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REVIEW
Inflammation and vitamin D: the infection connection
Meg Mangin •Rebecca Sinha •Kelly Fincher
Received: 1 November 2013 / Revised: 4 June 2014 / Accepted: 23 June 2014
The Author(s) 2014. This article is published with open access at Springerlink.com
Abstract
Introduction Inflammation is believed to be a contribut-
ing factor to many chronic diseases. The influence of
vitamin D deficiency on inflammation is being explored but
studies have not demonstrated a causative effect.
Methods Low serum 25(OH)D is also found in healthy persons
exposed to adequate sunlight. Despite increased vitamin D sup-
plementation inflammatory diseases are increasing. The current
method of determining vitamin D status may be at fault. The level
of 25(OH)D does not always reflect the level of 1,25(OH)2D.
Assessment of both metabolites often reveals elevated
1,25(OH)2D, indicating abnormal vitamin D endocrine function.
Findings This article reviews vitamin D’s influence on the
immune system, examines the myths regarding vitamin D
photosynthesis, discusses ways to accurately assess vitamin
D status, describes the risks of supplementation, explains the
effect of persistent infection on vitamin D metabolism and
presents a novel immunotherapy which provides evidence of
an infection connection to inflammation.
Conclusion Some authorities now believe that low 25(OH)D
is a consequence of chronic inflammation rather than the cause.
Research points to a bacterial etiology pathogenesis for an
inflammatory disease process which results in high 1,25(OH)2D
and low 25(OH)D. Immunotherapy, directed at eradicating
persistent intracellular pathogens, corrects dysregulated vitamin
D metabolism and resolves inflammatory symptoms.
Keywords Vitamin D Infection Inflammation
Immunotherapy
Introduction
Inflammation is involved in many chronic diseases and
concern has been raised about the influence of vitamin D
deficiency on inflammatory processes. When studies found
an association between inflammatory diseases and low
serum 25-hydroxyvitamin D (25(OH)D), further research
found evidence of low vitamin D in a large segment of the
general population. This led some authorities to declare a
world-wide epidemic of vitamin D deficiency and to rec-
ommend vitamin D supplementation. Experts are debating
the definition of vitamin D deficiency and the appropriate
vitamin D doses, while further research is being done to
determine if vitamin D supplementation has the intended
effect.
According to some current definitions of vitamin D
deficiency, even healthy persons, exposed to adequate
sunlight, are unable to acquire enough vitamin D without
supplementation. Often reiterated causes of vitamin D
deficiency can be disputed in the light of more current
research. In the absence of definitive studies, authorities are
questioning the wisdom of supplementing the general
population with vitamin D. The definition of Vitamin D
deficiency needs re-evaluation in view of the fact that low
25(OH)D is found in both healthy and sick individuals.
Concerns about vitamin D deficiency merit a closer look at
the current method of determining vitamin D status
because the level of 25(OH)D does not always reflect the
level of 1,25-dihydroxyvitamin-D (1,25(OH)2D). Analysis
of this active metabolite may reveal elevated 1,25(OH)2D)
in the presence of low 25(OH)D and lead to a diagnosis of
abnormal vitamin D endocrine system function.
An infectious pathogenesis posits that intracellular
bacteria disrupt the vitamin D regulated immune system,
resulting in persistent infection and chronic inflammation.
Responsible Editor: Mauro Teixeira.
M. Mangin (&)R. Sinha K. Fincher
Chronic Illness Recovery, Fort Worth, Texas, USA
e-mail: info@chronicillnessrecovery.org
Inflamm. Res.
DOI 10.1007/s00011-014-0755-z Inflammation Research
123
In the clinical setting, a novel immunotherapy is demon-
strating the ability to resolve vitamin D metabolism
dysfunction, restore immune function, and thus, eliminate
infection and reduce inflammation. This review ponders the
question, ‘‘Is low 25(OH)D a cause of, or a consequence of
inflammation?’’ The answer is found in the evidence that
adds persistent intracellular infection to the equation.
Vitamin D metabolism
The sequential metabolic processes that convert biologi-
cally inactive, parental vitamin D into active metabolites
begin when vitamin D
3
is photosynthesized in the skin or
when vitamin D
2
or D
3
is ingested. Vitamin D is trans-
ported to the liver where it is hydroxylated by an enzyme
(CYP2R1, also known as cytochrome P450 2R1) to pro-
duce 25(OH)D [1]. 25(OH)D is then transported to the
kidneys where it is hydroxylated by another enzyme
(CYP27B1, formerly 1a-hydroxylase) to produce
1,25(OH)2D. 1,25(OH)2D (also known as calcitriol), the
active metabolite, is the most potent steroid hormone in the
human body [2]. Feedback mechanisms regulate produc-
tion of 1,25(OH)2D in the kidneys via serum levels of
parathyroid hormone (PTH), fibroblast-like growth factor-
23 (FGF23) calcium, and phosphate [3]. 1,25(OH)2D is
also produced in many other tissues (e.g., skin, macro-
phages, colon, pancreas, blood vessels, etc.) by enzymatic
actions [4]. The vitamin D binding protein (VDBP) trans-
ports 1,25(OH)2D to the vitamin D receptor (VDR) in the
cell nucleus [5]. The VDR is a member of the nuclear
receptor family of ligand-regulated transcription factors.
1,25(OH)2D binds to the VDR and mediates the tran-
scription of DNA, triggered by signaling proteins, like
nuclear factor kappa-B (NFk-B) [6] (Fig. 1).
The influence of 1,25(OH)2D on the immune system is
one of its most important roles. 1,25(OH)2D regulates the
immune system via the VDR which is present in most
immune cell types, particularly in antigen-presenting cells
(APCs) such as monocytes, macrophages and dendritic
cells [7]. 1,25(OH)2D activates the VDR to express anti-
microbial peptides (AMPs) such as cathelicidin and beta
defensins which attack pathogens [8,9]. In general, the
innate immune system is enhanced and the adaptive
immune system is inhibited by 1,25(OH)2D [10,11]. Thus,
an effective immune response is heavily dependent on the
vitamin D endocrine system which performs a balancing
act of inflammation versus anti-inflammation.
Vitamin D deficiency
Concerns about vitamin D deficiency arose when studies
showed patients with autoimmune diseases have lower
levels of serum 25(OH)D and study subjects given vitamin
D had lower rates of autoimmune diseases and fewer
Fig. 1 Synthesis and
metabolism of vitamin D.
Sequential metabolic processes
convert biologically inactive,
parental vitamin D into active
metabolites
M. Mangin et al.
123
markers of inflammation [12,13]. However, authorities
have not agreed on the significance of low 25(OH)D and
without a consistent normal range for serum 25(OH)D, the
definitions of vitamin D insufficiency and deficiency from
the Vitamin D Council, the Endocrine Society and the
Institute of Medicine vary significantly.
The Vitamin D Council definition [14]:
•Deficient: 0–40 ng/ml
•Sufficient: 40–80 ng/ml
•High normal: 80–100 ng/ml
The Endocrine Society definition [15]:
•Deficiency B20 ng/ml
•Insufficiency = 20–29 ng/ml
The Institute of Medicine definition [16]:
•Risk/deficiency B12 ng/ml
•Risk/insufficiency = 12–20 ng/ml
•Sufficient = 20 ng/ml
In 2006, the Merck Manual listed 25–40 ng/ml as the
normal 25(OH)D range [17]. Recently, this range has
skyrocketed to 30–74 ng/ml [18]. Quest Diagnostics now
lists the upper limit of normal 25(OH)D as 100 ng/ml [19].
Laboratory reference ranges for serum 25(OH)D levels
have long been based upon average values from popula-
tions of healthy individuals but many people are now
supplementing with vitamin D. In the US, the leading
authority regarding medical research is the prestigious
Institute of Medicine (IOM). The 2010 IOM report on
vitamin D emphasized that the current measurements, or
cut-off points, of sufficiency and deficiency of 25(OH) D in
use by laboratories have not been set using rigorous sci-
entific studies. It suggests that since no central authority
has determined which cut-off points to use, reports of
deficiency and lab ranges may be skewed and numbers
overestimated [16]. Therefore, it would be prudent to use
the IOM vitamin D deficiency guideline in the clinical
setting, for clinical studies and when evaluating research
results.
Purported reasons for vitamin D deficiency
Is low 25(OH)D among the general population an accurate
assessment of vitamin D deficiency? Many reasons are
cited for the current ‘epidemic’ of vitamin D ‘deficiency’
but closer examination reveals these beliefs are based on
outdated or limited studies and can be challenged with
more recent research.
Melanin pigmentation is only one factor that determines
the amount of vitamin D
3
which is photosynthesized [20,
21]. Bogh et al. [22] measured the baseline serum
25(OH)D and total cholesterol levels of 182 fair-skinned
and dark-skinned subjects; and studied the effect of UV
radiation on their serum 25(OH)D levels. They found the
amount of serum 25(OH)D produced was determined by
the amount of cholesterol in the skin, not on skin pig-
mentation. Matsuoka et al. [23] investigated the effect of
racial pigmentation on vitamin D
3
formation, simulating
the process with a fixed dose of UVB radiation and con-
cluded that while racial pigmentation has a photo-
protective effect, it does not prevent the generation of
normal levels of active vitamin D metabolites. Persons with
dark skin also compensate for low 25(OH)D by rapidly
converting it to the active 1,25(OH)2D metabolite, thus
allowing them to maintain adequate vitamin D status [24].
Skin pigmentation does not appear to negatively affect
vitamin D status [25].
Clothing is a barrier to vitamin D photosynthesis but this
is an issue only for people who cover themselves from head
to toe [26]. It takes relatively little sunlight exposure to
acquire adequate stores of vitamin D and few people wear
enough clothes to prevent that from happening. Ten to
15 min of sunlight or daylight exposure to a small area of
skin (e.g., the forearm or face, etc.) twice a week, without
sunscreen, supplies all the vitamin D necessary for health
[27]. The belief that sunscreen lotion blocks vitamin D
production is based on a 1987 study done by Matsuoka
et al. [28] that was funded by the ultraviolet foundation,
which is supported by the tanning bed industry. Contra-
dictory information was provided by Diehl and Chiu [29]
which concluded that although sunscreens are effective,
many may not actually be blocking UV-B because they are
improperly or inadequately applied [30]. Thus, sunscreen
use may not actually diminish vitamin D synthesis in real
world use. However, prolonged unprotected sun exposure
should be avoided to reduce the risk of developing skin
cancer.
Although pollution can block some ultraviolet radiation,
even in urban areas of high pollution 50 % of UV rays
reach the ground [31]. A significant amount of UV radia-
tion exposure can be obtained in dense metropolitan areas;
tall buildings provide shade but shade gives up to 50 % of
UV rays. Indoor workers receive 10–20 % of outdoor
workers’ yearly UV exposure [31]; and for many, this may
be adequate, especially if sunlight exposure is higher when
they are not working. UV radiation is reflected or scattered
to varying extents by different surfaces. The scattering and
absorption of light by clouds may not significantly reduce
natural light exposure because over 90 % of UV rays may
penetrate clouds [31]. Environmental factors are rarely an
impediment to photosynthesis of adequate vitamin D.
As the skin ages, there is a decline in the cutaneous
levels of 7-dehydrocholesterol, resulting in a marked
reduction of the skin’s capacity to produce vitamin D
3
[32].
Inflammation, vitamin D, infection
123
However, despite the up to fourfold reduction in vitamin
D
3
production in a 70-year-old compared to a 20-year-old,
the skin has such a high capacity to make vitamin D
3
that
elders exposed to sunlight will produce an adequate
amount of vitamin D
3
to satisfy their vitamin D require-
ment [33,34].
A 1988 study by Webb et al. [35] is often cited to
support the conviction that latitude dramatically influences
the amount of solar radiation available to synthesize vita-
min D
3
. However, other researchers who conducted more
recent studies refute this hypothesis. Kimlin et al. [36]
report, ‘‘It may no longer be correct to assume that vitamin
D levels in populations follow latitude gradients’’. And
Lubin [37] states, ‘‘Geophysical surveys have shown that
UV-B penetration over 24 h, during the summer months at
Canadian north latitudes when there are many hours of
sunlight, equals or exceeds UV-B penetration at the
equator.’’ Ross et al. [16] report that ample opportunities
exist to form vitamin D (and store it in the liver and fat for
later use) from exposure to sunlight during the spring,
summer, and fall months even in the far north latitudes.
Acceptance of these vitamin D myths regarding photo-
synthesis prevents consideration of the alternate
hypothesis—low serum 25(OH)D, despite adequate pho-
tosynthesis of vitamin D
3
, is a result of an inflammatory
process.
Low vitamin D is found in healthy subjects
Many studies of healthy subjects have found levels of
25(OH)D that, by some vitamin D definitions, are declared
deficient (hypovitaminosis-D) [38,39]. Vitamin D levels
that are considered deficient have even been found in
persons who are exposed to abundant sunlight [40]. Bink-
ley et al. [41] showed a mean 25(OH)D level of 31.6 ng/ml
among healthy young adult Hawaiian surfers. It is clear
that low levels of 25(OH)D are found in both healthy
persons and those with autoimmune or chronic inflamma-
tory diseases. Opposing reasoning can be used to explain
this contradiction. One explanation reasons that healthy
persons with low 25(OH)D will become sick and sick
people will develop lower 25(OH)D levels (Fig. 2); how-
ever, studies do not support this hypothesis. The correct
explanation may be that, in the absence of disease, low
25(OH)D is normal.
Low vitamin D in the presence of diseases
Since low 25(OH)D is found in both healthy persons and
those with autoimmune or chronic inflammatory diseases,
assessing vitamin D status with the measurement of an
additional clinical marker may be helpful. It is asserted that
low levels of 25(OH)D accurately reflect vitamin D status;
however, measurement of 1,25(OH)2D often demonstrates
a positive correlation of elevated 1,25(OH)2D to inflam-
matory diseases (Fig. 2). This is illustrated by Blaney et al.
[42] in a study of 100 patients with autoimmune and
chronic disease which found that 85 % of subjects had
levels of 1,25(OH)2D higher than 46.2 pg/ml without
hypercalcemia. Although this serum level may be consid-
ered normal by some, lab ranges for 1,25(OH)2D may have
been skewed high by the presence of patients with unrec-
ognized persistent intracellular infection and thus,
dysregulated vitamin D metabolism. The Danish
1,25(OH)2D population data (from a large and reliable
study) found the mean value for 1,25(OH)2D in a normal
population was 29 pg/ml with a standard deviation of 9.5
[43]. More frequent measurement of both D-metabolites in
the clinical and research settings, may shed light on the true
meaning of low 25(OH)D.
Rickets is often cited as proof of the need for vitamin D
supplementation. However, a review of the metabolic
processes involved provides some prospective. Adequate
vitamin D is essential to prevent rickets, but adequate
calcium is equally important; if either calcium or vitamin D
is deficient, bone health suffers. Hypophosphatemia is the
common denominator of all rickets; low calcium intake
leads to hyperparathyroidism, which leads to high phos-
phorus excretion and, thus, phosphorus deficiency [44].
Rickets is rare in the developed world; however, children
in developing countries, who usually photosynthesize
enough vitamin D from sunlight, develop rickets if poverty
prevents them from eating enough calcium-rich food [45,
46]. Studies have found that rickets occurs in sunny
countries due to poor calcium intake and is cured with
increased calcium ingestion [47,48].
Osteoporosis is another disease which is closely linked
with vitamin D. Adequate vitamin D is an important factor
in maintaining bone health to avoid osteoporosis but a
Fig. 2 Interpretation of vitamin D deficiency via calcitriol measure-
ment. Since low 25(OH)D is found in both healthy persons and those
with autoimmune or chronic inflammatory diseases, assessing vitamin
D status with measurement of 1,25(OH)2D may be helpful
M. Mangin et al.
123
study by Reid et al. [49] published in The Lancet found
little evidence supporting the use of vitamin D supplements
by seniors hoping to improve bone density and ward off
potential fractures. 1,25(OH)2D maintains calcium
homeostasis between blood, cells and bones by stimulating
calcium absorption from the intestines, reabsorption in the
kidneys, and resorption in bones [50]. 1,25(OH)2D up-
regulates the VDR in the small intestine, which then
transcribes genes that shuttle calcium and phosphorus
through the intestinal epithelium. However, mucosal
response and calcium/phosphorus absorption are dependent
on a competent VDR and elevated 1,25(OH)2D reduces
VDR competence [51]. Thus, calcium and phosphorus
absorption may be inhibited if VDR function is impaired
by elevated 1,25(OH)2D. This is illustrated by Abreu et al.
[52] in a study of Crohn’s patients with elevated
1,25(OH)2D and low bone mineral density which con-
cluded that treatment of the underlying inflammation
would improve metabolic bone disease. In fact, there is
ample evidence that elevated 1,25(OH)2D leads to bone
loss. Brot et al. [53] found that elevated levels of
1,25(OH)2D were strongly associated with decreased bone
mineral density and content, and increased bone turnover.
When levels are above 42 pg/ml 1,25(OH)2D stimulates
bone osteoclasts. This leads to osteoporosis, dental frac-
tures and calcium deposition into the soft tissues [54].
Vanderschueren et al. [55] found that a combination of
high 1,25(OH)2D and low 25(OH)D is associated with the
poorest bone health.
Vitamin D supplementation
It is reasoned that if low 25(OH)D indicates a current or
potential disease state, then increasing 25(OH)D by sup-
plementing with vitamin D should provide some symptom
relief and/or protection. So far, there is scant evidence for
this hypothesis [56,57]. According to Ross et al. [16] in the
2010 IOM report, ‘‘Outcomes related to autoimmune dis-
orders, cancer, cardiovascular disease and hypertension,
diabetes and metabolic syndrome, falls and physical
performance, immune functioning, infections, neuropsy-
chological functioning, and preeclampsia could not be
linked reliably with calcium or vitamin D intake and were
often conflicting.’’ Despite the recent increase in vitamin D
supplementation, chronic diseases have increased and are
expected to continue increasing [58,59].
Consequently, more vitamin D experts are beginning to
reconsider vitamin D supplementation among the general
population [60]. Recommending higher vitamin D intake to
large populations carries the potential risk of overdosing
certain individuals [61]. It is difficult to ingest too much
vitamin D from food, and natural mechanisms regulate the
amount of vitamin D
3
photosynthesized from sunlight [62].
However, elevated 25(OH)D and hypervitaminosis-D can
occur due to vitamin D supplementation [63]. A study by
Noordam et al. [65] cast doubt on the causal nature of
previously reported associations between low levels of
vitamin D and age-related diseases and mortality. A com-
prehensive review by Autier et al. [65] concluded that low
concentrations of 25(OH)D are most likely an effect of
health disorders and not a cause of illness. Commenting on
the findings in a press statement, Autier et al. [64] advised
against vitamin D supplementation and explained the
observed discrepancy between observational and random-
ized trials:
Decreases in vitamin D levels are a marker of dete-
riorating health. Ageing and inflammatory processes
involved in disease occurrence and clinical course
reduce vitamin D concentrations, which would
explain why vitamin D deficiency is reported in a
wide range of disorders. We postulate that inflam-
mation is the common factor between most non-
skeletal health disorders and low 25(OH)D concen-
trations. Inflammatory processes involved in disease
occurrence and clinical course would reduce
25(OH)D, which would explain why low vitamin D
status is reported in a wide range of disorders.
However, increases in 25(OH)D have no effect on
inflammatory processes or on disorders at the origin
of these processes.
A 2014 meta-analysis by Bolland et al. [66] on the
effects of vitamin D supplementation on skeletal, vascular,
or cancer outcomes concludes that vitamin D supplemen-
tation with or without calcium does not reduce skeletal or
non-skeletal outcomes in unselected community-dwelling
individuals by more than 15 %. The authors further state
that future trials with similar designs are unlikely to alter
these conclusions. Because of emerging concerns about
elevated 25(OH)D, the IOM has shifted the paradigm from
thinking about ‘more is better’ to a more risk-averse
approach [67]. It has also challenged the notion that harm
should be viewed in terms of vitamin D toxicity such as
hypercalcemia, hypercalciuria, or metastatic calcification
and has advanced the concept of ‘harm’ in terms of chronic
disease outcomes and mortality [16]. Because adverse
effects of vitamin D supplementation may take decades to
be realized, clinicians (mindful of the medical ethics pre-
cept ‘‘First, do no harm’’) should err on the side of caution;
follow the IOM guideline and wait for the results of long-
term vitamin D studies.
Bacterial pathogenesis of low vitamin D hypothesis
If evidence indicates that most people get adequate vitamin
D from sunlight exposure but healthy persons are found to
Inflammation, vitamin D, infection
123
be ‘deficient’ by recent standards, what is the explanation
for this phenomenon? Vitamin D proponents use a disease
deficiency model to explain low levels of 25(OH)D. Their
hypothesis states low 25(OH)D causes chronic diseases;
however, a pathogenesis has not been elucidated [68]. Low
serum 25(OH)D in the presence of disease can also be
explained with a dysregulated vitamin D metabolism
model [69]. This hypothesis proposes that low vitamin D is
the consequence of a chronic inflammatory process caused
by persistent infection. The bacterial pathogenesis theo-
rizes that intracellular (cell wall deficient) bacteria invade
nucleated cells, use strategies to avoid destruction and
cause abnormal vitamin D endocrine function, resulting in
low vitamin D. Excess 1,25(OH)2D is produced in an effort
to up-regulate the VDR to transcribe AMPs; and 25(OH)D
is rapidly metabolized in the process, resulting in a low
serum level. The resulting elevated 1,25(OH)2D causes
chronic, systemic inflammation and its accompanying
symptoms (Fig. 3).
The existence of bacteria which are capable of invading
human cells has been known for over a century and are
described by many authors [70,71]. The lack of a cell wall
enables them to enter human cells and proliferate because
they fail to elicit an appropriate response when the immune
system is compromised. In particular, they enter the mac-
rophages—the very immune cells deployed to kill invading
pathogens. The inability of most research labs to culture
cell wall deficient (CWD) bacteria has been an obstacle to
their acceptance, and reliance on Koch’s postulates has
made it difficult to correlate CWD bacteria to specific
diseases [72]. But some researchers believe Koch’s pos-
tulates may have to be redefined in terms of molecular data
when dormant and non-culturable bacteria are implicated
as causative agents of mysterious diseases [73]. O
´Connor
et al. [74] (in their article entitled Emerging Infectious
Determinants of Chronic Diseases) report, ‘‘microbes can
now be irrefutably linked to pathology without meeting
Koch’s postulates’’ and ‘‘…powerful tools of molecular
biology have exposed new causal links by detecting diffi-
cult-to-culture and novel agents in chronic illness settings.’’
Domingue [75] commented, ‘‘This might translate into
an etiology for chronic inflammatory diseases, when the
stressed bacteria increase in numbers and overwhelm the
normal biological functions of the host.’’ Nunez [76] was
quoted in the University of Michigan Health System
newsletter, ‘‘In our study, the presence of bacterial
microbes inside the cell is what triggers the immune
response.’’ Rolhion and Darfeuille-Michaud [77] observed
that the presence of pathogenic invasive bacteria could be
the link between an innate immune response to invasive
bacteria and the development of inflammation. A number
of studies suggest disease associations with CWD bacteria
[78–83]. Verway et al. [79] report ‘‘…data suggest that at
least a subset of the genetic predisposition to Crohn’s
disease results from defects in the detection and/or pro-
cessing of intracellular pathogens by the innate immune
system.’’ O’Connor et al. [74] state, ‘‘The epidemiologic,
clinical, and pathologic features of many chronic inflam-
matory diseases are consistent with a microbial cause.
Infectious agents likely determine more cancers, immune-
Fig. 3 Proposed hypothesis for
chronic inflammation caused by
persistent intracellular infection.
Intracellular bacteria invade
nucleated cells and use
strategies to avoid destruction.
Excess 1,25(OH)2D is produced
in an effort to up-regulate the
vitamin D receptor to transcribe
AMPs; and 25(OH)D is rapidly
metabolized in the process,
resulting in a low serum level.
The resulting elevated
1,25(OH)2D causes chronic,
systemic inflammation and its
accompanying symptoms
M. Mangin et al.
123
mediated syndromes, neurodevelopmental disorders, and
other chronic conditions than currently appreciated.’’
CWD bacteria are considered communicable but not
contagious; protective immunity depends on an effective
cell-mediated immune response [80]. It is now well
appreciated that pathologic processes caused by infectious
agents may only emerge clinically after an incubation of
decades [81]. Among the speculated causes of the increase
in chronic infections are overuse of beta-lactam antibiotics
[82,83] and immunosuppression via excess 25(OH)D
production [84] or immunosuppressive medications [85].
Many microbiologists now believe at least some, if not all,
of the inflammation which drives the chronic disease pro-
cess is caused by the presence of these stealthy intracellular
pathogens [86]. A considerable body of experimental and
clinical evidence supports the concept that difficult-to-
culture and dormant bacteria are involved in latency of
infection and that these persistent bacteria may be patho-
genic [73,87,88]. McDougal [89] states, ‘‘Evidence now
confirms that non-communicable chronic diseases can stem
from infectious agents.’’
Effects of intracellular pathogens on the immune
system
Pathogens gain many advantages by parasitizing immune
cells and altering nuclear receptor activity. Tissue invasion
provides a privileged niche with access to host protein and
iron, sequestration from immune response, and a means for
persistence [90]. In the arms race of host–microbe co-
evolution, successful microbial pathogens have evolved
innovative strategies to evade host immune responses. For
example, ‘crosstalk manipulation’ undermines host defen-
ses and contributes to microbial adaptive fitness [91,92].
Pathogenic microbes also induce stress responses which
protect the cell from lethal factors, express proteases that
degrade AMPs, use biofilms as a shield and modulate host
cell motility to facilitate establishment of an infection [93,
94]. Genetic foreign and host protein interactions alter gene
transcription and translation mechanisms, and many spe-
cies survive by horizontal gene transfer [95,96].
It is theorized that bacteria have developed some of
these strategies in order to invade host cells and remain
undetected within cellular cytoplasm. Many bacterial
pathogens form antibiotic-tolerant persister cells which can
replicate within macrophages. In this form they can cause
subclinical infection and have been associated with chronic
diseases [95,97,98]. Intracellular bacteria can modulate
cytokine production [99]; and in monocytes and macro-
phages, cytokine activation markedly inhibits 1,25(OH)2D/
VDR gene transcription [100].
Macrophage microbicidal mechanisms are responsible
for the control and elimination of pathogens. 1,25(OH)2D
production and action in macrophages activates toll-like
receptors to increase expression of the AMP cathelicidin
which kills infectious invaders [101,102]. When the
immune system is fighting a persistent microbe, inflam-
matory molecules are continuously released in an effort to
kill the pathogen [103]. Immune defenses stimulate Th
17
cells and contribute to the development of chronic
inflammatory conditions [104,105]. An ineffective
immunological response causes low-grade inflammation
and phagocyte-inflicted tissue damage plays an important
role in many chronic diseases [106]; autoimmune patients
acquire a distinct pathogenic microbiota and multi-mor-
bidity often results [107,108]. Therefore, it is reasonable to
infer that bacteria have evolved strategies which allow
them to persist within host cells. The exact mechanisms are
unknown and warrant further study.
The compromised immune system, infection
and vitamin D
In an essay on the renin–angiotensin system (RAS) and
immune response, Smith [109] postulated that unresolved
cellular stress may be caused by infectious agents to avoid
adaptive immune responses. The host immune response has
developed many mechanisms to neutralize and remove
pathogenic bacteria. In turn, pathogenic bacteria have
developed mechanisms to alter and evade the host immune
response [110,111]. Regulation of the VDR is a common
mechanism used in the host defense against pathogens but
certain microbes have been shown to slow innate immune
defenses by down-regulating the VDR:
•Mycobacterium tuberculosis down-regulates VDR
activity [112].
•Mycobacterium leprae inhibits VDR activity through
down-regulation of CYP27B1 in monocytes [113].
•Aspergillus fumigatus secretes a toxin capable of
down-regulating the VDR in macrophages [114].
•Epstein–Barr virus lowers VDR activity [115].
•HIV completely shuts down VDR activity [116].
•In VDR knockout mice, a circumstance that closely
mimics extreme VDR dysregulation, 1,25(OH)2D lev-
els increase by a factor of ten [117].
Studies also point to immune system depression and
elevated 1,25(OH)2D in chronic diseases [118]:
•Sarcoidosis patients are deficient in cathelicidin despite
healthy vitamin D
3
levels [119].
•1,25(OH)2D is high ([60 pg/ml) in 42 % of Crohn’s
patients and the source of the active vitamin D may be
the inflamed intestine [52].
Inflammation, vitamin D, infection
123
•1,25(OH)2D is elevated in the synovial fluid of patients
with RA (rheumatoid arthritis) [120].
•Crohn’s disease decreases expression of cathelicidin
[121].
High levels of 1,25(OH)2D may result when down-
regulation of the VDR by bacterial ligands prevents the
receptor from expressing enzymes necessary to keep
1,25(OH)2D in a normal range [42]. Elevated 1,25(OH)2D
further reduces VDR competence, suppresses macrophage
function, and blocks the nuclear factor kappa-B pathway;
thus inhibiting immune system function [116,122,123].
Reducing the ability of the VDR to express elements of
innate immune function allows intracellular bacteria to
persist in the cytoplasm of nucleated cells and may account
for the increased susceptibility to non-bacterial co-infec-
tions that are commonly found in patients with chronic
illnesses [124,125]. Theoretically, immune system sup-
pression allows parasitic microbes to persist and proliferate
in host phagocytes, successfully compete for nutritional
resources, and displace commensal organisms from their
niche [126]. Elevated 1,25(OH)2D appears to be evidence
of a disabled immune system’s attempt to activate the VDR
to combat infection.
Autoimmune disease
Numerous examples can be found in which pathogens
express antigens that cross-react with host antigens or
induce local inflammatory responses that can lead to
autoimmune responses through a very complex set of cir-
cumstances [127]. The prevailing theory regarding the
etiology of autoimmune disease states that an overactive
immune system produces auto-antibodies against self, but
infection as an environmental factor in autoimmunity has
long been recognized. An alternate hypothesis posits a
bacterial etiology in which a persistent intracellular infec-
tion causes a cytokine release that induces signals to T cells
and B cells, and the antibodies they produce (to the intra-
cellular invader) include some that attack human proteins,
as well as target the pathogens [128,129]. Christen et al.
[130] explored this hypothesis, ‘‘In theory, a structural
similarity or identity between the host and an invading
pathogen might cause the immune system of the host to
react not only to the pathogen but also to self-compo-
nents.’’ Infections can act as environmental triggers
inducing or promoting autoimmune disease in genetically
predisposed individuals [131]; researchers have shown how
antinuclear antibodies (ANA) are created in response to
infectious agents [132,133].
Vitamin D appears to have a positive effect on auto-
immune disease due to immune system suppression [122,
134,135] and immune suppression is considered thera-
peutically beneficial for autoimmune diseases [136,137].
However, vitamin D proponents have failed to recognize
that positive effects are due to the immunosuppressive
effect of elevated 25(OH)D or to understand that immu-
nosuppression is contraindicated because of the probable
presence of intracellular infection. When the immune
system is suppressed clinical disease markers and symp-
toms are reduced but immunosuppression does not address
an underlying cause of persistent bacteria, thus relapse is
common [138]. Verway et al. [79] wonder, ‘‘Is a specific
pathogen responsible for disease or rather is a dysregulated
immune response generated against a complex microbial
population? Why would immune-suppressive drugs be
efficacious if the primary defect is an immune deficiency?’’
Much of current research focuses on finding drugs to
suppress inflammation but, according to Collins [139],
95 % of these studies have failed It seems clear a better
direction is needed. Immunotherapy which restores VDR
competence corrects dysregulated vitamin D metabolism
and eliminates intracellular bacteria could be the answer
(as discussed in the section titled Restoring VDR
Competence).
Dysregulated vitamin D metabolism
In a healthy individual, the complex interplay between
innate and adaptive immunity cooperates to mount an
appropriate response to infection through regulation of the
vitamin D endocrine system [140]. The immune system
detects and responds to the presence of intracellular bac-
teria by producing more 1,25(OH)2D to activate the VDR
and express the crucial endogenous AMPs which enable
the innate immune system to target intracellular pathogens
[141]. Renal production of 1,25(OH)2D is tightly self-
regulated, with the end product down-regulating its own
further production. In contrast, extra-renal tissues (e.g.,
uterine decidua and placenta, colon, breast, prostate,
spleen, bone, keratinocytes, melanoma and synovial cells,
pulmonary monocytes and macrophages, etc.) which pro-
duce 1,25(OH)2D are regulated by cytokines (e.g.,
interferon-gamma), lipopolysaccharide, nitric oxide and
intracellular VDBP, which activate the enzyme CYP27B1
to stimulate conversion of 25(OH)D to 1,25(OH)2D [142].
This extra-renal production of 1,25(OH)2D in tissues
infected with intracellular bacteria can result in an excess
in production of 1,25(OH)2D which may contribute to
depletion and low levels of 25(OH)D [143] (Fig. 4).
Because extra-renal production of 1,25(OH)2D is pri-
marily dependent on the availability of 25(OH)D [144],
supplementation with vitamin D to increase 25(OH)D may
promote the production of 1,25(OH)2D in non-renal tissues
M. Mangin et al.
123
that are sites of intracellular infection and result in
hypervitaminosis-D. Sunlight appears to play a part in this
process and many patients with autoimmune disease report
sun sensitivity. The skin (dermal fibroblasts and keratino-
cytes possess VDR) has the capacity to synthesize
1,25(OH)2D, and represents an important target tissue for
1,25(OH)2D [145]. If keratinocytes in the skin are infected,
natural regulation of photosynthesis may be thwarted and
solar energy may overstimulate cellular activity, resulting
in an increase in cutaneous production of vitamin D
3
,
25(OH)D and 1,25(OH)2D following sun exposure.
We hypothesize that when nucleated cells are parasit-
ized by intracellular bacteria, extra-renal production of
1,25(OH)2D increases, the kidneys lose control of
1,25(OH)2D production, and pro-hormone 25(OH)D
decreases due to rapid conversion to 1,25(OH)2D. The
following mechanisms are thought to be responsible
(Fig. 5):
•Inflammatory cytokines activate CYP27B1, an enzyme
that causes more 25(OH)D to be converted to
1,25(OH)2D [146].
•The microbial-repressed VDR cannot transcribe
CYP24A1 (formerly 24-hydroxylase), an enzyme that
breaks down excess 1,25(OH)2D [147].
•Excess 1,25(OH)2D binds the PXR (pregnane X
receptor), to inhibit conversion of vitamin D
3
to
25(OH)D so 25(OH)D is down-regulated [148].
•1,25(OH)2D inhibits the hepatic synthesis of 25(OH)D
[149].
Thus, low 25(OH)D may be a consequence of the
inflammatory process. More studies are concluding that
suboptimal circulating levels of vitamin D appear to be
caused by the disease process. Waldronn et al. [150] found
serum 25(OH)D was decreased following an acute
Fig. 4 Proposed hypothesis for
excess 1,25(OH)2D production
in bacterially-stimulated extra-
renal tissues. Extra-renal
tissues, which produce
1,25(OH)2D, are regulated by
cytokines, lipopolysaccharide,
nitric oxide and intracellular
VDBP, which activate the
enzyme CYP27B1 to stimulate
conversion of 25(OH)D to
1,25(OH)2D, resulting in low
25(OH)D
Fig. 5 Proposed hypothesis for dysregulated vitamin D metabolism
caused by intracellular pathogens. Theoretically, when nucleated cells
are parasitized by intracellular bacteria, extra-renal production of
1,25(OH)2D increases, the kidneys lose control of 1,25(OH)2D
production, and pro-hormone 25(OH)D decreases due to rapid
conversion to 1,25(OH)2D
Inflammation, vitamin D, infection
123
inflammatory insult (i.e., orthopedic surgery) and con-
cluded that hypovitaminosis-D may be the consequence
rather than cause of chronic inflammatory diseases. Ferder
et al. [151] state, ‘‘…there may be a relationship between
inflammatory processes induced by chronic overstimula-
tion of the renin angiotensin system (RAS) and the
worldwide vitamin D deficiency. In fact, the pandemic of
vitamin D deficiency could be the other face of increased
RAS activity, which could potentially cause a lower
activity or lower levels of Vitamin D.’’
Diagnosis of dysregulated vitamin D metabolism
Assessing dysregulated vitamin D metabolism has the
potential to guide clinical practice [152,153]. Vitamin D
status is currently determined by measuring the level of
serum 25(OH)D which, presumably, reflects the serum
levels of other vitamin D metabolites (e.g., vitamin D
3
,
vitamin D
2
and 1,25(OH)2D, etc.). This measurement may
not, however, provide enough information to assess vitamin
D endocrine function. The clinical utility of measuring
1,25(OH)D is not fully understood, but it is clear that
associations are being made between this active metabolite
of vitamin D and disease states [154]. 1,25(OH)2D is not
being used as a measure associated with vitamin D nutri-
tional status or as an intermediate marker related to health
outcomes, or even routinely assessed in vitamin D research.
In the context of solving the puzzle of low 25(OH)D, the
reasons cited for this lapse fail to consider the possibility of
abnormal levels in the presence of chronic inflammation:
•1,25(OH)2D has a short half-life (hours) and fluctuates
rapidly.
However, a high result may be discovered even at
trough level.
•1,25(OH)2D levels are regulated by PTH, calcium,
phosphate.
This is not true if extra-renal production is prevalent
[143].
•1,25(OH)2D does not decrease until 25(OH)D is very
low.
A low 25(OH)D may be a sign that 1,25(OH)2D is
abnormally high [55].
•1,25(OH)2D is only over-produced in hypercalcemic
disease states such as sarcoidosis.
Studies show this is not true [42].
•1,25(OH)2D may be elevated as a result of up-
regulation of the CYP27B1 enzyme.
This begs the question, Why is this enzyme elevated
[146]?
Measuring both 25(OH)D and 1,25(OH)2D (and PTH,
calcium, phosphate when indicated) as clinical markers in
chronic disease is more likely to provide a true picture of
vitamin D status, than measuring 25(OH)D alone [155,
156] (Table 1). Measuring 1,25(OH)2D should be consid-
ered in patients with low 25(OH)D, abnormal laboratory
results (especially inflammatory markers), a diagnosis of
autoimmune disease or other chronic inflammatory illness,
or signs of chronic systemic inflammation. For example,
elevated 1,25(OH)2D may serve as a marker of Crohn’s
disease [52]. The 1,25(OH)2D test is a delicate assay which
is only done in specialized laboratories. False low results
have been observed due to apparent sample mishandling;
freezing for transport is advised to prevent sample degra-
dation due to agitation. A high result is always accurate.
Restoration of VDR competence
The ability to mount an appropriate immune system
response to intracellular infection is highly dependent on a
competent VDR [159]. When it appears that 1,25(OH)2D is
unable to up-regulate the VDR due to microbial activity,
VDR competence may be restored with another VDR
ligand which acts as an agonist; an agonist increases the
signal transduction activity of a cell when bound to a
receptor on that cell. Over 3000 synthetic VDR ligands
have been identified, but most of these 1,25(OH)2D ana-
logues have no clinical use because of their undue
disruption to calcium regulation [160]. A number of non-
vitamin D VDR ligands have also been identified: curcu-
min, omega-6 fatty acids (e.g., arachidonic acid, linoleic
acid), and lithocolic acid (LCA) but are not being used for
this purpose [161,162].
Angiotensin receptor blockers (ARBs) have been
shown, via in silico molecular modeling, to modulate VDR
activation [163]. The most promising ARB, olmesartan
medoxomil (brand name Benicar
) was estimated to have a
Ki value in the low nanomolar range, similar to the Ki
values of the natural VDR ligands [163]. Olmesartan has
been noted to cause a significant reduction in elevated
1,25(OH)2D within weeks of initiation, which provides
Table 1 D-metabolites tests
Serum 25(OH)D [157]
CPT code: 82306 [157]
Lowest mortality reported at 20 ng/ml [158]
Immunosuppression reported when higher than 30 ng/ml [122]
Serum 1,25(OH)2D [157]
CPT code: 82652 [157]
ICD-9 code:
275.40 Disorder of calcium metabolism, unspecified [157]
Maximum normal =45 pg/ml [17]
M. Mangin et al.
123
further evidence of its ability to up-regulate the VDR
[164]. Olmesartan is believed to decrease elevated
1,25(OH)2D by several VDR-mediated effects (Fig. 6).
The up-regulated VDR:
•transcribes CYP24A1 and CYP3A4 (enzymes which
reduce 1,25(OH)2D production) [147].
•represses CYP27B1 (the enzyme that hydroxylates
25(OH)D to 1,25(OH)2D) so less 1,25(OH)2D is
produced [146].
Consequently, renal control of 1,25(OH)2D production
is restored and extra-renal production of 1,25(OH)2D is
reduced. A decrease in elevated 1,25(OH)2D means less
systemic inflammation, as these studies of olmesartan
indicate:
•Improvement of glycemic control and insulin resistance
was only observed in the olmesartan group and these
effects of olmesartan might be mediated by an anti-
inflammatory action [165].
•Olmesartan treatment significantly reduced serum lev-
els of inflammatory markers; h-CRP, h-TNFa, IL-6,
MCP-1 after 6 weeks of therapy [166].
•Blocking angiotensin-converting enzyme induces
potent regulatory T cells and modulates TH1- and
TH17-mediated autoimmunity [167].
•Blocking angiotensin II receptor increases bone mass
[168,169].
Olmesartan acts in a manner similar to 1,25(OH)2D to
reduce inflammation and, by inference, improve immune
system function. VDR and RAS receptors are distributed in
almost the same tissues. The endogenous VDR ligand
1,25(OH)2D down-regulates the RAS by repressing renin
gene expression to reduce inflammation via the nuclear
factor-kappa B pathway [170]. Olmesartan has a similar
effect in that it reduces angiotensin II (a peptide that is
implicated in the inflammatory process) [171]. Inappro-
priate stimulation of the RAS has been associated with the
pathogenesis of hypertension, heart attack and stroke [151].
Ferder et al. [151] state, ‘‘Changes in RAS activity and
activation of the VDR seem to be inversely related, making
it possible to speculate that both systems could have a
feedback relationship. The combination of RAS blockade
and VDR stimulation appears to be more effective than
each one used individually.’’ Blocking angiotensin II and
stimulating the VDR is what olmesartan appears to
accomplish and this function is consistent with a theory of
VDR incompetence (Fig. 7).
In patients with autoimmune disorders and inflammatory
symptoms, olmesartan is noted to provoke an increase in
inflammatory symptoms indicative of a Jarisch–Herxhei-
mer reaction (JHR). JHR is a cascade of reactions including
inflammation, cytokine release, and endotoxin release as
part of the immune response to the disintegration of
infected cells [172]. This immunopathology suggests
transcription of AMPs by an activated VDR, points to the
presence of occult infection and provides additional evi-
dence that olmesartan is a VDR agonist [167,173,174].
Theoretically, olmesartan restores VDR competence and,
thus, phagocytosis leads to bacterial death; consequently,
inflammation is temporarily increased by cytokine reaction
to microbial endotoxins and cellular debris from dead host
cells and bacteria [175].
Hajishengallis and Lambris [92] conclude that a block-
ade of hijacked receptors of the innate immune system may
offer promising options to control infection and associated
immunopathology. Although this use of olmesartan is off-
label, its safety profile is well established [176]. The
multiple, documented beneficial effects of olmesartan,
including the ability to reduce cardiovascular and kidney
disease, prevent migraines, and reduce oxidative stress,
also suggest it could play a key role in the resolution of
chronic systemic inflammation [177,178].
Clinical use of olmesartan
Olmesartan is being used as a novel VDR ligand in the
clinical setting [179]. Immunotherapy with olmesartan may
also include pulsed administration of select MIC (mini-
mum inhibitory concentration) oral antibiotics to weaken
and help eradicate the intracellular pathogens. With each
antibiotic dose, inflammatory symptoms (JHR) wax and
wane, providing further evidence of persistent infection
[180]. Changes in laboratory findings (e.g., BUN, creati-
nine, CRP, blood counts, liver enzymes) often point to
areas of occult inflammation. A correlating treatment
Fig. 6 Proposed hypothesis for restoring renal control of
1,25(OH)2D with olmesartan. Olmesartan is believed to decrease
elevated 1,25(OH)2D by several mechanisms
Inflammation, vitamin D, infection
123
strategy is the avoidance of excessive sunlight exposure,
foods high in vitamin D and vitamin D supplements to
maintain serum 25(OH)D at a level (20–30 ng/ml) that is
not likely to suppress the immune system and inhibit
bacterial elimination [122,135,137].
Accumulating case reports now support the observation
that a number of complex, chronic conditions can be
improved by restoring VDR function using this type of
immunotherapy [179,181,182]. It is becoming increas-
ingly clear that microbes slow down immune reactivity by
dysregulating the VDR, ultimately to increase their chance
of survival. Immune modulatory therapies that enhance
VDR expression and activity should, therefore, be con-
sidered in the clinical setting [183].
Discussion
Vitamin D is essential for many important biological pro-
cesses and most people get an adequate supply from
exposure to sunlight (Table 2). Long-term studies are
needed to determine if low 25(OH)D in healthy individuals
leads to disease. Evidence that vitamin D supplementation
cures or prevents chronic disease is inconsistent. Despite
increased supplementation chronic inflammatory diseases
are on the rise. Attention to the alternate hypothesis—low
25(OH)D is a consequence of the chronic disease process,
provoked by persistent intracellular infection—may be
crucial to reversing this trend and needs further research.
The prevailing dogma that the level of serum 25(OH)D
provides an accurate assessment of vitamin D status needs
closer examination. Circulating levels of 25(OH)D may not
be an accurate reflection of vitamin D status. In those with
an autoimmune disease or chronic inflammatory symp-
toms, 1,25(OH)2D may be elevated. This can lead to
osteoporosis and cause inhibition of innate immunity,
which is contraindicated in the presence of infection. The
resulting immunosuppression may promote persistent
Fig. 7 Effect of treatment with
olmesartan and antibiotics on
inflammatory symptoms.
Olmesartan up-regulates the
vitamin D receptor to improve
innate immune system function
and reduce elevated
1,25(OH)2D. Avoidance of
immunosuppressants and
elevated 25(OH)D also
improves immune system
function. Inflammatory
symptoms gradually resolve as
intracellular bacteria are slowly
eliminated with the help of
select low-dose, pulsed
antibiotics
Table 2 Key points
Vitamin D is a steroid hormone which regulates immune system
function
Photosynthesis of vitamin D
3
provides adequate vitamin D stores for
most individuals
Low levels of 25(OH)D are seen in healthy individuals, as well as
those with chronic inflammatory conditions
Studies are inconsistent regarding the health benefits of increasing
vitamin D stores; vitamin D supplementation may have negative
effects
25(OH)D may not always reflect the level of 1,25(OH)D; accurate
assessment of vitamin D status depends on measuring both
metabolites
Intracellular, cell wall deficient bacteria may cause dysregulated
vitamin D metabolism and impaired immune system function
A novel, non-vitamin D VDR ligand (an angiotensin receptor blocker)
appears to reactivate the immune system, restore VDR competence,
correct dysregulated vitamin D metabolism and reduce
inflammatory symptoms
M. Mangin et al.
123
infection which has been implicated in chronic inflamma-
tory diseases.
Human cells live in harmony with many types of
microbes but some microbes may become pathogenic under
commonly experienced conditions. The innate immune
system is designed to kill pathogens via 1,25(OH)2D-
mediated VDR transcription of anti-microbial peptides but
microbes may use strategies which down-regulate the VDR
in order to live and reproduce within nucleated host cells.
Studies using more advanced cell culture and molecular
techniques are confirming the presence of previously
undetected intracellular bacteria. Defense mechanisms that
intracellular bacteria use to persist and proliferate need to be
investigated. Pathogen-induced VDR dysfunction which
causes the release of pro-inflammatory cytokines appears to
be at the root of chronic disease and low 25(OH)D.
Improving VDR activation may be the key to reducing
inflammatory diseases. Treatments that up-regulate the
VDR to restore normal immune function, reduce inflam-
mation and eradicate persistent bacterial infections require
further research. An immunotherapy which has demon-
strated efficacy in reversing vitamin D metabolism
dysfunction and reducing inflammatory symptoms is cur-
rently being used by clinicians and warrants formal study.
In summary, elevated 1,25(OH)2D, often accompanied
by reduced 25(OH)D, is a clinical sign of dysregulated
vitamin D metabolism and evidence that the immune sys-
tem is competing with parasitic microbes for VDR
dominance. Failure of the immune system to mount an
effective anti-microbial response results in persistent
intracellular infection. This induces relentless inflammation
(immunopathology) which causes tissue damage and dis-
ease symptoms.
Acknowledgments The authors wish to gratefully acknowledge the
reviewers who commented on the original manuscript and provided
helpful, expert advice. We thank the editor of Inflammation Research,
Dr. Mauro Teixeira, for his kind consideration of our work. Special
thanks to Tapen Sinha for sharing with us his expertise regarding
manuscript formatting and submission. We thank Tom Mangin, Belinda
Fenter, Terry Fenter, Debbie Yeager and John Yeager for their support.
And we acknowledge with gratitude the generous donors to Chronic
Illness Recovery who have enabled us to continue our research.
Open Access This article is distributed under the terms of the
Creative Commons Attribution License which permits any use, dis-
tribution, and reproduction in any medium, provided the original
author(s) and the source are credited.
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