Fatigue Because of Mold Exposure: Pathophysiology

Illness caused by mold and mycotoxin exposure is
gaining more traction and attention. Because the paradigm shift occurs, mold and
mycotoxin-induced illness should be brought to the forefront of clinical
education, in school curriculum and continuing education. In the busy life
of the clinician, soundbites and snippets of clinical management are considered
gold. The difficulty therein is that MMII is multifaceted, and, as a result, comes
in different forms, including allergy, infection, colonization, mycotoxicosis,
and Chronic Inflammatory Response Syndrome – potentially in addition to
other less defined clinical pictures. Consequently, management of MMII cannot be
reduced into isolated soundbites, lest we aim to overstate and under-deliver,
thus failing case management. A perfect example of this really is fatigue like a symptom
of MMII.

The definition of fatigue, although simple at face value, can
be difficult to truly resolve. It may be considered a standalone symptom, and also the
word itself is often used interchangeably with Chronic Fatigue Syndrome/Myalgic
Encephalomyelitis . Although CFS may include a constellation of
symptoms beyond fatigue, this could still be the sole and major symptom. For that
sake want to know ,, fatigue as a standalone symptom will be examined.
However, there are some key pieces of research that demonstrate the remarkable
interplay between fatigue and mold exposure that the reader ought to keep in
mind. A current article, published in 2023, reported that 39.4% of CFS patients
sampled reported that their the signs of post-exertional malaise were triggered
with a mold exposure.1 Moreover, another study demonstrated that 93%
of CFS patients put together to possess at least 1 mycotoxin within their urine, while
nearly 30% of CFS patients had a lot more than 1 mycotoxin present in their urine.2

However, correlations between fatigue and mold exposure can occur
in real-world cases where CFS/ME isn't the topic of investigation. An individual
case study of 12 people exposed to Alternaria tenuis in in their
workplace reported fatigue as a prominent symptom.3 Moreover, a
study of school children in Malaysia demonstrated a correlation between total
fungal DNA and tiredness in 22.1% of study participants. Further regression
analysis revealed positive associations between the signs of fatigue and also the
presence of Aspergillus versicolor and/or the mycotoxin verrucarol.4
While there are many similar pieces of research in the literature,
one will be hard-pressed to locate an article that goes as far as to investigate
the pathophysiology of the reported fatigue. This is when in-vitro and animal
studies help to fill the data gap.

In the clinical setting, fatigue is a common complaint of MMII
clients; however, the pathophysiology isn't sought and therefore improperly
addressed. This is understandable considering that clinicians are overworked, pressed
for time, and concerned about insurance coverage and the patient thought of
cost and cost. As result, MMII clients may undergo a litany of presumptive
treatments targeted at addressing fatigue, but without resolution. The result is
wasted money and time and, in some instances, exacerbation of illness and
potentially damaged rapport.

Understanding the Mechanisms

In to properly treat MMII-related fatigue, one
must first attempt to understand its pathophysiology. Admittedly, there
numerous ways that mold and mycotoxin exposure may cause fatigue; however, the
length of this article will limit us to examining the implications of decreased
oxygenation, decreased mitochondrial functioning, and neurotransmitter
imbalance. Decreased oxygenation migh result from reduced hemoglobin levels,
poor hemoglobin functionality, and compromised blood delivery. Decreased mitochondrial functioning can happen through
frank mitochondrial damage, lipid peroxidation and oxidative damage, altered
mitochondrial metabolism, and nutrient deficiencies.

Decreased Oxygenation

Oxygenation that's dependent upon hemoglobin health is
impacted by the nutrients iron, B12, and folate. Iron deficiency is usually
implicated in fatigue, and it is usually the first factor to be looked at when
fatigue is initially reported. Iron depletion occurs via 2 mechanisms in MMII. Research demonstrates
the mycotoxins ochratoxin A5 and citrinin6,7 can
sequester Fe3+, thus possibly interfering
with host availability. Further exacerbating hemoglobin dysfunction, fungal
infections could also extract heme,8-13 from hemoglobin, thereby causing
decreased functionality, damage, and potentially frank decreases in hemoglobin

The interplay of iron with MMI becomes complicated using the
introduction of “nutritional immunity,” the process by which, within the
face of the infection, the host's system will endeavour to sequester nutrients in
order to control the pathogenicity of the offending agent.14,15 In
the situation of fungal infections, the body will sequester iron, thereby removing
it from circulation. As a result, it can not be of use towards the infective
agent, nor to the host. The patient may seem as iron “deficient” if total
serum iron is the sole parameter examined. It's imperative that the full
laboratory work-up is performed to be able to assess whether iron sequestration is
occurring, as indicated by possible elevations in hepcidin, lactoferrin,
ferritin, and haptoglobin in the face of a low serum iron.16 In
these cases, you should identify and treat the infection before
supplementing with iron, as supplementation can perpetuate fungal growth17-20
and mycotoxin production.20,21

Yet, mycotoxin effects on
oxygenation via hemoglobin disruption do not stop with iron. Decreased hemoglobin
might be of a B12- or folate-induced macrocytic anemia, arising from
mycotoxin exposure. For example, the mycotoxin deoxynivalenol interferes
with absorption of 5-methylenetetrahydrofolate ,22 while the
group of mycotoxins called “fumonisins” can hinder folate transport23
– accomplished partly by disturbing the transcription of folate receptors.24,25 Research also demonstrates
that the ileum, the foci of B12 absorption in the gut, is broken by aflatoxin,26
fumonisins,27,28 and DON.29-32 Fatigue because of macrocytic
anemia is simply one possible issue resulting
from interruption of those nutrients; let us not forget the implications of
disruption of the methylation pathway.

Nutrient levels aren't the sole means by which hemoglobin can
be impacted by mycotoxin exposure. In animal studies, frankly low hemoglobin
levels have been correlated with contact with secondary metabolites of Stachybotrys,33 in addition to
exposure to other mycotoxins,49 such as ochratoxin,34-38 fusarium-based
mycotoxins,39-41 fumonisin B-1,42 T-2 toxin,43
aflatoxin,44,45 and also combinations of mycotoxins.46-48
In animals, the mycotoxin sporidesmin has been confirmed
to promote the conversion of hemoglobin to non-functional methemoglobin and, in
some instances, to result in irreversible oxidative damage, as indicated by the presence
of Heinz bodies.50

Decreased oxygenation via depressed hemoglobin levels or
depressed functionality of hemoglobin is simply one
etiology of the fatigue seen with MMI. Additionally of concern is decreased
oxygenation because of decreased blood delivery. Mycotoxins are widely
known to be cardiotoxic51-68; in the cardiomyocyte, they have been shown
to reduce mitochondrial functioning59,66 and disrupt calcium balance,64,67
which might potentially correlate using the findings of reduced contractility55-57,68
and reduced cardiac output.51-53,56,60,61-63,69

Decreased Mitochondrial Functioning

Mitochondria are the powerhouses from the cells; their
proper functionally is imperative to healthy levels of energy. Mycotoxins are
known disruptors of
mitochondrial functioning, as mediated by oxidative stress70-72; this
can lead to disruptions of membrane potential, calcium homeostasis, and
enzymes for example cytochrome oxidase and NADH dehydrogenase.73-77
Moreover, mycotoxins for example ochratoxin A/B/C, T-2, citrinin, DON , stergimatocystin, zearalenone, the aflatoxin group, the fumonisin
group, beauvericin, and others are known initiators of lipid peroxidation,5,71,77,109-128
which can also injure mitochondrial functionality.

Further exacerbating mitochondrial dysfunction, the interface
between nutrient status and MMII, once more comes up. Zinc is required
for correct mitochondrial functioning, and numerous mycotoxins have been
implicated in zinc issues. For instance, the fusariotoxin toxin T-2 interferes
with zinc absorption,78 ochratoxin A leads to a reduction in
intracellular zinc concentrations,79 and aflatoxin exposure continues to be
correlated with zinc deficiencies.80 Once more, nutritional immunity
should be thought about when confronted with what appears to be a zinc “deficiency” at
first glance. Once the host is confronted with a infection, extracellular
zinc is sequestered by various means, including zinc transporters and zinc-binding
proteins for example calprotectin. Keeping zinc sequestered in various
intracellular compartments, such as lysosomes, zincosomes, and endosomes,
means less bioavailable zinc for that mitochondria, thus potentially
disturbing mitochondrial function. As adequate zinc levelsare
required for both fungal survival81-101 and mycotoxin production,102
the correction of nutritional immunity-induced zinc “deficiencies” may wreak
havoc otherwise properly ordered with respect to infection management.

Neurotransmitter Imbalance

Important towards the etiology of fatigue is the relationship of mycotoxins to dopamine levels. Neurotransmitter imbalances are theorized to have an impact on fatigue, particularly an increased ratio of serotonin to dopamine.103 Studies have correlated fatigue to reduce levels of dopamine precursors104 and decreased basal ganglia activation.105 Some mycotoxins, in a position to cross the blood-brain barrier, can interfere with proper neurotransmitter production and performance. Animal research demonstrates a low level of dopamine with DON106 exposure. Meanwhile, ochratoxin A causes depletion of striatal dopamine107 and impairment of phenylalanine hydroxylase activity,108 which might also lead to a reduction in dopamine synthesis.


The goal of this article is to remind the physician
that although a patient's symptoms may look like a deficiency-induced fatigue
initially, there may be a deeper cause than a simple nutritional deficit.
Always test nutrient status before implementing an intervention, and in
instances where mold exposure is of high clinical suspicion, consider ordering
urine mycotoxin testing, fungal serology, or antigen detection to assess
underlying cause. For iron assessment, consider running a CBC ,
total iron, TIBC, transferrin, ferritin, and haptoglobin. For B12 and folate
assessment, consider a CBC , homocysteine, and methylmalonic
acid, at least; to further assess cellular utilization, RBC folate, serum
folate, and serum cobalamin may also be useful. For zinc assessment, consider
zinc and alkaline phosphatase; further assessment may involve
measurements of copper and ceruloplasmin.

Assessment of nutrient status, in conjunction with MMII
assessment, is especially essential in instances of nutritional immunity
associated with infection. Proper ordering of treatment is the most
importance, as correcting a presumed “deficiency” prior to identifying and
clearing an infection may worsen the individual. The difficulty, therein, is the fact that
serology and antigen detection testing for fungal infections are flawed.
However, if these tests do return positive results, it is crucial that
measures automatically get to eradicate infection before
correcting the “deficiency.” It is such scenarios that it's reasonable to
use antifungal interventions, that is in juxtaposition with lots of current
practices of providing an antifungal for any positive urine mycotoxin test. The
latter boosts the risk of antifungal resistance as well as increases the risk
of mortality for millions of people worldwide every year, including
immunocompetent and immunocompromised people alike. If nutrient screening does
not reveal any actionable deficiencies, but there is a high suspicion or known
mold exposure or elevated urine mycotoxins, consider testing for oxidative
damage. Lipid peroxide testing can be achieved via malondialdehyde,
commonly referred to as a TBARS assay or lipid peroxide testing. Additional
oxidative stress assessments may include 8-OH-deoxyguanosine and GGT levels.