl alcohol and possibly methyl alcohol. These would be metabolized by stage one into acetaldehyde, propylaldehyde, butylaldehyde and possibly formaldehyde.
– Alcohol and acetaldehydes result in foggy brain, toxic brain, feeling ‘poisoned’ and so on.
– Alcohol also upsets blood sugar levels – this makes the sufferer crave sugar and refined carbohydrates (the very foods bugs need in the upper gut to ensure their own survival). This is arguably a clever evolutionary ploy by bugs to ensure their own survival.
• Odd sugars – Such as D-lactate. This has to be detoxified by lactate dehydrogenase, a liver enzyme. If this is raised then it could point to a problem with gut fermentation. It may result in lactic acidosis. Indeed this phenomenon is much better described in the vet world: D-lactate is a recognized cause in cattle of neurological manifestations; products of fermentation are thought to be a cause of laminitis (hoof inflammation) in horses.
Indeed the encephalopathy (effect on brain function) of liver failure  can be treated by gut-only antibiotics to wipe out unwelcome overgrowth of fermenting gut flora.
• Other things I don’t yet know about!
In theory the above toxins should all be detoxified by the P450 cytochrome system, but in practice some of these can spill over into the systemic circulation with a simple poisoning effect and resultant production of free radicals and inhibition of the mitochondria.
Tests for Upper Gut Fermentation
• Biolab’s Gut fermentation profile  measures levels of alcohol in the blood. It also looks for short chain fatty acids, which are desirable products of fermentation by friendly bacteria in the large bowel.
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• D-lactate could be measured by a simple blood test  following a carbohydrate meal.
• Hydrogen sulfide can be tested for with a urine test – for details see “CFS – hydrogen sulfide, gut bacteria and mitochondrial dysfunction.” 
• A good clinical test for gut fermentation is whether one produces wind or gas (belching, bloating, feeling full, noisy gut etc) after food!
Which bugs are there? One can look at stool samples, but of course that does not tell us where the bugs came from. Comprehensive digestive stool analysis with parasites  is sometimes helpful.
The principles of treatment are:
• Stone Age Diet  – it is sugar and refined carbohydrate which bugs most love to ferment. The diet needs to be low glycemic index (see “Hypoglycemia” ) and rich in raw or lightly cooked vegetables. This is because these foods contain a range of natural antimicrobials to inhibit bacterial overgrowth in the upper gut, together with many enzymes essential for their own digestion and fibre for fermentation in the large bowel by friendly bacteria into short chain fatty acids.
• Improve digestion by checking for Hypochlorhydria (low stomach acid)  and Pancreatic Function  because quick efficient digestion of food means that there is less available to be fermented downstream.
One may need acid supplements, pancreatic enzymes or bile acids to achieve this.
Indeed, there may be a role for vitamin C as ascorbic acid. Ascorbic acid is acid and so improves digestion of protein. It is also toxic to all microbes including bacteria, yeast and viruses, as well as being an important antioxidant – indeed the eventual receiver of all electrons from free radicals. Humans, guinea pigs and fruit bats are the only mammal species which cannot make their own vitamin C and so we have to get it in food.
Scaling up from other mammals, we should be consuming 2 to 6 grams of vitamin C daily (a hundred fold more than the government RDA of 30mgs daily!). One could get the dose just right so that ascorbic acid with food sterilizes the upper gut, but is absorbed and has no effect on the lower gut. If one takes excessive vitamin C, it will cause diarrhea as too much gets into the lower gut, kills off the bugs there and empties the gut completely!
• Replete with probiotics. For this to be effective one should take high doses of actively fermenting probiotics. I like to use Kefir, which is easily grown on many substrates (I use soya milk) and one sachet lasts a lifetime since one culture can be grown from the previous. See “Probiotics”  and Kefir.
• Kill off the offending bugs in the upper gut. My guess is that all the above should be put in place first. This is because of the immune system in the gut, which has become programmed to accept the status quo. If it was not, then it would kick out the unwanted bugs!
– One has to change the gut environment first, as above, to make it conducive to no bugs,
– Then try eradicating the bugs.
One fails to correct the gut environment and the bugs will simply recolonize. At present I do not know what the best strategies will be, but my suggestions would be as follows:
• Ascorbic acid (vitamin C) – see above.
• Viracin – this is zinc tannate, which is markedly astringent and has the ability to attack the cell walls of many microbes. A suggested dose would be 600mg three times daily and then adjust the dose subsequently according to response. It should be taken on an empty stomach away from meals and supplements or it will simply bind these up.
• Grapefruit seed extract – a total of 1600mgs a day in three separate doses. Be mindful that grapefruit seed extract can inhibit the P450 detox enzymes, but on balance where there is fermentation it does good overall!
• Artemisia annua (artemisinin or chinese wormwood) 100-200mgs three times daily.
• Antibiotics may be helpful (but should always be combined with antifungals – see “Yeast Problems and Candida” ). I would recommend rifaximin 200mg three times daily for three days, then a maintenance dose of 200 mg daily and then re-check a urine test to see if we are making progress. [Rifaximin  is a ‘non-systemic antibiotic, meaning very little passes through the GI wall into the circulation, as is common for other oral antibiotics.]
• Herbal medicine – I do not know enough about this, but my guess is that there are many herbal preparations which could prove to be very useful! For example:
– Many Indian spices have antiseptic properties such as cloves and tumeric (curcurim).
– Garlic, oregano, marjoram, juniper, cranberry, Echinacea, sage all have antiseptic effects and could be used in food preparation as much as possible.
“Let thy food be thy medicine and thy medicine be thy food!” said Hippocrates (460-377 BC). He was right!
Fermentation produces wind and many other gut symptoms. Get this right, and:
• The gut will settle down,
• The foggy (toxic) brain will clear,
• And energy levels will improve,
… as mitochondria can function more normally.
What Causes Upper Gut Fermentation?
• Western lifestyles!
• Failure to inoculate the gut at birth with the correct friendly bacteria – see “Probiotics.” 
• Diet that is:
– High in sugar and refined carbohydrate,
– Low in fresh vegetables and fiber,
– Low in vitamin C,
– Low in other micronutrients.
• Modern medication including:
– Antibiotics, which wipe out the gut flora,
– Pill and HRT (hormone replacement therapy), which suppress the immune system and encourage yeast overgrowth,
– Acid blockers such as antacids, H2 blockers and proton pump inhibitors, which inhibit stomach acid production. See “Hypochlorhydria – Lack of Stomach Acid” .
* This article (No. 456) is excerpted with kind permission from Dr. Myhill’s patient-education website (DrMyhill.co.uk ). ®Sarah Myhill Limited, Registered in England and Wales: Reg. No. 4545198. For ME/CFS patients, a special feature of Dr. Myhill’s site is her free 179-page online book – Diagnosing and Treating Chronic Fatigue Syndrome .
Individuals in the UK can, with a doctor’s referral, directly order many of the diagnostic tests mentioned by obtaining kits from and mailing samples to Dr. Myhill. See <a href="http://www.drmyhill.co.uk/tests.cfm
“>test list and details.
Note: This information has not been evaluated by the FDA. It is generic and in respects theoretical and is not meant to prevent, diagnose, treat or cure any condition, illness, or disease. It is very important that you make no change in your healthcare plan or health support regimen without researching and discussing it in collaboration with your professional healthcare team.