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Organic Acids – Part 12Dr. Jeff Moss

© Dr. Jeff Mosshttp://www.MossNutrition.comhttp://www.FMTown.com

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Using organic acids to Using organic acids to resolve chief complaints resolve chief complaints

and improve quality of life in and improve quality of life in chronically ill patientschronically ill patients

P t XIIP t XII

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Part XIIPart XIIJeffrey Moss, DDS, CNS, DACBNJeffrey Moss, DDS, CNS, DACBN

[email protected]@mossnutrition.com

413413--530530--0858 (cell)0858 (cell)

Compounds of bacterial Compounds of bacterial oror

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or or yeast/fungal origin yeast/fungal origin

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Summer of work exposes medical students to system’s ills, The New York Times, September 9, 2009

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“…a tidal wave of chronic illness…”

Baracos VE. Overview on metabolic adaptation to stress, pp. 1-13.

“An understanding of the nature of stress is fundamental to the rational design of nutrient mixtures to feed patients whose homeostasis has been altered

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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.”

Bengmark S. Acute and “chronic” phase reaction – a mother of disease, Clin Nutr,

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reaction a mother of disease, Clin Nutr, Vol. 23, pp. 1256-66, 2004



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Chronic inflammation, inflammaging

Hyperinsulinemia/Insulin resistance

Key deficiencies or excesses, i.e.,

Calories, macronutrients, B

vitamins, zinc, selenium, iodine,

sleep, psychological and chemical stress, movement against

gravity, weight

Low calorie intake and excessive

carbohydrate/protein ratio – Refeeding

syndrome

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THE CREATION OF THE EXCESSIVE CATABOLIC PHYSIOLOGY “RESPONSE”

Sarcopenia/Loss of lean body mass

Low grade chronic metabolic acidosis/fluid electrolyte imbalance

Gut dysfunction/atrophy

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. 144-152, 2009

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g , , pp ,



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Intestinal dysbiosis markers:Intestinal dysbiosis markers:Basic conceptsBasic concepts

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Basic conceptsBasic concepts

Lord RS & Bralley JA. Eds., Laboratory Evaluations for Integrative and Functional Medicine, 2nd

Edition

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Edition, Metametrix Institute, Duluth GA, 2008



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• “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

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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.”

“Some of the compounds discussed in this section are exclusively produced by…intestinal microbial metabolism,

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by…intestinal microbial metabolism, whereas others may have small

contributions from human metabolic pathways.”

• “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

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to the lag phase for the onset of logarithmic growth rates characteristic of most bacteria.”



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• “It is during this most intense growth phase when the microbial counts rise from 105 to 1011/g that metabolic products are most actively produced.”

• “Thus, by measuring their products in urine, information principally about the

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p p ymid- or transitional-gut microbial mass may be obtained.”

BenzoateBenzoateHippurateHippurate

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HippurateHippurate

• “…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

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Dietary polyphenols generally persist into the lower small intestine because they are resistant to degradation by digestive fluids.”



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Food sources of benzoate and Food sources of benzoate and hippuratehippurate

• “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 ”

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mainly benzoate and hippurate.• “Quinic acid, a tetrahydroxybenzoic acid

compound found in tea, coffee, fruits, and vegetables is also largely metabolized to benzoic acid by intestinal bacteria and excreted as hippurate.”

Food sources of benzoate and Food sources of benzoate and hippuratehippurate

• “Benzoic acid is also a common food component. It is used as a preservative in packaged foods such as pickles and

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lunch meats, and it occurs naturally in cranberries and other fruits.”

• “This should be taken into account when interpreting elevated hippurate levels in urine.”

• “Whether the source is dietary intake or jejunal bacterial metabolism, benzoate should be rapidly converted to hippurate by conjugation with glycine. Glycine and pantothenic acid can be limiting factors in this process.”

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• “Elevated benzoate is a confirmatory marker for inadequacy of glycine or pantothenic acid for conjugation reactions.”



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“The organic solvent, toluene, is detoxified by oxidation to benzoic

id d ti hi t ”

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acid and excretion as hippurate.”

PhenylacetatePhenylacetate

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PhenylacetatePhenylacetatePhenylproprionatePhenylproprionate

• “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 ”

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urine.

• “However, phenylacetate is a trace product of endogenous phenylalanine catabolism that can accumulate in the phenylalaninemic state found in phenylketonuria.”



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• “The similar compound that has two –CH2- groups instead of one, phenylproprionate (PPA), is also produced by anaerobic flora.

• “PPA does not normally appear in human urine, however, because it is

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human urine, however, because it is metabolized by mitochondrial medium-chain acyl-CoA-dehydrogenase (MCAD).”

Clostridium difficile can also produce

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PPA.

CresolCresolHydroxybenzoateHydroxybenzoate

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HydroxybenzoateHydroxybenzoate



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• “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 very similar to phenol and is highly toxic.”

• “Cresol excretion is not affected by dietary protein intake suggesting that the bacterial

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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.”

• “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

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along with Lactobacillus casei, Shirota, and Bifidobacterium breve to human subjects.”

• “Strains of Escherichia coli can produce p-hydroxybenzoate from glucose.”

HydroxyphenylacetateHydroxyphenylacetate

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HydroxyphenylacetateHydroxyphenylacetate



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• “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

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urine if P. vulgaris is the predominant organism.”

• “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 associated with anaerobic bacterial overgrowth.”

• “Use of antibiotics that act primarily against

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p y gaerobic bacteria (such as neomycin) can encourage the growth of protozoa and anaerobic bacteria than then produce greater amounts of these compounds.”

• “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 ”

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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.”



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HydroxyphenylproprionateHydroxyphenylproprionate

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HydroxyphenylproprionateHydroxyphenylproprionate

• “Increased excretion of m-hydroxyphenylproprionate (m-HPPA) was found in healthy human volunteers who consumed 1,000 mg of polyphenols as grape seed extract.”

• “Low levels of urinary m-HPPA, therefore, can indicate low intake of caffeic acid and the

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proanthocyanidins found in grapes and other foods.”

• “High levels of m-HPPA, on the other hand, may indicate increased bacterial metabolism of dietary catechins and caffeic acid.”

“When p-HPPA is elevated with concurrent elevation in tyrosine, then the possibility of intestinal clostridial

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the possibility of intestinal clostridial production from dietary tyrosine

should be considered.”



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3,43,4--DihydroxyphenylproprionateDihydroxyphenylproprionate

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DihydroxyphenylproprionateDihydroxyphenylproprionate(3,4(3,4--DHPP)DHPP)

• “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.”

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• “Although other organisms may produce 3,4-DHPP, clostridia is the most commonly encountered genera among those susceptible to Flagyl.”

IndicanIndican

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IndicanIndican



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• “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.”

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• “Indoxyl sulfate (also known as indican) can be measured colorimetrically by conversion to colored oxidation products…”

• “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 105 organisms/g ”

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above 105 organisms/g.• Lactobacillus salivarius, Lactobacillus plantarum, and

Lactobacillus casei were more effective in achieving reduced indican than were two strains of Lactobacillus acidophilus.”

• “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.”

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p y

• “Urinary indican does not rise in patients with steatorrhea not due to pancreatic insufficiency, nor in the normal subjects who receive pancreatic enzymes.”



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• “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

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y gdietary protein.”

• “The relationship between increased indican and incomplete digestion might be utilized as a measure of protein digestive adequacy.”

• “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.”“I di l ti h l d th t

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• “Indican elevation has revealed that impaired protein digestion and increased bacterial conversion of tryptophan is a complication of cirrhosis or the liver.”

“Some degree of malabsorption was found in 30% of an elderly population by combinations of indican with the

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by combinations of indican with the Shilling and other tests.”



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Products of dietary Products of dietary carbohydate:carbohydate:

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carbohydate:carbohydate:DD--LactateLactate

• “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 ”

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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.”

• “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.”

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lactic acidosis.

• “Elevated levels of D-lactate were found in blood samples of 13 out of 470 randomly selected hospitalized patients.”



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• “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

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appendicitis, and for differentiating perforated from simple appendicitis.”

• “Whatever the origin, patients are managed with antibiotics and probiotics, including Saccharomyces boulardii.”

• “When D-lactate is elevated, supplementation with D-lactate-producing species of Lactobacillus is contraindicated, and steps to reduce bacterial populations should be considered.”

• “Not all species of Lactobacillus produce significant D-lactate…”

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g

• “Once the carbohydrate excess in the small intestine is controlled, a recommended approach to managing recolonization with probiotic species is to supplement with species that do not produce D-lactate.”

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“In summary, urinary D-lactate elevation may predict bacterial

overgrowth as a result of: carbohydrate malabsorption,

ischemic bowel, certain types of pancreatic insufficiency, acute

appendicitis, and surgical

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pp , gprocedures that compromise upper gastrointestinal function. Diagnosis

and treatment of D-lactic acidosis can significantly improve patient

outcomes.”

TricarballylateTricarballylate

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TricarballylateTricarballylate

• “As its name implies, tricarballylate (tricarb) contains three carboxylic acid groups that are ionized at physiological pH to give a small molecule with three negative charges akin to the structure of the powerful chelating agent EDTA.”

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• “Magnesium is bound so tightly by tricarb that magnesium deficiency results from overgrowth of tricarb-producing intestinal bacteria in ruminants.”



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DD--ArabinitolArabinitol

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DD ArabinitolArabinitol

• 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

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y p pratio of DA to creatinine in serum or urine.”

• “Measuring serum DA allows prompt diagnosis of invasive candidiasis.”

Treatment considerationsTreatment considerations

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• “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 ”

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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.”

• “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

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• 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.”

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Some concluding, big picture Some concluding, big picture thoughts on organic acidthoughts on organic acid

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thoughts on organic acid thoughts on organic acid testingtesting

• 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.

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• 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 deficiency, malabsorption and/or metabolic dysregulation, i.e., altered metabolism due to chronic inflammation.

• 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

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• Energy production• Metabolic inflammation (“metaflammation”)• Neurochemistry/stress physiology• Detoxification pathways• GI dysfunction



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Thank you!!

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