Butyrate Overload Induced Pungent Body Odor Emission - v14

Plasma butyrate, propionate and
acetate overload induced pungent body

odor emission
(Clochard-Smell-Syndrome)
Proposal
Dermatologist: The eccrine glands do only produce

water and salt…
Patient: But what if it is butyric acid salt?
Dermatologist: Nooooo, it’s only water and salt! It

must be bacteria, it must be!!!
Author
Danny Kunz (danny.kunz@gmx.de)

Applied Computer Science - Research & Development
(From 2016-12-11 to 2017-02-08)
Non final version/work in progress

Plasma butyrate, propionate and acetate overload induced pungent body odor emission
danny.kunz@gmx.de
Inhalt
Abstract ................................................................................................................................................... 5
Overview of the proposed butyrate path in the human body with liver enzyme deficiency and without
................................................................................................................................................................. 7
Butanoate metabolism from nutrient to eccrine sweat in detail ........................................................... 9
Small intestinal enzyme digestion ....................................................................................................... 9
Large intestinal microbiome pathways regarding carbohydrates and proteins ............................... 10
Intestinal short chain fatty acids to liver transport ........................................................................... 11
Intestinal epithel transport ........................................................................................................... 11
Liver ................................................................................................................................................... 12
Liver metabolism with isobutyryl dehydrogenase deficiency ....................................................... 12
Liver metabolism with assumed [ACSS/ACSM] deficiency ................................................................ 13
Butyrate blood plasma flow after liver fails to reduce them ............................................................ 13
Eccrine sweat glands ......................................................................................................................... 13
Comparison organic acidurias like Biotin Deficiency and assumed ACSS/ACSM deficiency ................. 14
Biotin deficiency ................................................................................................................................ 14
ACSS/ACSM deficiency ...................................................................................................................... 15
Isovaleric acidemia ............................................................................................................................ 16
Difference in IVA between Nutrient induces Leucine overload and muscle protein induced
Leucine overload ........................................................................................................................... 17
Discussion regarding the existence of apocrine Bromhidrosis ............................................................. 18
Facts and assumptions of the apocrine Bromhidrosis theory recaptured ........................................ 18
Phenomena by apocrine Bromhidrosis patients which contradicts the theory ............................... 18
Hyperhidrosis with increased Lactate plasma levels..................................................................... 18
Discussion about the metabolic relationship of acetate overload to Trimethylaminuria of type 2 ..... 19
Discussion regarding reported Trimethylamine type 2 odors .......................................................... 19
Discussion of reported smell types of positive tested TMAU2 patients ....................................... 19
Transient histamine intolerance syndrome in combination with reduced choline degradation
pathway ............................................................................................................................................. 21
Secondary overload of the EC 1.2.1.3 and EC 1.2.1.5 enzyme results in increased levels of
Histamine and decreased S-Adenosyl-Homocysteine production ................................................ 21
Reduced S-Adenosyl-Homocysteine production results in low Homocysteine regeneration with a
reduced Choline and Betaine degradation pathway......................................................................... 22
Decreased small intestinal choline absorption based on affected Choline degradation pathway
leads to higher Choline levels in the large intestinal tract and to a higher TMA production ........... 23
High histamine levels in specific days in menstruation cycle correlate with high TMA levels ......... 24
Page 2
danny.kunz@gmx.de
Reduced histamine levels after antibiotics intake for several days .............................................. 24
High Histamine levels induce increased HCL production in pancreas which leads to a reduction of
amylase enzymes........................................................................................................................... 24
DAO inhibition after high Histamine levels ....................................................................................... 24
High Indole levels based on a inhibited Tryptophan degradation pathway and transporter ........... 26
Low Cysteine levels will result in reduced EC 1.2.1.5 and EC 1.2.1.3 enzyme regeneration ............ 27
Citrullinuria ........................................................................................................................................ 28
Further involved metabolic pathways effects ................................................................................... 28
EC 1.2.1.3 inhibition ...................................................................................................................... 28
EC 1.2.1.5 inhibition ...................................................................................................................... 30
Acetate neogenesis and the Acetyl-CoA metabolism ........................................................................... 32
Insulin and Glucagon effects on Acetyl-CoA generation within cells ................................................ 32
Decreased glucose resorption results in glucose malabsorption in the small intestinal tract ......... 32
Environmental intereffects with the butyrate emission of the eccrine sweat glands .......................... 33
Clothes ............................................................................................................................................... 33
Washing machine .............................................................................................................................. 33
Buildings / Apartment / Workplace .................................................................................................. 33
Dietary options to reduce the amount of acetate, propionate and butyrate resorbed into the blood
plasma ................................................................................................................................................... 34
Reduce the amounts produced in the large intestinal tract by microbes......................................... 34
Reduce the amounts resorbed in the small intestinal tract .............................................................. 34
Increase the amounts of energy rich foods with no increase of SCFAs in blood plasma.................. 34
Reduce the amount of acetogenesis ................................................................................................. 35
Other things........................................................................................................................................... 36
Volatiles ................................................................................................................................................. 37
Further research themes ....................................................................................................................... 38
Secondary markers for plasma butyrate overload ............................................................................ 38
Increased TSH in blood plasma ..................................................................................................... 38
Decreased BDNF in blood plasma ................................................................................................. 38
Secondary marker for nitrogen compounds in blood based on FMO3 enzyme defect .................... 38
Citrullinemia .................................................................................................................................. 38
Possible dietary supplements helping to reduce the carbohydrate digestion ................................. 38
Possible medication reported in helping to reduce the Trimethylamine effects ............................. 38
Desmopressin ................................................................................................................................ 38
Black Seed Oil (Nigella Sativa) ....................................................................................................... 38
Page 3
danny.kunz@gmx.de
Decreased sugar breaking enzymes in the intestinal tract like in lactase intolerance ..................... 38
Images ................................................................................................................................................... 39
Pathway map ......................................................................................................................................... 40
To investigate ........................................................................................................................................ 41
PGC-1α............................................................................................................................................... 41
Insuline .............................................................................................................................................. 41
Obsolete ................................................................................................................................................ 42
Secondary N-Methyl-Transferase overload based on overloaded diamineoxidase pathway .......... 42
Butyrate halftime in blood plasma induced right axillary Bromhidrosis with no left axillary
Bromhidrosis ..................................................................................................................................... 42
Assumed BHMT enzyme deficiency with a resulting increased TMA level in the large intestinal tract
........................................................................................................................................................... 43
Blocked intestinal sulfide pathway in Cystathioninuria .................................................................... 44
Current further known disorders with pungent smell and their relevance in plasma saturation of
volatile substrates ............................................................................................................................. 44
Plasma isobutyryl saturation within patients of Isobutyric acidemia ........................................... 44
Free fatty acids emitted from apocrine glands in apocrine Bromhidrosis .................................... 47
Trimethylaminuria Type 2 ............................................................................................................. 49
Current state of research of liver functionality related to short chain fatty acids ........................... 49
Page 4
danny.kunz@gmx.de
Abstract
The following work shows
 A theoretical metabolic pathway based on an assumed deficiency of the EC 6.2.1.2 butyrate

CoA ligase enzyme which results in the symptoms of classical “apocrine Bromhidrosis”
 A theoretical metabolic pathway based on the assumed deficiency of the EC 6.2.1.1 acetate
CoA ligase enzyme which results in the symptoms of Trimethylamineuria Type 2 (TMAU2)
patients with an acetic (sour/biting) and propionatic (sweaty/biting) smell component
 A theoretical metabolic subpathway which is based on an assumed deficiency of the EC
1.2.1.5 enzyme which results in the symptoms of TMAU2 patients with an indole (fecal)
smell
And subsequently
 That classical “apocrine” Bromhidrosis may actually be based on eccrine sweat gland
excretion of butyric acid salts (butyrates)
 Butyrates produced in the large intestinal tract are not broken down correctly in the
intestinal epithelium cells and in the liver
 In its salt form the butyric acid is plasma pH neutral transported within the blood
plasma further into the body, getting then available to the eccrine sweat ducts to be
released into the eccrine sweat where its salts naturally instable in aqua solutions
will dissolve into the free butyric acid form
 A deficiency of the EC 6.2.1.1 enzyme will result in increased acetate levels within intestinal
epithelium and liver cells. This further results in the inhibition of the EC 1.2.1.3 and EC 1.2.1.5
aldehyde dehydrogenase enzymes
 The inhibition of the EC 1.2.1.3 and EC 1.2.1.5 enzymes result in an inhibition of the EC
1.4.3.22 Diamineoxidase enzyme and the EC 2.1.1.8 Histamine-N-Methyltransferase (HNMT)
enzyme. This leads to two inhibited pathways of histamine degradation and as a result to
high histamine levels within intestinal epithelium and liver cells.
 Inhibition of Histamine degradation over the EC 2.1.1.8 HNMT results in a reduction
of the coupled Betaine-Homocysteine-S-Methyltransferase (BHMT) activity which
results in an inhibited Choline and Betaine degradation pathway.
 Increased amounts of Choline and Betaine within the intestinal epithelium cells will
then result in the Choline and Betaine transporters to stop transporting Choline and
Betaine from the intestinal tract to the hepatic portal vein.
 The decreased absorption of Betaine and Choline will result in higher amounts of
those nutrients within the large intestinal tract, where they are digested by microbial
activity into Trimethylamine
 The increased Trimethylamine amount absorbed from the large intestinal tract will
then overload the FMO3 enzyme of the liver which results in Trimethylaminuria
 Additionally high Histamine levels will result in
 Higher gastric acid levels (in combination with high acetylcholine levels )
 Increased immune system reactions around the intestinal tract epithelium
cells
 Migraine
Page 5
danny.kunz@gmx.de
 The inhibition of the EC 1.2.1.3 and EC 1.2.1.5 enzymes also results in an inhibited major and
the minor Tryptophan degradation pathway.
 Increased levels of Tryptophan in intestinal epithelium cells will result in the
Tryptophan transport to fail like for Choline and Betaine
 Higher Tryptophan levels in the large intestinal tract will occur also, which results in
higher Indole levels in the large intestinal tract based on the microbial degradation of
Tryptophan
 Higher Indole amounts will be resorbed into the blood stream and will overload the
CYP enzyme based degradation into Indoxyl and will result in higher Indole-3-Sulfat
levels in urine
 The inhibition of the EC 1.2.1.5 will also result in
 inhibited Dopamine, Noradrenaline, Adrenaline degradation comparable to the
COMT enzyme affect which is strongly related to depression and schizophrenia
 inhibited L-Thyroxine (T4) production which will result in high TSH blood levels since
the TSH has to be increased to produce the same amount of T4
 The inhibition of the EC 1.2.1.3 will result in inhibited Gamma-Amino-Butyric-Acid (GABA)
biosynthesis which results in anxiety disorders. Further higher Putrescine levels are
expected.
 The inhibition of EC 1.2.1.3 will also result in an inhibited degradation pathway of ornithine
which results in higher ornithine amounts to be broken down to citrulline. Citrulline will be
expected to be increased in urine.
 The inhibition of the EC 1.2.1.3 and EC 1.2.1.5 will result in multiple aldehyde compounds
including acetaldehyde to build up in intestinal and liver and lung cells. Those chemicals are
class 1 carzinogens. Increased amounts of the EC 1.2.1.3 enzymes have been tremendously
reported to be present in carcinoma cells. It is expected that the enzyme production will
react of the increased acetate levels within the cells with higher EC 1.2.1.3 enzyme levels.
 ACSS1 genes have been reported to have mutations found in carcinoma cells. EC 6.2.1.1 and
EC 6.2.1.2 are located on the ACSS1 gene
Page 6
danny.kunz@gmx.de
Overview of the proposed butyrate path in the human body with liver
enzyme deficiency and without
eccrine Heart
glands
Butyryl-CoA
Butyrate
Liver
Intestinal tract
Abbildung 1 - Overview over the butyrate path in the human body
Page 7
danny.kunz@gmx.de
Gastrologist: It’s a bacterial overgrowth thing in the

gut. But there are billions of microbes in there, we
can’t exactly say, what they are all doing!
Patient: So you needed to talk to them all and asked

for their mobile number…but they didn’t give it to
you?
Page 8
danny.kunz@gmx.de
Butanoate metabolism from nutrient to eccrine sweat in detail

Small intestinal enzyme digestion
Small intestinal tract
Cellulose
Stomach Carbohydrates Large intestine
Resistant
starch
Starch
[alpha amylase] [alpha amylase]
Oligosaccharides
Lactose Disaccharides Trisaccharides Monosaccharide
[dextrinase,
[lactase]
maltase,sucrase glucoamylase]
Glucose Fructose Galactose

absorption
Intestinal
Image 1 - Carbohydrate enzyme digestion in the small intestinal tract
Page 9
danny.kunz@gmx.de
Large intestinal microbiome pathways regarding carbohydrates and

proteins
Glucose, Fructose
Carbohydrates,
Hexosen
Pyruvate Oxaloacetat
Acetate Acetyl-CoA Lactate Succinate
Leucine Acetoacetyl-CoA Lactoyl-CoA Succinyl-CoA
Proteins Lysine Crotonyl-CoA Propionyl-CoA
Valine Butyryl-CoA Propionate
Butyrate
Image 2 –Bacterial metabolic pathways in large intestinal tract
Page 10
danny.kunz@gmx.de
Intestinal short chain fatty acids to liver transport
Propionate
Acetate
Butyrate
Propionate
Acetate
Butyrate
Image 3 - Large intestines to liver salt transport
Intestinal epithel transport
Propionate
Acetate
Butyrate
Propionate
Acetate
Butyrate
Image 4 - Intestinal salt to blood plasma transport
Page 11
danny.kunz@gmx.de
Liver
Butyrate
Butyryl-CoA
Propionyl-CoA
Succinyl-CoA
Image 5 - Normal liver butyrate metabolism
Liver metabolism with isobutyryl dehydrogenase deficiency
Butyrate
Acidosis
Butyryl-CoA Butyric acid

Butyryl
dehydrogenase
deficiency
Propionyl-CoA
Succinyl-CoA
Image 6 - Liver butyrate metabolism in organo aciduria cases
Page 12
danny.kunz@gmx.de
Liver metabolism with assumed [ACSS/ACSM] deficiency
Butyrate Butyrate
ACSS deficiency
Butyryl-CoA No acidosis
Propionyl-CoA
Succinyl-CoA
Image 7 - Liver butyrate metabolism with ACSS/ACSM enzyme deficiency
Butyrate blood plasma flow after liver fails to reduce them
Eccrine sweat glands
Page 13
danny.kunz@gmx.de
Comparison organic acidurias like Biotin Deficiency and assumed

ACSS/ACSM deficiency
Biotin deficiency
Leucine Butyrate
Isovaleryl-CoA Butanoyl-CoA
β -Methyl-
Crotonyl-CoA
crotonyl-CoA
[EC 6.4.1.4 MCCC] [EC 4.2.1.17 ECH]
Fatty acid
Lactate β -Methyl- 3-Hydroxy-
biosynthesis
glutaconyl-CoA butanoyl-CoA
Acetaldehyde
Malonyl-CoA
β -Hydroxy-β-
methylglutaryl-
[EC 1.2.1.3] CoA
[EC 1.1.1.27 LD]
Acetate
Acetoacetate
Glycolysis H+
Acetoacetyl-CoA
Pyrovate [PC]
Acetyl-CoA
[EC 4.1.1.32 GTP]
Oxaloacetat α-Ketoglutarate
Malate Succinyl-CoA
Fumerate
Succinate
Methyl-malonyl-
CoA
2-Methyl-
malonyl-CoA
[EC 6.4.1.3 PCC]
Propionyl-CoA
Propionate
Image 8 - Compromised metabolic pathways in biotin deficiency
Page 14
danny.kunz@gmx.de
ACSS/ACSM deficiency
Fatty acid
biosynthesis
Ethanol Malonyl-CoA Butyrate

[EC 6.2.1.2 ACSM]
Lactate Acetaldehyde
Butanoyl-CoA
[EC 1.2.1.3]
Acetate
[EC 1.1.1.27 LD] Crotonyl-CoA
[EC 6.2.1.1 ACSS]
Glycolysis 3-Hydroxy-
Acetoacetyl-CoA
butanoyl-CoA
Pyrovate Acetyl-CoA
Oxaloacetat α-Ketoglutarate
Malate Succinyl-CoA
Fumerate
Succinate
Methyl-malonyl-
CoA
2-Methyl-
malonyl-CoA
Propionyl-CoA
[EC 6.2.1.1 ACSS]
Propionate
Image 9 - Compromised metabolic pathways in ACSS/ACSM deficiency
Page 15
danny.kunz@gmx.de
Isovaleric acidemia
Leucine
Cell cytosol
Leucine
[EC 2.6.1.4.2]
4-Methyl-2-
oxopentanoate
[EC 1.2.4.4]
3-Methyl-1-
ThPP
hydroxybutyl-ThPP
Lipoamide-E
[EC 1.2.4.4]
[EC 1.8.1.4] S-(3-Methyl-

H+ butanoyl)-
dihydrolipoamide-E Mitochondria
Dihydro-
lipamide-E [EC 23.1.168] Carnitine Carnitine
3-Methyl-butanoyl-CoA [Carnitin Acyl Transferase II]

[Carnitin Acyl Transferase I]
3-Methyl- 3-Methyl- 3-Methyl-butanoyl-CoA
butanoyl- [EC 1.3.8.4 IVD]
[EC 3.1.2.20]
Carnitine bleeding
butanoyl-
stops Carnitine Carnitine
Carnitintransporter
to work
3-Methyl-butanoate
3-Methyl-crotonyl-CoA
3-Methyl-butanoate
3-Methyl-
butanoyl-Carnitine
Image 10 - Isovaleric acidemia metabolic pathway in detail
 Overload with H+
 Carnitin drainage
 Isovalerate production (3-Methyl-butanoate) which is emitted in urine and eccrine sweat
glands
 Time to smell is about 7-30 days in high acid situations, otherwise no strong smell is known
o Much higher smell rate than in Bromhidrosis patients, which needs several months
to smell
 Defects are in all mitochondria
o Leucine is synthesized from muscle cells in extreme exercise situations, so the body
can be flooded by the whole cell system / in ACSS situation only the liver can get
butyrates from the large intestinal tract
 Urine is loaded in case the whole body produces leucine
 50% of cases don’t show isovalerate levels in urine
o Carnitin levels are debleeding within cells, so the mitochondria is unable to produce
energy
Page 16
danny.kunz@gmx.de
Difference in IVA between Nutrient induces Leucine overload and muscle protein induced
Leucine overload
 Muscle induced will affect the whole body
o Urine will contain a lot
 Nutrient overload will mainly affect the liver
o Urine will contain metabolites transiently
Page 17
danny.kunz@gmx.de
Discussion regarding the existence of apocrine Bromhidrosis

Facts and assumptions of the apocrine Bromhidrosis theory recaptured
 Fact is that there is no evidence for bacteria being involved
 Triglycerides emitted by the apocrine glands are not elevated in comparison between
Bromhidrosis and non Bromhidrosis patients
 That the apocrine glands are producing the fatty acids is a pure assumption based on the
idea, that eccrine glands do only emit water and salts
Phenomena by apocrine Bromhidrosis patients which contradicts the

theory
Hyperhidrosis with increased Lactate plasma levels
Similar symptoms and differentiation to Lactate acidosis

 Both groups have Hyperhidrosis, since the lactate blood level is the main regulating factor for
the eccrine gland cells
 Acidosis happens e.g. if lactate is converted into pyruvate and pyruvate is using the acetyl-
CoA pathway (e.g. not enough oxygen available) which produces H+ cation, which changes
the blood plasma pH.
 Acidosis does not happen if pyruvate can be normally metabolized to oxaloacetate
Alternative Lactate producing intestinal pathway for carbohydrates and sugar similar to
the Butyrate pathway
 Similar pathway of butyrates and lactates both based on pyruvate path
Page 18
danny.kunz@gmx.de
Discussion about the metabolic relationship of acetate overload to

Trimethylaminuria of type 2
Discussion regarding reported Trimethylamine type 2 odors
Discussion of reported smell types of positive tested TMAU2 patients
The UCL dietary unit (Dr. Lachmann) did a research of the type of smells positive tested TMAU
patients recognize.
1
Abbildung 2 - TMAU webinar with dietitians of the UCL unit
The most prominent recognized smell was fecal.
A fecal smell is based on multiple families of chemicals:
 Amines (Trimethylamine, Dimethylamine, Indole)

 Thiols (methylmercaptan)
 sulfides (dimethylsulfide)
 short chain fatty acids (butyric acid, valeric acid, propionic acid)
So it is obvious, that if such smell occurs in patients of such a statistical group, that the emitted
chemicals have a broader range than only trimethylamine.
1
https://www.youtube.com/watch?v=wB3zN5JkD2I
Page 19
danny.kunz@gmx.de
That means that people having “apocrine” Bromhidrosis (which in fact is eccrine) will have mostly the
short chain fatty acid smells, where people having a genetic defect in the fmo3 enzyme will mostly
have amines, sulfides and scatols in their sweat.
Some of the TMAU2 patients with fecal odor will have an overall reduced efficiency of the liver, for
one or multiple reasons - reasons which are possibly individual or common over all patients.
Nevertheless is the role of thiols and short chain fatty acids not to be underestimated. If
underestimated it has to be calculated with a high damage such people inflict in buildings, public
transports and so on without having a change getting a hospital place for their illness and where they
could were protection clothes known by laboratory workers (they protect normally the inside from
the outside but it works the other way around the same).
In fact people are basically criminalized, since they will be legally responsible for damages as long as
they can’t show that those damages are based on an illness.
Page 20
danny.kunz@gmx.de
Transient histamine intolerance syndrome in combination with reduced

choline degradation pathway
Secondary overload of the EC 1.2.1.3 and EC 1.2.1.5 enzyme results in increased levels of
Histamine and decreased S-Adenosyl-Homocysteine production
reduction of acetate
overload
[EC 1.2.1.3 EC 1.2.1.5]
1
enzyme overload
Acetaldehyde Acetate
2
Histamine [EC 1.4.3.22 DAO] [EC 1.2.1.3]
Imidazole- Imidazole-4-
S-Adenosyl-
acetaldehyde acetate
methionine
[EC 2.1.1.8 HNMT]

S-Adenosyl-
homocysteine
N-methyl-
histamine
Methyl-
imidazole-
acetaldehyde
[EC 1.2.1.5]
Methyl-
imidazole-
acetic acid
Image 11 - Secondary overload of EC 1.2.1.3 and EC 1.2.1.5 enzymes results in Histamine overload and inhibited S-
Adenosyl-Homocysteine regeneration capabilities
 increased Histamine levels in cells will induce Migraine in many individuals when cells release
Histamine
 Headaches are known from high alcoholic consumption which overloads the EC 1.2.1.3 and
EC 1.2.1.5, too, since ethanol is degraded to Acetate
 Imidazole-acetaldehyde inhibits DAO
 DAO is mostly excreted in the intestinal tract
 HNMT is available in liver
Page 21
danny.kunz@gmx.de
Reduced S-Adenosyl-Homocysteine production results in low Homocysteine

regeneration with a reduced Choline and Betaine degradation pathway
Propionyl-CoA
Cysteine
Cystathionine
2
Serine Histamine
S-Adenosyl-
methionine
4 3 S-Adenosyl-
[EC 2.1.1.8 HNMT]
homocysteine
Choline Homocysteine
Primary
homocysteine
Betaine production N-methyl-
betaine- pathways in liver
[EC 1.2.1.8] histamine
aldehyde
[EC 2.1.1.5 BHMT]
Methyl-
imidazole-
Dimethyl acetaldehyde
glycine [EC 1.2.1.5]
Methyl-
Methionine imidazole-
acetic acid
Image 12 - Reduced Homocysteine regeneration in liver leads to increased Choline and Betaine levels
Page 22
danny.kunz@gmx.de
Decreased small intestinal choline absorption based on affected Choline

degradation pathway leads to higher Choline levels in the large intestinal
tract and to a higher TMA production
Small intestinal
tract
Choline
Choline
betaine-
aldehyde
[EC 1.2.1.8]
betaine
betaine
[EC 2.1.1.5 BHMT]
dimethylglycine Vitamine
B12
sarcosine
Large intestinal glycine
tract
serine
pyruvate
Choline
betaine
[Choline TMA lyase]
[betaine reductase]
Trimethyl Trimethyl
amine amine
[FMO3]
TMAO
Image 13 - Increased TMA production in the large intestinal tract based on a reduced Choline absorption in the small
intestinal tract
Page 23
danny.kunz@gmx.de
High histamine levels in specific days in menstruation cycle correlate with

high TMA levels
 Histamine levels are increased in menstruation cycle days with high estrogen levels
 This based on the fact, that the histamine is released from the cells into the blood stream.
Therefore the histamine is unavailable for the cell metabolism to create S-Adenosyl-
homocysteine, which leads to increased choline levels.
Cell
Histamine Histamine
[EC 2.1.1.8 HNMT]
N-methyl-
histamine
Reduced histamine levels after antibiotics intake for several days

 Antibiotics (polymyxin) do force a release of histamine
High Histamine levels induce increased HCL production in pancreas which leads to a
reduction of amylase enzymes
 High histamine
 Stimulus for more gastric acid production
 To low ph destroys enzymes like amylase
 Amylase breaks down carbohydrates in small intestina
 Large intestinal bacteria get to much carbohydrates
 Higher bacterial chemical production…especially more SCFAs
DAO inhibition after high Histamine levels

 In some reports of people with Histamine intolerance syndrome, the DAO was unable to
catalyze reactions, but after a period of time with a histamine diet, the DAO functions
recovered
Page 24
danny.kunz@gmx.de
 Is there possibly a inhibition after the first high histamine load given, which inactivates the
DAO and possibly the HNMT, too? So people would get stuck in this pathway?
Page 25
danny.kunz@gmx.de
High Indole levels based on a inhibited Tryptophan degradation pathway

and transporter
Small intestinal
tract
Tryptophan Tryptamine
Tryptophan
[EC 1.13.1111, EC 1.13.1152]
Indole-3-
N-Formyl- acetaldehyde
kynurenin
[EC 1.2.1.3]
[EC 3.5.1]
Indole-
acetate
Kynurenin
[EC 1.14.13.9] 3-hydroxy-
3-hydroxy- anthranilat
Large intestinal kynurenin
[EC 3.7.1.3]
[EC 1.13.11.6]
tract 2-amino-3-
carboxymuconat-
6-semialdehyde Quiniolate
[EC 4.1.1.45]
2-amino-
muconate-
semialdehyde Picolinate
[EC 1.2.1.3, EC 1.2.1.5]
2-amino-
Tryptophan
muconate
Indole
Indole 2-oxoadipate
[P450]
Indoxyl
Glutaryl-CoA
Indole-3-
sulfat
Crotonyl-CoA
3-Hydroxy-
butanoyl-CoA
Acetoacetyl-CoA
Image 14 - Inhibited Tryptophan degradation leads to accumulation of indole in the large intestinal tract and liver
 Increased indole levels

 If EC 1.2.1.5 is primary deficient, a stronger indole (smell) with no sour smell is expected
 Difference between EC 1.2.1.3 and EC 1.2.1.5 is where they are produced. (One within
mitochondria, one in cytosol)
Page 26
danny.kunz@gmx.de
Low Cysteine levels will result in reduced EC 1.2.1.5 and EC 1.2.1.3 enzyme
regeneration
 Cysteine is a building block of the aldehyde dehydrogenases
 A chronical Cysteine depletion like in Cysthationinuria will reduce the EC 1.2.1.5 and EC
1.2.1.3 levels
Propionyl-CoA
α-Ketobutyrate
1 [Cystathionase]
Cysteine
Cystathionine
3
Histamine
Serine
S-Adenosyl-
methionine
4 2 S-Adenosyl-
[EC 2.1.1.8 HNMT]
homocysteine
Choline Homocysteine
Primary
homocysteine
Betaine production N-methyl-
betaine- pathways in liver
[EC 1.2.1.8] histamine
aldehyde
[EC 2.1.1.5 BHMT]
Methyl-
imidazole-
Dimethyl acetaldehyde
glycine [EC 1.2.1.5] Cysteine
dependent
Methyl- enzyme
acetic acid
Image 15 – Cysteine depletion in Cysthationinuria
Page 27
danny.kunz@gmx.de
Citrullinuria
Cell cytosol
Arginin [ASL]
Argininosuccinate
Limiting enzyme in urea cycle
[ASS]
Aspartate
N-Acetyl- Putrescine Ornithine

Citrullin
Putrescine
[EC 1.4.3.22 DAO]
4-Amino-
[EC 1.4.3.4] butanal
[EC 1.2.1.3]
N4-Acetyl-
GABA
aminobutanal Mitochondria
[EC 1.2.1.3]
N4-Acetyl- Ornithine Citrullin

amino-
butanoate
[OTC]
Image 16 - Citrullinuria based on a inhibited EC 1.2.1.3 or DAO enzyme
 Citrullin should be raised in Urine (Aminoacid analysis), since the second Ornithine
degradation path is inhibited and the Urea cycle has its limiting capacity in the ASS enzyme.
Further involved metabolic pathways effects

EC 1.2.1.3 inhibition
Expected Halitosis of Putrescin and reduced GABA levels
Putrescine
4-Amino-
butyraldehyde
[EC 1.2.1.3]
GABA
Page 28
danny.kunz@gmx.de
 Putrescin has a very unpleasant smell of dead cells
Expected increased Indole-3-acetaldehyde levels
Tryptophan
Tryptamine
NH3
Indole-3-
acetaldehyde
[EC 1.2.1.3]
Indole-
acetate
 Indole smells like fecal
Expected higher aldehyde levels after resorption of alcohol leads to higher cancer risk
1-Alcohol
[EC 1.1.1.1]
Aldehyde
[EC 1.2.1.3]
Fatty acid
Image 17 - Alcohol degradation inhibited with overloaded EC 1.2.1.3
 Alcohol degradation is lowered by already overloaded EC 1.2.1.3

 Alcohol itself can overload the EC 1.2.1.3 which results in head ache, very likely induced by
raised histamine levels
Page 29
danny.kunz@gmx.de
EC 1.2.1.5 inhibition
Reduced Dopamine, Noradrenaline and Adrenaline degradation
Dopamine Noradrenaline Adrenaline
[EC 1.2.1.5]
[EC 1.2.1.5] [EC 1.2.1.5]
Homovanillate Vanillylmandelic
acid
Image 18 - Dopamine, Noradrenaline and Adrenaline degradation issue in EC 1.2.1.5 enzyme defect
 If acetate is passing the blood brain barrier, it would affect the dopamine degradation
 A dopamine effect should only take place, if the EC 1.2.1.5 enzyme itself is dysfunctional,
which would result in Schizophrenia
 Vergleich zu COMT Enzym (EC 2.1.1.6), an dem als Dopaminabbau enzym bzgl. Schizophrenie
geforscht wird ;Solomon Snyder, Johns Hopkin University
Page 30
danny.kunz@gmx.de
Increased Thyroid Stimulating Hormone (TSH) levels in blood plasma
Tyramine
[EC 1.4.3.4, EC 1.4.3.21]
4-Hydroxy-
phenyl-
acetaldehyde
[EC 1.2.1.5]
4-Hydroxy-
phenyl-acetate
[EC 1.2.3.13 ???]
4-Hydroxy-
phenyl-
pyruvate
[EC 2.6.1.1, EC 2.6.1.5]
Tyrosine
[EC 1.11.1.8]
L-Thyroxine
Image 19 - Inhibited Tyrosine degradation pathway
 L-Thyroxine production is inhibited

 TSH production is increased to stabilize the amounts of L-Thyroxine being produced
Page 31
danny.kunz@gmx.de
Acetate neogenesis and the Acetyl-CoA metabolism

 Glucose transport into cells will increase the Acetyl-CoA amount
 Acetyl-CoA can be recycled to keto bodies or acetate
 As a result, every Acetyl-CoA will produce acetate as buffer over EC 3.1.2.1 but will be
regenerated to Acetyl-CoA in much smaller amounts.
 Acetate will build up in times of energy peaks
Fatty acid
biosynthesis
Ethanol Malonyl-CoA
Lactate Acetaldehyde
[EC 1.2.1.3]
Acetate
[EC 1.1.1.27 LD]
[EC 6.2.1.1 ACSS]
Glycolysis
[EC 3.1.2.1]
Pyrovate Acetyl-CoA
Image 20 - Acetate neogenesis
Insulin and Glucagon effects on Acetyl-CoA generation within cells

 High Insuline levels will result in a higher glucose absorption by cells, which increases the
Acetyl-CoA load
 Glucagon will increase the buildup of triglyceride stores
 Based on the high Acetate levels over time, there will be continuous generation of Acetyl-
CoA based on the cumulated amount of Acetate.
 Glucose will be reduced into Acetyl-CoA in smaller amounts, so blood levels should decrease
only slowly.
 Insulin will be kept high due to the decreased glucose consumption
Decreased glucose resorption results in glucose malabsorption in the small

intestinal tract
 Glucose transporter is reduced
 Glucose will not be absorbed fully in the small intestinal tract
 Increased bacterial activity, which results in higher H2 leves
 Higher H2 Levels will result in higher Acetate genesis via bacteria (Acetogens)
 High pancreatic acid levels will result in better pH environment (low pH) within the small
intestinal tract, which favorites acetogens related to sulfur and methan producing bacteria
Page 32
danny.kunz@gmx.de
Environmental intereffects with the butyrate emission of the eccrine

sweat glands
Clothes
Polyester clothes do absorb butyric acid and release it again. So they get contaminated faster than
natural fiber clothes. Nevertheless every type of clothes material will be contaminated over time.
Washing machine
Modern washing machines have a plastic tub. Plastic does absorb butyric acid and releases it again –
so it can be contaminated with butyric acid over time.
Buildings / Apartment / Workplace
Page 33
danny.kunz@gmx.de
Dietary options to reduce the amount of acetate, propionate and

butyrate resorbed into the blood plasma
Reduce the amounts produced in the large intestinal tract by microbes
 Avoid…
o Resistant starch
o Dietary fiber
 corn
 Salad
 Vegetables2
o Proteins containing large amounts of
 Lysine
 Valine
 Leucine
 Isoleucine
o Combinations of nonliquid fats with carbohydrates3
Reduce the amounts resorbed in the small intestinal tract

o Butyrate containing foods
 (Soft-) Cheese
 Butter
o Acetate
 Vinegar
o Propionate
 E280 (Propionic acid)
 E281 (Natrium propionate)
 E282 (Calciumpropionate)
 E283 (Kaliumpropionate)
Increase the amounts of energy rich foods with no increase of SCFAs in

blood plasma
 Increase intake of
o Vegetable oils
 Sunflower oil
 Rape seed oil
 Supplements
o Amylases4
o Proteases5
o Cellulase6
2
Only the cellulose is problematic, so to juice vegetables, removing the resulting cellulose would work
3
Fats will surround carbohydrates and reduce area amylase can break them down, so they will travel with the
fat into the large intestinal tract easier
4
Since gastric acid production is too high, more amylase is degradet and carbohydrates should not reach the
large intestinal tract
5
Proteins containing Lysine, Leucine, Isoleucine and Valin should not reach the large intestinal tract
Page 34
danny.kunz@gmx.de
o Medical clay7
Reduce the amount of acetogenesis

 Avoid Monosaccharides (Sugar)
 Avoid eating of proteins in combination with carbohydrates
o Better combine carbohydrates with a lots of oil8
6
Cellulase cannot be broken down by normal digestive enzymes but cellulose should not reach the large
intestinal tract
7
Reduces the resorption of nutrients in epithelia cells and microbes
8
Oils and fats a degraded into same amounts of Acetyl-CoA as well as Succinyl-CoA which makes the Acetyl-
CoA being processed by the TCA-cycle
Page 35
danny.kunz@gmx.de
Other things
 Acetaldehyde / all aldehydes
o are listed as carcinogen9
 Disulfiram10
o Disables EC 1.2.1.10 Acetaldehyd dehydrogenase
o Alcohol leads to direct strong hangover effects
 Hypermethioninuria11
o Smell of boiled cabbage in sweat, urine, breath
o Can occur with homocystinuria, tyrosinemia, galactosemia
 Methionine deficiency leads to hepatic fat accreation12
9
https://en.wikipedia.org/wiki/Acetaldehyde
10
https://en.wikipedia.org/wiki/Disulfiram
11
See genetics home reference for hypermethioninemia
12
https://www.ncbi.nlm.nih.gov/pubmed/25561085
Page 36
danny.kunz@gmx.de
Volatiles
 Indole
o Intense fecal odor13
 Butyrate / butyric acid
o Biting sweat like smell, especially when it gets contact with water
 Acetate / acetic acid
o Sour smell
 Putrescine
o Dead and rotting cells / like infection
o Humans have a natural avoidance instinct towards this chemical, since it signals
infections
13
https://en.wikipedia.org/wiki/Indole
Page 37
danny.kunz@gmx.de
Further research themes

Secondary markers for plasma butyrate overload
Increased TSH in blood plasma
Butyrates do bind T3 or T4 which results in an increased thyroid production levels, which is shown as
increased TSH without increased T3 or T4 levels (latent Hypothyreose)
There are two reasons why TSH wents up:
 Thyroid cells are destroyed/reduced, so that the resulting cells have to have a higher
production level to hold the T3/T4 levels
 T3/T4 is bound somewhere in the body and the thyroid has to increase production to hold
the T3/T4 levels
Decreased BDNF in blood plasma

Butyric acid is a HDAC Inhibitor – Body reduces BDNF since there is already a HDI in place
Secondary marker for nitrogen compounds in blood based on FMO3 enzyme

defect
Citrullinemia
Possible dietary supplements helping to reduce the carbohydrate digestion

 Phaseolin (known as carbohydrate blocker to reduce body weight)
Possible medication reported in helping to reduce the Trimethylamine

effects
Desmopressin
 Vermindert die Ausscheidung von Wasser in der Niere
 Durch erhöhtes Wasser im Blutplasma erniedrigt sich der Elektrolythaushalt. Dadurch
verringern die ekkrinen Drüsen die Ausscheidung von Elektrolyten
Black Seed Oil (Nigella Sativa)14

 Insuline increasing effects
 Reduces glucose absorption from intestinal tract
Decreased sugar breaking enzymes in the intestinal tract like in lactase

intolerance
14
Ahmad, P. 340
Page 38
danny.kunz@gmx.de
Images
Image 1 - Carbohydrate enzyme digestion in the small intestinal tract ................................................. 9
Image 2 –Bacterial metabolic pathways in large intestinal tract .......................................................... 10
Image 3 - Large intestines to liver salt transport .................................................................................. 11
Image 4 - Intestinal salt to blood plasma transport .............................................................................. 11
Image 5 - Normal liver butyrate metabolism ........................................................................................ 12
Image 6 - Liver butyrate metabolism in organo aciduria cases............................................................. 12
Image 7 - Liver butyrate metabolism with ACSS/ACSM enzyme deficiency ......................................... 13
Image 8 - Compromised metabolic pathways in biotin deficiency ....................................................... 14
Image 9 - Compromised metabolic pathways in ACSS/ACSM deficiency ............................................. 15
Image 10 - Isovaleric acidemia metabolic pathway in detail ................................................................ 16
Image 11 - Secondary overload of EC 1.2.1.3 and EC 1.2.1.5 enzymes results in Histamine overload
and inhibited S-Adenosyl-Homocysteine regeneration capabilities ..................................................... 21
Image 12 - Reduced Homocysteine regeneration in liver leads to increased Choline and Betaine levels
............................................................................................................................................................... 22
Image 13 - Increased TMA production in the large intestinal tract based on a reduced Choline
absorption in the small intestinal tract ................................................................................................. 23
Image 14 - Inhibited Tryptophan degradation leads to accumulation of indole in the large intestinal
tract and liver ........................................................................................................................................ 26
Image 15 – Cysteine depletion in Cysthationinuria............................................................................... 27
Image 16 - Citrullinuria based on a inhibited EC 1.2.1.3 or DAO enzyme ............................................. 28
Image 17 - Alcohol degradation inhibited with overloaded EC 1.2.1.3 ................................................ 29
Image 18 - Dopamine, Noradrenaline and Adrenaline degradation issue in EC 1.2.1.5 enzyme defect
............................................................................................................................................................... 30
Image 19 - Inhibited Tyrosine degradation pathway ............................................................................ 31
Image 20 - Acetate neogenesis ............................................................................................................. 32
Image 21- Pathway map ........................................................................................................................ 40
Image 22 - Induced HNMT histamine overload by acetate reduction ................................................. 42
Image 23 - Assumed compromised pathways with BHMT deficiency .................................................. 43
Page 39
Plasma butyrate, propionate and acetate overload induced pungent body odor emission danny.kunz@gmx.de
Pathway map
TMAU2 Indole-3- Indole-
FECAL acetaldehyde acetate
Tryptamine
[EC 1.2.1.3]
Apocrine
Tryptophan 2-amino-3- 2-amino- Bromhidrosis
carboxymuconat- muconate- 2-amino-
... semialdehyde
6-semialdehyde muconate
... [EC 4.1.1.45] [EC 1.2.1.3]
Butyrate
Kynurenin
[EC 6.2.1.2 ACSM]
Quiniolate Picolinate Butanoyl-CoA

Propionyl-CoA
[EC 4.4.1.1]
Cysteine Pyruvate
[EC 4.4.1.1] NH3 H2S
...
Crotonyl-CoA
Apocrine
Cystathionine Bromhidrosis
3-Hydroxy- Valine
butanoyl-CoA
Pyruvate ...
Isobutyryl-CoA Propionate
Glutamate Acetoacetyl-CoA
Serine Ethanol [EC 6.2.1.1 ACSS]
...
TMAU 2
ACETIC Methyl- Propinoyl-CoA
Acetaldehyde malonate- [EC 1.2.1.27]
5,2- semialdehyde
Glutathione L-γ-Glutamylcysteine
Methylene- [EC 1.2.1.3]
[EC 1.2.1.3]
THF Acetate
[EC 6.2.1.1 ACSS]
[EC 1.2.1.3, EC 1.2.1.5] Methyl-

Acetyl-CoA [EC 6.4.1.3]
malonate
enzyme overload
[EC 2.1.2.10] Acetaldehyde
[EC 3.1.2.1] [EC 6.2.1.1]
[EC 6.2.1.x ???]
S-Amino- THF
Lipoylprotein methyldihydro- TCA
lopoylprotein Histamine [EC 1.4.3.22 DAO] [EC 1.2.1.3] [EC 5.1.99.2] [EC 5.1.99.1]
cycle
Imidazole- Imidazole-4- Succinyl-CoA R-Methyl- S-Methyl-
S-Adenosyl-
acetaldehyde acetate malonyl-CoA malonyl-CoA
methionine
TMAU2
FISHY Glycine [EC 2.1.1.8 HNMT]
S-Adenosyl-
homocysteine
Homocysteine
Primary
betaine- homocysteine
Choline aldehyde Betaine production N-methyl-
[EC 1.2.1.8] pathways in liver
Acetylcholine histamine
[EC 2.1.1.5 BHMT]

Dimethyl Methyl-
glycine imidazole-
acetaldehyde
CDP-choline Sarcosine
Phosphocholine [EC 1.2.1.5]
Methyl-
Lecithin acetic acid
S-Adenosyl-
homocysteine
[EC 2.1.1.17 PEMT]
Dimethyl-
Phosphatidyl- S-Adenosyl-
ethanolamine methionine
Homocysteine
S-Adenosyl-
[Ptdss1]
homocysteine
[EC 2.1.1.17 PEMT]
Monomethyl- S-Adenosyl-
Phosphatidyl- methionine
ethanolamine S-Adenosyl-
homocysteine
[EC 2.1.1.17 PEMT]
S-Adenosyl-
methionine
Phosphatidyl- Phosphatidyl-L-
L-Serine ethanolamine
Image 21- Pathway map
Page 40
danny.kunz@gmx.de
To investigate
PGC-1α
 ROS,RNS
 Cold exposure
 Endurance exercise
o Determines lactate metabolism
 cAMP / CREB
 Protein kinase B
 SIRT1
o Induces gluconeogenesis
 Proposed β-aminoisobutryric acid (BAIBA) as messenger molecule; increase PGC-1a in white
fat
BAIBA seems to increase metabolism in fat cells via PPARα receptors;regulation of insulin and
triglycerides and cholesterol
BAIBA is produced in the catabolism of Thymine
Insuline
 Insuline decreased blood sugar (cells are taking the glucose up)
 Glucagon increased blood sugar
 Kohlenhydratreiche Nahrung -> Insulin ins Blut ausgeschüttet -> cells are taking up glucose
and save it as glycogen or use it as energy source (glykolyse)
 Einfluss auf Fettstoffwechsel (hemmt Lipolyse/abbau von fett)
 Insulin hemmt die hepatische Gluconeogenesis
Page 41
danny.kunz@gmx.de
Obsolete
Secondary N-Methyl-Transferase overload based on overloaded
diamineoxidase pathway
reduction of acetate
overload
[EC 1.2.1.3]
enzyme overload
Acetaldehyde Acetate
Histamine [EC 1.4.3.22 DAO] [EC 1.2.1.3]

Imidazole- Imidazole-4-
acetaldehyde acetate
[EC 2.1.1.8 HNMT]
N-methyl-
histamine
Image 22 - Induced HNMT histamine overload by acetate reduction
Butyrate halftime in blood plasma induced right axillary Bromhidrosis with

no left axillary Bromhidrosis
 Sodium butyrate has a half time of 7 minutes in blood plasma
 Blood flow speed
o Aorta 40cm/s
o Capillaries 0,03 cm/s
o Vena 15 cm/s
 Result are a significant butyrate blood plasma gradient from the right side after the liver to
the left side at the intestinal tract
Page 42
danny.kunz@gmx.de
Assumed BHMT enzyme deficiency with a resulting increased TMA level in

the large intestinal tract
Small intestinal
tract Choline
Choline
betaine-
aldehyde
[EC 1.4.3.22 DAO]
betaine
Histamine Imidazole-
betaine Shared genes / Same acetaldehyde
[EC 2.1.1.5 BHMT] enzyme group [EC 2.1.1.8 HNMT]
dimethylglycine
N-methyl-
Vitamine
B12 histamine
sarcosine
Large intestinal tract glycine
serine
pyruvate
Choline
Dimethyl-
betaine
sulfide
[Choline TMA lyase]
[betaine reductase]
Methyl-
thioether Trimethyl Trimethyl
amine amine
Methyl-
mercaptan [FMO3]
TMAO
Sulfide
Homocystein
Vitamine
Homocystein Serine B12
[EC 2.1.1.5 BHMT]
Cystathionine Methionine
Propionyl-CoA
Image 23 - Assumed compromised pathways with BHMT deficiency
Page 43
danny.kunz@gmx.de
Blocked intestinal sulfide pathway in Cystathioninuria

Liver
Acetyl-CoA
Oxaloacetat
α-Ketoglutrate
Malate Succinyl-CoA
Fumerate
Succinate
Methyl-malonyl-
CoA
2-Methyl-
malonyl-CoA
Propionyl-CoA
Intestinal tract
Acetate
α-Ketobutyrate
Cysteine
Cysteine
[Cystathionase]
Cystathionine
Serine Serine
Homocystein Sulfide
Homocystein
Methyl-
mercaptan
Methyl-
thioether
Dimethyl-
sulfide
Current further known disorders with pungent smell and their relevance in
plasma saturation of volatile substrates
Plasma isobutyryl saturation within patients of Isobutyric acidemia
There are two known organic aciduria disorders (mostly diagnosed in children) which are called
 Isovaleric acidemia15
15
https://en.wikipedia.org/wiki/Isovaleric_acidemia
Page 44
danny.kunz@gmx.de
 Isobutyric acidemia16
In the isovaleric acidemia case, there is an increase of isovaleric acid in the body which is based on
the saturation of Isovaleryl-CoA17 (3-Methylbutanoyl-CoA) of the blocked leucine pathway.
The affected children have been described to have a very prominent and pungent skin smell of
isovaleric acid in acute illness phases.
The same is for children with Isobutyric acidemia, even if the known cases of that disorder are far
less than the isovaleric acidemia cases.
The current known issue of the amino acid disorders is a faulty ACAD818 gene which leads to a
reduced working efficiency of the Acyl-Dehydrogenase enzymes (Isovaleric dehydrogenase,
isobutryic dehydrogenase).
As we later see, that the blocked isobutyryl pathway is basically the reason why precursors like
butyrate can in those cases not be oxidated by the intestinal epithelium and liver into their CoA
bound form. So a saturation of butyrates in the plasma is happening, which are as salts emitted into
the eccrine sweat glands and there producing the pungent odor.
In fact the patients with those amino acid disorders are reported to show those skin smells within a
rough range from 7 up to 30 days (newborns in coma with severe forms and occurring death).
Based on the genetic driven enzyme defect the butyrates are in such cases nowhere in the human
body reduced, even if all mitochondria (all body cells) have those enzymes, not only the liver.
This is would be different to people having a blocked liver pathway for whatever reason. They would
emit butyrates as well, but in a much lower amount and their butyrate level in the blood would not
increase to a toxic level (as with an organic aciduria), since the rest of the human body cells will break
down the butyrates properly.
Just to mention: today for the organic acid disorders a default test is in place thanks to the newborn
screening program, which is the acyl-carnitin-test of dried blood plasma.
It is not clear yet, if this test would be responsive for the lower butyrate level of the other groups of
patients. But perhaps a provocation test (valine, glucose) similar to the TMAU test and with blood
plasma taken close behind the liver would be successful.
16
http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Expert=79159
https://books.google.de/books?id=TpnuCQAAQBAJ&pg=PA391&lpg=PA391&dq=isobutyric+acidemia&source=
bl&ots=gSLWJgfaDs&sig=JOb_t7LQZXdvfXF4EH8G4aUNf9M&hl=de&sa=X&ved=0ahUKEwjTzsWHruTQAhVB5xo
KHYpLA-MQ6AEITjAF#v=onepage&q=isobutyric%20acidemia&f=false
https://www.ncbi.nlm.nih.gov/pubmed/12359132/
17
http://www.genome.jp/dbget-bin/www_bget?C02939
18
https://www.ncbi.nlm.nih.gov/gene/27034
Page 45
danny.kunz@gmx.de
19
Abbildung 3 - Valine, Leucine, Isoleucine pathway
19
http://www.genome.jp/kegg/pathway/map/map00280.html
Page 46
danny.kunz@gmx.de
Free fatty acids emitted from apocrine glands in apocrine Bromhidrosis

For years there is the discussion about the reasons of apocrine Bromhidrosis which is not based on
Hyperhidrosis (Highly increased amount of sweat of the eccrine glands).
Research papers in dermatology where all based on one simple but questionable assumption, that
the eccrine sweat glands, as the only produce water and salt, cannot be the source of any short chain
fatty acid kind of smell. On the other hand, the apocrine glands, which produce triglycerides, which
are precursors for skin bacteria, which for sure produce short chain fatty acids are the only possible
path for gaining a strong smell.
To this day, it was not possible to identify such bacteria or actually show that the SCFAs where based
on bacterial overgrowth. (For many patients even major applications of alcohol or other bacteria
reducing agents did not help at all)
Strong concentrated Aluminiumchlorid agents were used mainly to reduce the produced eccrine
secretion output, which in fact lead to a reduction of bromhidrosis smell, but in many cases it did not
solve the problem really.
The major assumption was that the reduction of water will prevent bacteria to grow.
In fact it might simply be the case, since the dissociation of butyrates into its acid form strongly
depends on the humidity level of the salt, a reduction of humidity would reduce the dissociation of
butyric acid salts into their free acid counterpart.
In their main work “Human Body odor” the brothers Inaka showed, that it is unlikely that skin
bacteria are the main reasons, since they measured the triglyceride precursors and compared the
data from patients with bromhidrosis and non bromhidrosis patients. They stated that there are no
significant differences in triglycerides found. So they assumed the apocrine glands itself would
produce the SCFAs. Based on that assumption their solution was to remove the apocrine sweat
glands by surgery. (No one at this point ever questioned, that if there are no bacteria involved, why it
has to be the apocrine glands to be the fatty acid producers – this is pretty much a flawed
assumption)
In the following will be shown, that those fatty acids on the skin, could be based on eccrine excretion
of butyrates, which then in fact would dissolve into the short chain fatty acid counterparts when
released into the eccrine sweat gland channel.
As butyric acid is in its pure state in low concentration hard to olfactory describe or to localize, it is
highly possible, that it was only perceived in the axilliary region of many patients, where normal skin
bacteria add 3-methyl-hexanoic acid to it after some time. So the “smell” in the axillary regions of
those patients could be a mixture of the butyric (very biting smell, lesser sweaty) acid and the normal
3-methyl-hexaonic acid smell (not biting, but sweaty) of the apocrine gland based microbes.
In fact this was stated by several authors of articles in that subject, that they were not able to select
apocrine or eccrine glands only, since they are too close to each other on the skin surface to separate
the secretions.
Page 47
danny.kunz@gmx.de
The idea, that the apocrine glands are responsible for the smell, seems to be based on the
assumption, that the eccrine glands are only emitting water and salt. This would still be true, with the
only difference, that the salt would be a butyric salt.
Page 48
danny.kunz@gmx.de
Trimethylaminuria Type 2
A disorder known and researched for the last 40 years is the fish odor syndrome
(Trimethylaminuria/TMAU).
There are two types:
 A primary and genetic based form, where the FMO3 liver enzyme has a one of many known
defects, which leads to an increased Trimethylamine (TMA) amount in urine.
 A secondary form, where there is too much TMA in the urine, but this is not based on a faulty
FMO3 enzyme. Reasons are unknown; one of the ideas is that a wrong gut microbiome is
responsible.
Trimethylamine is responsible for a pungent smell of “dead fish”, in fact smells pretty much like
“dead animal” as well as of ammonia like (urine like), depending on the concentration and
combination with other chemicals.
Interestingly patients with positive TMAU tests are reporting various smells like fecal smells, burnt
rubber, urine like smell and more.
So it is obvious, that there are combinations of other chemicals in the sweat secretion of those
patients. Possibly there are different amines or thiols up to skatols involved.
Some patients report a very biting and sour smell, which is very likely not an amine smell, since
amines are alkaline in nature. So there is a probable factor of short chain fatty acids involved as well.
Even if patients report, that they are not able to wash it off from clothes, there is a high probability of
SCFAs being involved, this would make the smell bity and hard to remove in clothes.
The currently main theory or idea is that for the secondary TMAU type, a dysfunctional gut
microbiome is responsible. In fact this would be easy to measure by fecal analysis, which is already in
place by alternative practitioner (e.g. by enterosan laboratory), but no such test cases are known.
Current state of research of liver functionality related to short chain fatty

acids
Page 49
danny.kunz@gmx.de
20
Abbildung 4 - Liver function related to short chain fatty acids
20
http://www.nature.com/nrendo/journal/v11/n10/fig_tab/nrendo.2015.128_F5.html
Page 50

Butyrate Overload Induced Pungent Body Odor Emission - v14

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Butyrate Overload Induced Pungent Body Odor Emission - v14

Uploaded by

Copyright:

Available Formats

Plasma butyrate, propionate and

acetate overload induced pungent body

Dermatologist: The eccrine glands do only produce

Patient: But what if it is butyric acid salt?

Dermatologist: Nooooo, it’s only water and salt! It

Danny Kunz (danny.kunz@gmx.de)

Non final version/work in progress

 A theoretical metabolic pathway based on an assumed deficiency of the EC 6.2.1.2 butyrate

Abbildung 1 - Overview over the butyrate path in the human body

Gastrologist: It’s a bacterial overgrowth thing in the

Patient: So you needed to talk to them all and asked

Butanoate metabolism from nutrient to eccrine sweat in detail

Small intestinal tract

Stomach Carbohydrates Large intestine

[alpha amylase] [alpha amylase]

Lactose Disaccharides Trisaccharides Monosaccharide

Glucose Fructose Galactose

Image 1 - Carbohydrate enzyme digestion in the small intestinal tract

Large intestinal microbiome pathways regarding carbohydrates and

Acetate Acetyl-CoA Lactate Succinate

Leucine Acetoacetyl-CoA Lactoyl-CoA Succinyl-CoA

Proteins Lysine Crotonyl-CoA Propionyl-CoA

Valine Butyryl-CoA Propionate

Image 2 –Bacterial metabolic pathways in large intestinal tract

Intestinal short chain fatty acids to liver transport

Image 3 - Large intestines to liver salt transport

Intestinal epithel transport

Image 4 - Intestinal salt to blood plasma transport

Image 5 - Normal liver butyrate metabolism

Liver metabolism with isobutyryl dehydrogenase deficiency

Butyryl-CoA Butyric acid

Image 6 - Liver butyrate metabolism in organo aciduria cases

Liver metabolism with assumed [ACSS/ACSM] deficiency

Image 7 - Liver butyrate metabolism with ACSS/ACSM enzyme deficiency

Butyrate blood plasma flow after liver fails to reduce them

Eccrine sweat glands

Comparison organic acidurias like Biotin Deficiency and assumed

[EC 4.1.1.32 GTP]

[EC 6.4.1.3 PCC]

Image 8 - Compromised metabolic pathways in biotin deficiency

Ethanol Malonyl-CoA Butyrate

[EC 6.2.1.1 ACSS]

Image 9 - Compromised metabolic pathways in ACSS/ACSM deficiency

[EC 1.8.1.4] S-(3-Methyl-

3-Methyl-butanoyl-CoA [Carnitin Acyl Transferase II]

Image 10 - Isovaleric acidemia metabolic pathway in detail

Discussion regarding the existence of apocrine Bromhidrosis

Phenomena by apocrine Bromhidrosis patients which contradicts the

Similar symptoms and differentiation to Lactate acidosis

Discussion about the metabolic relationship of acetate overload to

The most prominent recognized smell was fecal.

A fecal smell is based on multiple families of chemicals:

 Amines (Trimethylamine, Dimethylamine, Indole)

Transient histamine intolerance syndrome in combination with reduced

[EC 2.1.1.8 HNMT]

Reduced S-Adenosyl-Homocysteine production results in low Homocysteine

Decreased small intestinal choline absorption based on affected Choline

Large intestinal glycine

High histamine levels in specific days in menstruation cycle correlate with

[EC 2.1.1.8 HNMT]

Reduced histamine levels after antibiotics intake for several days

DAO inhibition after high Histamine levels

High Indole levels based on a inhibited Tryptophan degradation pathway