Organic Acids Part 12 Dr. Jeff Moss

Transcription

1 Using organic acids to resolve chief complaints and improve quality of life in chronically ill patients Part XII Jeffrey Moss, DDS, CNS, DACBN (cell) 1 Compounds of bacterial or yeast/fungal origin 2 1

2 3 Summer of work exposes medical students to system s s ills, The New York Times, September 9, 2009 a tidal wave of chronic illness 4 2

3 Baracos VE. Overview on metabolic adaptation to stress, pp An understanding of the nature of stress is fundamental to the rational design of nutrient mixtures to feed patients whose homeostasis has been altered by one or more stressors. All stresses may be presumed to be associated with characteristic modifications in the metabolism of lipids, carbohydrates, amino acids, and micronutrients. 5 Bengmark S. Acute and chronic phase reaction a mother of disease, Clin Nutr, Vol. 23, pp ,

4 7 Key deficiencies or excesses, i.e., Calories, macronutrients, B vitamins, zinc, selenium, iodine, sleep, psychological and chemical stress, movement against gravity, weight Chronic inflammation, inflammaging Low calorie intake and excessive carbohydrate/protein ratio Refeeding syndrome Hyperinsulinemia/Insulin resistance Gut dysfunction/atrophy Low grade chronic metabolic acidosis/fluid electrolyte imbalance Sarcopenia/Loss of lean body mass THE CREATION OF THE EXCESSIVE CATABOLIC PHYSIOLOGY RESPONSE 8 4

5 Su KP. Biological mechanism of antidepressant effect of omega-3 fatty acids: How does fish oil act as a mind-body interface? Neurosignals, Vol. 17, pp ,

6 Intestinal dysbiosis markers: Basic concepts 11 Lord RS & Bralley JA. Eds., Laboratory Evaluations for Integrative and Functional Medicine, 2 nd Edition, Metametrix Institute, Duluth GA,

7 Small molecular weight products can appear in urine, revealing metabolic activities of the microbes that inhabit the mucosal layer and lumen of the gut. The compounds have a wide range of relative toxicities, with cresol near the upper end and hippurate and benzoate at the lower end. Absorbed bacterial metabolic products may undergo further metabolism in host tissues, mainly liver and kidney. 13 Some of the compounds discussed ssed in this section are exclusively produced by intestinal microbial metabolism, whereas others may have small contributions from human metabolic pathways. 14 7

8 The anatomical region of the gut that is most likely to yield bacterial metabolites is the middle or transitional gut, including the terminal ileum and the ascending colon because the passing of chyme to the lower ileum corresponds to the lag phase for the onset of logarithmic growth rates characteristic of most bacteria. 15 It is during this most intense growth phase when the microbial counts rise from 10 5 to /g that metabolic products are most actively produced. Thus, by measuring their products in urine, information principally about the mid- or transitional-gut microbial mass may be obtained. 16 8

9 Benzoate Hippurate 17 bacterial catabolism of dietary polyphenols may be the predominant origin or benzoate, which is normally conjugated with glycine in the liver to form hippurate. Dietary polyphenols generally persist into the lower small intestine because they are resistant to degradation by digestive fluids. 18 9

10 Food sources of benzoate and hippurate Coffee, fruits and vegetables are sources of beneficial chlorogenic acid, over 57% of which is recovered in urine as organic acids, mainly benzoate and hippurate. Quinic acid, a tetrahydroxybenzoic acid compound found in tea, coffee, fruits, and vegetables is also largely l metabolized to benzoic acid by intestinal bacteria and excreted as hippurate. 19 Food sources of benzoate and hippurate Benzoic acid is also a common food component. It is used as a preservative in packaged foods such as pickles and lunch meats, and it occurs naturally in cranberries and other fruits. This should be taken into account when interpreting elevated hippurate levels in urine

11 Whether the source is dietary intake or jejunal bacterial metabolism, benzoate should be rapidly converted to hippurate by conjugation o with glycine. Glycine and pantothenic acid can be limiting factors in this process. Elevated benzoate is a confirmatory marker for inadequacy of glycine or pantothenic th acid for conjugation reactions. 21 The organic solvent, toluene, is detoxified by oxidation to benzoic acid and excretion as hippurate

12 Phenylacetate Phenylproprionate 23 Intestinal bacterial action on dietary polyphenols causes the appearance of phenylacetate (PAA) in urine. For individuals with normal, healthy intestinal function, phenylacetate should not appear at more than background concentrations in urine. However, phenylacetate is a trace product of endogenous phenylalanine catabolism that can accumulate in the phenylalaninemic state found in phenylketonuria

13 The similar compound that has two CH 2 - groups instead of one, phenylproprionate (PPA), is also produced by anaerobic flora. PPA does not normally appear in human urine, however, because it is metabolized by mitochondrial mediumchain acyl-coa-dehydrogenase (MCAD). 25 Clostridium difficile can also produce PPA

14 Cresol Hydroxybenzoate 27 Dietary polyphenols or tyrosine residues from dietary proteins are the parent compounds from which urinary p-cresol, p- hydroxybenzoate, and p- hydroxyphenylacetate are formed. Cresol has a chemical structure t very similar il to phenol and is highly toxic. Cresol excretion is not affected by dietary protein intake, suggesting that the bacterial responsible reside in the lower portions of the small intestine where amino acids from dietary protein rarely penetrate. These bacterial apparently produce cresol from intestinal secretions and well as from dietary sources

15 A large majority of adult celiac disease patients were found to excrete unusually high amounts of p-cresol. Cresol excretion was found to be lowered by administration of prebiotic substrate (oligofructose-enriched inulin) along with Lactobacillus casei, Shirota, and Bifidobacterium breve to human subjects. Strains of Escherichia coli can produce p-hydroxybenzoate from glucose. 29 Hydroxyphenylacetate 30 15

16 Both the transamination to form p- hydroxyphenylacetate (HPA) and the decarboxylation to p-cresol are carried out by Clostridium difficile. Since Proteus vulgaris can do only the first of these steps, HPA will increase in urine if P. vulgaris is the predominant organism. 31 p-hydroxyphenylacetic aciduria has been found useful in detecting small bowel disease associated with Giardia lamblia infestation, ileal resection with blind loop, and other diseases of the small intestine ti associated with anaerobic bacterial overgrowth. Use of antibiotics that act primarily against aerobic bacteria (such as neomycin) can encourage the growth of protozoa and anaerobic bacteria than then produce greater amounts of these compounds

17 Patients with cystic fibrosis or other conditions that severely impair amino acid absorption can demonstrate the potential for intestinal bacterial conversion of phenylalanine and tyrosine to phenyl compounds that appear in urine. These patients tend to excrete very high levels of phenylacetate and p- hydroxyphenylacetate. However, since tyrosine released from dietary protein is rapidly absorbed in most individuals; conversion of tyrosine to p- hydroxyphenylacetate may be a rarely observed sign of dysbiosis in humans. 33 Hydroxyphenylproprionate 34 17

18 Increased excretion of m- hydroxyphenylproprionate (m-hppa) was found in healthy human volunteers who consumed 1,000 mg of polyphenols as grape seed extract. t Low levels of urinary m-hppa, therefore, can indicate low intake of caffeic acid and the proanthocyanidins found in grapes and other foods. High levels l of m-hppa, on the other hand, may indicate increased bacterial metabolism of dietary catechins and caffeic acid. 35 When p-hppa is elevated with concurrent elevation in tyrosine, then the possibility of intestinal clostridial production from dietary tyrosine should be considered

19 3,4- Dihydroxyphenylproprionate (3,4-DHPP) 37 Numerous reports have been received of patients with Clostridium overgrowth confirmed by stool culture, where elevated levels of 3,4-DHHP have fallen to baseline with Flagyl, but were unaffected by nystatin. Although other organisms may produce 3,4-DHPP, clostridia is the most commonly encountered genera among those susceptible to Flagyl

20 Indican 39 Bacteria in the upper bowel produce the enzymes that catalyze the conversion of tryptophan to indole. Absorbed indole is converted in the liver to indoxyl, which is then sulfated to allow for urinary excretion. Indoxyl sulfate (also known as indican) can be measured colorimetrically by conversion to colored oxidation products 40 20

21 An elevated level of urinary indican is an indication of upper bowel bacterial overgrowth. Certain patients such as those with celiac disease may be at greater risk. Oral, unabsorbed antibiotics reduce indican excretion. Indican excretion is also reduced when the gut is populated with strains of Lactobacillus at levels above 10 5 organisms/g. Lactobacillus salivarius, Lactobacillus plantarum, and Lactobacillus casei were more effective in achieving reduced indican than were two strains of Lactobacillus acidophilus. 41 Indican testing can aid in differentiating pancreatic insufficiency from biliary stasis as the cause of steaorrhea (fatty stools). Patients with steatorrhea due to pancreatic insufficiency show a rise of indican from low values to above normal when they are treated with pancreatic enzyme extract. Urinary indican does not rise in patients with steatorrhea not due to pancreatic insufficiency, i nor in the normal subjects who receive pancreatic enzymes

22 The interpretation of indican results is complicated by impaired protein digestion, which increases the tryptophan available for bacterial action. Even patients with normal intestinal bacterial populations can show increased postprandial indican excretion when they fail to digest dietary protein. The relationship between increased indican and incomplete digestion might be utilized as a measure of protein digestive adequacy. 43 Indican evaluation has been used to assess intestinal absorption of tryptophan in scleroderma. Increased urinary indican has been shown to correlate with enteric protein loss. Indican elevation has revealed that impaired protein digestion and increased bacterial conversion of tryptophan is a complication of cirrhosis or the liver

23 Some degree of malabsorption was found in 30% of an elderly population by combinations of indican with the Shilling and other tests. 45 Products of dietary carbohydate: D-Lactate 46 23

24 Nanomolar concentrations of D-lactic acid may be produced in human tissues, but it is a major metabolic product of several strains of bacteria that inhabit the human gut. Under conditions of carbohydrate malabsorption, D-Lactate is simultaneously increased in blood and urine. D-Lactic acidosis due to overgrowth of Lactobacillus plantarum was reported in a child who developed an unusual encephalopathic syndrome due to neurotoxic effects of D-lactate. 47 Procedures as mild as stomach stapling may lead to D-lactic acidosis. Precipitating factors include use of antibiotics and medium-chain triglycerides. Carbohydrate malabsorption associated with pancreatic insufficiency can also induce D- lactic acidosis. Elevated levels of D-lactate were found in blood samples of 13 out of 470 randomly selected hospitalized patients. t 48 24

25 The specficity and sensitivity of urinary D-lactate has led to the test being proposed for routine diagnosis of bacterial infections. D-lactate has also bee reported to be a marker for diagnosis of acute appendicitis, and for differentiating perforated from simple appendicitis. Whatever the origin, patients are managed with antibiotics and probiotics, including Saccharomyces boulardii. 49 When D-lactate is elevated, supplementation with D-lactate-producing species of Lactobacillus is contraindicated, and steps to reduce bacterial populations should be considered. d Not all species of Lactobacillus produce significant D-lactate Once the carbohydrate excess in the small intestine is controlled, a recommended approach hto managing recolonization with probiotic species is to supplement with species that do not produce D-lactate

26 51 In summary, urinary D-lactate elevation may predict bacterial overgrowth as a result of: carbohydrate malabsorption, ischemic i bowel, certain types of pancreatic insufficiency, acute appendicitis, and surgical procedures that compromise upper gastrointestinal function. Diagnosis and treatment of D-lactic acidosis can significantly improve patient outcomes

27 Tricarballylate 53 As its name implies, tricarballylate (tricarb) contains three carboxylic acid groups that are ionized at physiological ph to give a small molecule e with three negative charges akin to the structure of the powerful chelating agent EDTA. Magnesium is bound so tightly by tricarb that magnesium deficiency results from overgrowth of tricarbproducing intestinal bacteria in ruminants

28 D-Arabinitol 55 D-Arabinitol (DA) is a metabolite of most pathogenic Candida species, in vitro as well as in vivo. The rate of DA appearance in the body equals the urinary excretion rate and is directly proportional to the concentration ratio of DA to creatinine in serum or urine. Measuring serum DA allows prompt diagnosis of invasive candidiasis

29 Treatment considerations 57 Although species identification is not possible from the limited number of urinary markers currently detected, and no antibiotic sensitivity testing can be done, the information available is sufficient for clinical decisions about appropriate interventions. Since the microbial compounds that appear in the urine originate in the lumen of the gut, oral sorbents that bind them and prevent their absorption can be used

30 This approach is especially helpful for those compounds of high toxicity like cresol. Activated charcoal may be used for this purpose The generally sound advice of using a high-fiber diet rich in legumes and other whole foods is an effective way of achieving lowered transit times and less exposure to intestinal toxicants

31 Some concluding, big picture thoughts on organic acid testing 61 Organic acids testing is the one assay that can, most likely, give the most comprehensive overview of the metabolic basis of your chronically ill patient s chief complaints. It does not replace foundational methods of diagnosis such as history, lean body mass, basic blood chemistry, etc. Rather, it functions best as a second tier test when basics have not yielded satisfactory results. Virtually all of the analytes are products of amino acid metabolism. Therefore, it must be determined if normal findings in the lower ranges are artifacts of amino acid/protein i deficiency, i malabsorption and/or metabolic dysregulation, i.e., altered metabolism due to chronic inflammation

32 Most labs performing this assay only consider the findings in terms of micronutrient need. A large body of research indicates that organic acids is also an excellent tool to gain information on the following: Protein/amino acid deficiency and imbalance Insulin metabolism Acid/alkaline balance Energy production Metabolic inflammation ( metaflammation ) Neurochemistry/stress physiology Detoxification pathways GI dysfunction 63 Thank you!! 64 32