The involvement of acetate, aspartate,
butyrate and enzymatic cofactors in the
HASD CFS/ME model
Authors: Joshua Leisk, Aline Noçon ©2021
Key words: Epstein-Barr Virus (EBV), hyperlactatemia, chronic fatigue syndrome / myalgic
encephalomyelitis (CFS/ME), fibromyalgia, alpha-ketoglutarate dehydrogenase deficiency,
pyruvate dehydrogenase deficiency, herpesvirus autoimmune spectrum disorder
In cells, where mitochondria are utilising glutaminolysis and transamination - whether caused by
normal function or when specifically altered by eg. virally induced overexpression of KGA,
GLS1, GLUD1 and/or GLUD2 - key enzymatic reactions for energy production are reversed
during the transamination of aspartate=>oxaloacetate and α-KG=>glutamate + ammonia,
consuming additional pyridoxal 5-phosphate (P5P).
Excessive glutaminolysis and transamination increases nitrogen / urea burden, while consuming
aspartate, before further consuming acetate and butyrate for increased α-KG=>[..]=>glutamine
disposal via the phenylacetylglutamine (PAGN) pathway to urine. Further, this elevates lactate
and affects neighbouring cell metabolism via the lactate shuttle.
Depletion of acetate could lead to many impaired reactions involving acetyl-CoA, with
implications to beta-oxidation pathways, mitochondrial function, pyruvate:lactate balance and
any pathways that require an acetyl donor, such as choline=>acetylcholine and
Depletion of acetate would cause further dysregulation to the urea cycle (UC), creating an
elevation of glutamate, acting as a rate limiting factor for glutaminolysis and further causing
impairment of mitochondrial Nicotinamide Adenine Dinucleotide (NAD+):NADH redox, favouring
Aspartate depletion also dysregulates production of reactive oxygen species (ROS), sex
hormones, thyroid hormones, alpha-melanocyte-stimulating hormone, GABA and dopamine
Depletion of butyrate dysregulates immune and mitochondrial apoptotic regulation via Nuclear
Factor Kappa B (NF-κB) signalling. It further impacts nitrogen metabolism.
The depletion of NAD+ acts as a rate limiting factor for many enzymatic reactions, including
glutamate dehydrogenase (GDH), further impairing glutamate<=>α-KG metabolism.
We further describe a role for acetate, aspartate, butyrate, P5P and Vitamin B5 in a therapeutic
intervention against the HASD model for CFS/ME.
In “The true nature of an autoimmune disease” we hypothesised a complex, extensible model of
impaired mitochondrial and metabolic disorders in human herpesvirus (HHV) seropositive
CFS/ME as part of a Herpesvirus Autoimmune Spectrum Disorder (HASD).
Our disease model appears compatible with the “IDO metabolic trap” proposed by Kashi A,
Davis R et al., and the PDH deficiencies reported by Fluge et al..
We previously hypothesised a complex disease model, where a metabolic blockade, or loop,
could be induced, resulting as a simultaneous α-ketoglutarate dehydrogenase (α-KGDH) and
pyruvate dehydrogenase (PDH) deficiency, with dysregulated beta-adrenergic signalling
cascade and impaired hepatic gluconeogenesis, phasic hyperlactatemia and hyperammonemia.
We further described a number of interventions for this blockade and known limitations for this
array of therapeutic interventions, where α-ketoglutarate (α-KG) continues to accumulate, as an
untreated artefact of the original disorder, resulting in elevated Urea Cycle (UC) burden and
further contributing to a state of delayed mitochondrial impairment, proportional to previous
Further investigation into therapeutically resolving these remaining impairments has uncovered
an extension to our described disease model. This allows for a more complete understanding
and formation of a comprehensive treatment plan.
The HASD CFS/ME model is primarily based around metabolic impairments caused by
alterations to metabolic behaviour in HHV-infected latent hepatic cells, with further complications
associated with any lytic activity.
Herein, we further extend the HASD model and examine the roles of aspartate, acetate,
butyrate and enzymatic cofactor depletion as causal factors in achieving and / or maintaining
the metabolic blockade previously described.
Aspartate, or aspartic acid is a key metabolite for many enzymatic reactions, including those in
transamination of α-KG to oxaloacetate.
Extending the HASD model, we further propose that in the CFS/ME subtype acetate, aspartate
and enzymatic cofactors are depleted through enhanced rates of hepatic glutaminolysis and
transamination, further altering glucose and lactate metabolism. This may also be
relevant to other infected tissues, as a secondary complication in HASD CFS/ME.
A sequence for glutaminolysis and transamination to oxaloacetate (and malate) is described
1. [Glutamine] into
[glutamate + ammonia],via
2. [Glutamate] into
[α-KG + ammonia],via
[GDH / glutamate pyruvate transaminase (GPT) / glutamate oxaloacetate
3. [Aspartate + α-KG] transaminases into
[oxaloacetate + glutamate], via
[P5P, aspartate aminotransferase (AST)].
4. [Oxaloacetate + NADH + H+] becomes
[malate + NAD+], via
[malate dehydrogenase (MDH)].
EBV, CMV, HHV-6 and Kaposi's sarcoma-associated herpesvirus (KSHV) have all been
demonstrated to rely on glutaminolysis and glycolysis for maintaining latent and lytic
persistence. This was previously mentioned as exhibiting similar traits to Warburg-style
cancer cells and senescent cells.
The depletion of aspartate would cause further dysregulation to the UC at argininosuccinate
(ASA), creating an elevation of systemic nitrogen while limiting transamination.
With Complex V impairment due to elevated α-KG (or α-KGDH deficiency) and transamination,
aspartate deficiency could further cause impairment to Nicotinamide Adenine Dinucleotide
(NAD+):NADH redox, favouring NADH and depleting NAD+.
This depletion of NAD+ acts as a rate limiter for many enzymatic reactions, including glutamate
dehydrogenase (GDH), further impairing glutamate<=>α-KG metabolism.
The depletion of aspartate could also trigger replenishment from (extracellular) pyruvate via
pyruvate carboxylase, altering lactate:pyruvate balance. Pyruvate pathways would be
further confounded by acetyl-CoA depletion, discussed further on, perhaps sustaining
Aspartate depletion could also dysregulate production of ROS, sex hormone synthesis,
thyroid hormone synthesis, alpha-melanocyte-stimulating hormone (α-MSH) synthesis,
melatonin, gamma aminobutyric acid (GABA) and dopamine release.
This may also cause dysregulated energy production, circadian rhythm, unrefreshing sleep,
dysregulation of diurnal cortisol and dysregulation of a-KG levels via compensation by
melatonin-mediated exosome creation.
Skin and hair pigmentation may also be affected, via decreased α-MSH, melatonin, cyclic
adenosine monophosphate cAMP and cyclic guanosine monophosphate (cGMP).
With decreased α-MSH, antimicrobial and anti-inflammatory functions may be impaired against
eg. Candida albicans, Escherichia coli, and Staphylococcus aureus.
Melatonin has also shown beneficial properties against elevated liver enzymes.
Aspartate / aspartic acid exists as both left (L) and right (D) isomers and they each have
different functions in humans. L-aspartate is found in abundance and converted to D-aspartate
on-demand in the liver, heart, lung, stomach, intestines, salivary glands, semen, central nervous
system, knee cartilage, testis, pre-ovulatory ovarian follicle and retinae. A deficiency of
D-aspartate could cause impaired synthesis functions for these organs / tissues.
D-aspartic acid supplementation has yielded mixed results for testosterone production in males.
This suggests a deficiency may act as a rate limiting factor and exogenous dosing to
supraphysiological levels may not have a linear effect for steroidogenesis pathways. However,
the described excitatory effects of D-aspartate against glutamate receptors could prove
problematic in patients with a urea cycle defect, hyperammonemia or HASD CFS/ME.
Based on these factors, further investigation into L-aspartate and NOT D-aspartate as a
potential treatment for CFS/ME patients (and all diseases / disorders suggested as related to
the HASD disease model) could be warranted.
In the HASD CFS/ME model, hyperammonemia (HA) and hepatic encephalopathy (HE) has
been described as partially responsible for encephalomyelitis, with lactatemia being another
Aspartate, in the form of L-ornithine-L-aspartate (LOLA) has been demonstrated to prevent HE,
increasing mental status while decreasing serum and spinal fluid ammonia levels, by increasing
both UC efficiency and glutamine (GLN) synthesis.
Acetate, or acetic acid is another common metabolite in many pathways, including regulation of
systemic nitrogen. Phenylacetate (PA) is a key metabolite in an important nitrogen disposal
pathway via incorporation of glutamine into phenylacetylglutamine (PAGN). See “Figure 1”,
(De Las Heras J et al.).
Acetate, in the form of L-ornithine phenylacetate (LOPA), has been demonstrated to prevent HE
via this same pathway.
In addition to clinical use for UC disorders, PA and its precursor phenylbutyrate (PB) are
known for being histone deacetylase (HDAC) inhibitors. PA and PB also exhibit inconclusive
results for inhibiting various cancers. Butyrate may decrease C-terminal binding protein (CtBP)
and glutaminolysis via SIRT4. HDAC inhibitors, when used in combination with
aldactone to arrest late-stage EBV (and perhaps other HHV) lytic replication, may assist in
reducing HHV latent cell burden.
Fruit vinegars contain acetic acid. They have also been shown to contain unique organic acids,
such as succinic acid. These vinegars have been demonstrated to reduce oxidative stress,
improve metabolism, aid recovery and reduce fatigue by enhancing glycogen repletion in both
rat liver and skeletal muscle post-exercise[11].
With a surprising nod towards claims made by alternative health practitioners, these specific
vinegars which contain organic acids (and other compounds) relate to the therapeutic
interventions previously described. Depending on the fermentation process, these can contain
variable and/or suboptimal amounts to elicit a response].
The fermentation process for each vinegar requires normal activity from the same families of
bacteria which inhabit our gut microbiome. The relationship between the end-products from both
gut microbiome fermentation and vinegar fermentation processes are direct. In both microbial
fermentation processes, depending on the prebiotics, bacteria and nutrient cofactors, the
end-products are highly variable, yet predictable].
Relative to these fermentation variables, a healthy gut microbiome and/or commercial vinegar
may create appropriate organic acid profiles suitable for therapeutic use in HASD CFS/ME. A
more concentrated, powdered vinegar may warrant further investigation for inclusion in a pilot
study. It was shown that 1L of finished apple cider vinegar may contain between 1-1600mg of
succinic acid, typically 5000mg of acetic acid, along with variable amounts of pyruvate, malic
acid, butyric acid, aspartic acid and many other compounds.
Unlike the poorly-understood and chaotic conditions surrounding the human gut microbiome,
creating vinegars is a highly controlled process which uses specific prebiotics (fruits) and a
controlled microbial environment. This leads to a consistent end-product which is analogous to
key activities of a healthy gut microbiome].
High levels of lactate are created as a symptom in the HASD CFS/ME model. Lactatemia
could increase species of gut bacteria such as Escherichia, Klebsiella, Serratia, Vibrio and
Pseudomonas, while also decreasing species of gut bacteria such as Firmicutes, Bacteroidetes,
Faecalibacterium, Roseburia and Eubacterium. This may cause a reduction of circulating
butyrate. Butyrate notably inhibits NF-κB and assists with regulation of systemic
NF-κB is both a proapoptotic and antiapoptotic regulatory factor. Inhibiting NF-κB has been
shown to reverse the Warburg effect, induces apoptosis in both EBV-infected cells and some
cancer cells, as well as decreasing tumorigenesis.
NF-κB controls mitochondrial gene expression, including cAMP response element (CREB)
binding protein (CBP) transcriptional co-activators. NF-κB functions as a catalytic subunit in
Complex IV and can influence enzymatic activity in respiratory electron transport chain (ETC)
complexes. cAMP has also been indicated in the HASD CFS/ME model to have relevance to
hepatic gluconeogenesis and lactate metabolism.
In Alzheimer’s Disease, NF-κB signalling controls amyloid β-induced mitochondrial dysfunction
and was somewhat modulated by creatine.
As butyrate and aspartate are both metabolites for nitrogen disposal via PB=>PA=>PAGN, a
depletion of either could lead to dysregulation of NF-κB signalling and further alterations to
B-cells and CD4+, CD8+T cells. A deficiency of acetate can influence these same
A deficiency of aspartate could also impair microbial secretion of acetic acid, as recently
indicated in the pathogenesis of type 1 diabetes. Dietary intake of high-amylose maize starch
(HAMS) that has been acetylated (HAMSA) or butyrylated (HAMSB) was shown to alter
microbial diversity and affect disease progression.
It was further shown that succinate, acetate and butyrate secretion dramatically increased when
a high-amylose diet was combined with casein, soy or potato proteins, respectively. A
high-amylose and soy protein diet was also shown to reduce blood urea by 42% in rats.
These combined results suggest that an appropriate dietary intake of these food items may
provide beneficial microbiome alterations in HASD CFS/ME and related diseases.
Acetic acid was demonstrated to alleviate dextran sulfate sodium (DSS)-induced colitis in mice,
by inhibiting both interferon (IFN)-γ-producing T helper (Th)1 and IL-17-producing CD4+ effector
cell lineage (Th17) responses, as well as NOD-like receptor protein3 (NLRP3) inflammasomes.
It also activates the mitogen-activated protein kinase (MAPK) signal pathway.
Vinegar / acetic acid was shown to increase AMP-activated protein kinase (AMPK), peroxisome
proliferator-activated receptor γ (PPARγ) and PPARγ coactivator-1α (PGC-1α) in male rats,
modulating spontaneous hypertension. This could have additional relevance for metabolism in
Acetic acid has been demonstrated to selectively induce apoptosis in gastric cancer cells.
Further investigation of acetic acid against latent cell viability may be warranted.
In humans, consumption of vinegar decreased obesity, total cholesterol and triglycerides. It
further improved insulin sensitivity in diabetics and lowered gastric emptying. Additionally, acetic
acid enhanced muscle blood flow and glucose uptake in humans with impaired glucose
tolerance and hypertriglyceridemia. Melanoidins from fruits vinegars reduced ROS in normal
human liver cells, protecting them from oxidative stress through a mitophagy-dependent
Acetic acid can be bound to coenzyme A to produce acetyl-CoA. When acetyl-CoA is combined
with aspartate by neuronal aspartate N-acetyltransferase (NAT8L), N-acetylaspartate is formed.
Acetyl-CoA is also used to create acetylcholine from choline. A reduction of acetylcholine
could impair muscle activation and cognition.
These are just two examples. Impaired acetyl-CoA production could have significant
consequences for the synthesis of the many products requiring acetylation, such as
acetyl-L-carnitine or N-acetylserotonin. Acetyl-L-carnitine is essential for the beta-oxidation of
fatty acids. An impairment to this pathway could result in decreased mitochondrial efficiency
and potentially cause a compensatory effect of increased catecholamine secretion, leading to
postural orthostatic tachycardia syndrome (POTS), dysautonomia and cortisol dysregulation.
Acetyl-CoA can also be synthesised from pyruvate by PDH. Where PDH is also impaired, by eg.
PDH Kinase, an acetyl-CoA deficiency can occur. When combined with an acetate shortage,
deficiencies of N-acetylaspartate and acetylcholine may result, causing cognitive impairment.
In pigs, it has been shown that Acetyl-CoA derived from inflammation-induced fatty acid
oxidation promotes hepatic malate-aspartate shuttle activity and glycolysis. This was
demonstrated via hepatic injections of lipopolysaccharide (LPS), suggesting the existence of a
further extension and additional input to our HASD CFS/ME disease model. This input would
consist of circulating LPS, as secreted from LPS-positive bacteria, and subsequent bowel
permeability issues. Circulating LPS would induce or complicate the same metabolic blockade
via hepatic metabolic alterations and further impair immune response via decreased
CD4+/CD25+ and CD4+/Foxp3.
Figure 1- Flowchart for HASD CFS/ME Model v1.1
(High-resolution available in supplemental files)
Here we have explored a notion that administration of buyrate, aspartate / aspartic acid and
acetate / acetic acid, along with enzymatic cofactors P5P (preferred form of Vitamin B6) and the
CoA precursor, pantothenic acid (Vitamin B5) may alleviate metabolic deficiencies capable of
inducing or sustaining key symptoms described in the HASD CFS/ME disease model
We have further explored how vinegar fermentation processes closely resemble helpful gut
microbiome fermentation processes and how HASD CFS/ME symptoms could negatively impact
the gut microbiome, complicating the disorder.
Specific dietary alterations - increased hydration, reduced protein intake, increased amylose
starch, potatoes, rice, soy and casein may provide long term benefits to HASD CFS/ME
outcomes - moreso, if combined with repopulation of beneficial gut bacteria.
When possibly combined with some of the previously described therapeutic interventions,
these additions may address and ameliorate all hypothesised gaps in the array of discussed
treatment options and therefore allow for a complete remission of HASD CFS/ME symptoms, in
a non-lytic viral state, where the root cause matches the scope of the model.
In veterinary sciences, acetic acid and enhanced hydration has also been mentioned as an
acute intervention for hyperammonemia symptoms, by conversion to a non-toxic form. This
could also prove worthy of investigation for decreasing or arresting acute HE-like symptoms of
post-exercise malaise in HASD CFS/ME.
Further research is needed. Case reports and a pilot study to follow.
With special thanks to J Carlson, S Asnani and M Kaczmarek.
Data Availability Statement
All materials used have been cited. Images were created in Draw.IO and source files to extend
this model are available upon request to the corresponding author.
JL conceived the design and authored the manuscript. AN reviewed methodology, provided
oversight and guidance, expert lab experience, analysis skills, audited / validated citations and
edited the manuscript. All authors critically reviewed the final manuscript.
This work was unfunded and conducted out of human interest.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or
financial relationships that could be construed as a potential conflict of interest. Authors have
previously joint-filed a patent relating to the formulation of a treatment protocol.
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