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Inflammation and vitamin D: the infection connection

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Abstract and Figures

Introduction: Inflammation is believed to be a contributing 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 supplementation 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.
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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
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
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
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
Inflamm. Res.
DOI 10.1007/s00011-014-0755-z Inflammation Research
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
is photosynthesized in the skin or
when vitamin D
or D
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
M. Mangin et al.
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
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
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
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
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
Inflammation, vitamin D, infection
However, despite the up to fourfold reduction in vitamin
production in a 70-year-old compared to a 20-year-old,
the skin has such a high capacity to make vitamin D
elders exposed to sunlight will produce an adequate
amount of vitamin D
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
. 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
, is a result of an inflammatory
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.
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
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
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
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
[7883]. 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.
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
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
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
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
1,25(OH)2D is elevated in the synovial fluid of patients
with RA (rheumatoid arthritis) [120].
Crohn’s disease decreases expression of cathelicidin
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
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.
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
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
25(OH)D so 25(OH)D is down-regulated [148].
1,25(OH)2D inhibits the hepatic synthesis of 25(OH)D
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
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
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
vitamin D
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
However, a high result may be discovered even at
trough level.
1,25(OH)2D levels are regulated by PTH, calcium,
This is not true if extra-renal production is prevalent
1,25(OH)2D does not decrease until 25(OH)D is very
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
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.
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
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
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
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].
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
Table 2 Key points
Vitamin D is a steroid hormone which regulates immune system
Photosynthesis of vitamin D
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
25(OH)D may not always reflect the level of 1,25(OH)D; accurate
assessment of vitamin D status depends on measuring both
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.
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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Inflammation, vitamin D, infection
... Since all tissues in the body need vitamin D metabolites, vitamin D deficiency negatively affects all body systems. Hypovitaminosis D increases generalized inflammation and oxidative stress, vulnerability to infections, risks for several vital diseases, and worsens all chronic conditions [30][31][32]. Besides, vitamin D has pleiotropic effects, especially on the immune, musculoskeletal, cardiovascular, pulmonary, neurological, gastrointestinal, and renal systems. Vitamin D deficiency increases the susceptibility to infections, the severity [1], complications, and deaths [33][34][35]. ...
... Sufficient calcitriol synthesis within immune cells prevents inflammation, oxidative stress, infections, and autoimmune diseases [30,31]. Calcitriol suppresses the expression of inflammatory cytokines and increases the expression of anti-inflammatory cytokines and anti-oxidants [59,70]. ...
... Calcitriol suppresses the expression of inflammatory cytokines and increases the expression of anti-inflammatory cytokines and anti-oxidants [59,70]. Most chronic diseases are accompanied by chronic inflammation, which maintains the condition [30]. In addition, calcitriol enhances the production and release of antimicrobial peptides, cathelicidin, and beta-defensin via its autocrine and paracrine signaling. ...
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The prevalence of chronic diseases increases with age, especially in those with co-morbidities. The two most common denominators are the high prevalence of vitamin D deficiency and concentrations of angiotensin-converting enzyme receptor-2 (ACE2). Whether vitamin deficiency initiates or aggravates chronic diseases is unclear. Hypovitaminosis D negatively affects all body systems, especially the musculoskeletal immune systems. Many chronic conditions and infections can be minimized using the right vitamin D supplements administered at the right frequency (daily or once weekly) or direct exposure to one-third of the skin between 10:30 AM and 1:30 PM, in summer-like sunlight, for up to 60 minutes depending on the skin tone. It is advisable to wear sunglasses and a brimmed hat to protect one’s eyes and face. Maintaining the population serum 25(OH)D concentration above ng/mL (i.e., sufficiency) ensures a better immune system, minimizing symptomatic diseases and reducing infections and chronic diseases. The best clinical outcome and longevity are expect from maintaining the serum 25-hydroxyvitamin D concentrations between 50 and 80 ng/mL.
... Vitamin D deficiency universally impairs its intended benefits in all body systems. Its deficiency increases the vulnerability to infections, increases generalized inflammation, increases risks for diseases and infections, and worsens chronic diseases [12,39,40]. Consequently, hypovitaminosis increases the susceptibility to infections and diseases and enhances the severity of illnesses [41], leading to increased complications and premature deaths [42][43][44]. ...
... Sufficient calcitriol synthesis within immune cells prevents autoimmune reactions profoundly and controls inflammation and infections [39,40]. These physiological actions manifest by suppressing the expression of inflammatory cytokines and increasing the expression of anti-inflammatory cytokines and anti-oxidative compounds [70,94]. ...
... These physiological actions manifest by suppressing the expression of inflammatory cytokines and increasing the expression of anti-inflammatory cytokines and anti-oxidative compounds [70,94]. Most chronic diseases are associated with chronic inflammation that maintains the disease process [39]. In addition, calcitriol enhances the production and release of antimicrobial peptides, cathelicidin, and beta-defensin via its autocrine and paracrine actions (Figure 1). ...
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Apart from developmental disabilities, the prevalence of chronic diseases increases with age especially in those with co-morbidities: vitamin D deficiency plays a major role in it. Whether vitamin D deficiency initiates and/or aggravates chronic diseases or vice versa is unclear. It adversely affects all body systems but can be eliminated using proper doses of vitamin D supplementation and/or safe daily sun exposure. Maintaining the population serum 25(OH)D concentration above 40 ng/mL (i.e., sufficiency) ensures a sound immune system, minimizing symptomatic diseases and reducing infections and the prevalence of chronic diseases. This is the most cost-effective way to keep a population healthy and reduce healthcare costs. Vitamin D facilitates physiological functions, overcoming pathologies such as chronic inflammation and oxidative stress and maintaining broader immune functions. These are vital to overcoming chronic diseases and infections. Therefore, in addition to following essential public health and nutritional guidance, maintaining vitamin D sufficiency should be an integral part of better health, preventing acute and chronic diseases and minimize their complications. Those with severe vitamin D deficiency have the highest burdens of co-morbidities and are more vulnerable to developing complications and untimely deaths. Vitamin D adequacy improves innate and adaptive immune systems. It controls excessive inflammation and oxidative stress, generates antimicrobial peptides, and neutralizes antibodies via immune cells. Consequently, vitamin D sufficiency reduces infections and associated complications and deaths. Maintaining vitamin D sufficiency reduces chronic disease burden, illnesses, hospitalizations, and all-cause mortality. Vulnerable communities, such as ethnic minorities living in temperate countries, older people, those with co-morbidities, routine night workers, and institutionalized persons, have the highest prevalence of vitamin D deficiency—they would significantly benefit from vitamin D and targeted micronutrient supplementation. At least now, health departments, authorities, and health insurance companies should start assessing, prioritizing, and encouraging this economical, non-prescription, safe micronutrient to prevent and treat acute and chronic diseases. This approach will significantly reduce morbidity, mortality, and healthcare costs and ensure healthy aging.
... Vitamin D plays an important role in bone hemostasis, prevention of some cardiovascular diseases, stimulation of insulin secretion, and the regulation of the immune system and inflammatory processes (6,7). Individuals with vitamin D deficiency are prone to infection and sepsis (8,9). Vitamin D plays an important role in the regulation of immunomodulatory function through the presence of vitamin D receptors in most immune cells (10). ...
... Interestingly, some previous evidence suggested an interaction between response to ICI and vitamin D metabolism. For example, a decrease in the vitamin D binding protein (DBP), which sequestrates calcidiol and blocks its conversion to calcitriol in T cells [15], was associated with a prolonged overall survival in patients with advanced renal cancer treated with the anti-PD-L1 atezolizumab [16]. ...
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Background: Hypovitaminosis D can have a negative prognostic impact in patients with cancer. Vitamin D has a demonstrated role in T-cell-mediated immune activation. We hypothesized that systematic vitamin D repletion could impact clinical outcomes in patients with cancer receiving immune-checkpoint inhibitors (ICIs). Methods: We planned a prospective observational study (PROVIDENCE) to assess serum vitamin D levels in patients with advanced cancer receiving ICIs (cohort 1 at treatment initiation, cohort 2 during treatment) and the impact of systematic repletion on survival and toxicity outcomes. In an exploratory analysis, we compared the clinical outcomes of cohort 1 with a control cohort of patients followed at the participating centers who did not receive systematic vitamin D repletion. Results: Overall, 164 patients were prospectively recruited in the PROVIDENCE study. In cohort 1, consisting of 101 patients with 94.1% hypovitaminosis (≤ 30 ng/ml) at baseline, adequate repletion with cholecalciferol was obtained in 70.1% at the three months re-assessment. Cohort 2 consisted of 63 patients assessed for vitamin D at a median time of 3.7 months since immunotherapy initiation, with no patients having adequate levels (> 30 ng/ml). Even in cohort 2, systematic supplementation led to adequate levels in 77.8% of patients at the three months re-assessment. Compared to a retrospective control group of 238 patients without systematic vitamin D repletion, PROVIDENCE cohort 1 showed longer overall survival (OS, p = 0.013), time to treatment failure (TTF, p = 0.017), and higher disease control rate (DCR, p = 0.016). The Inverse Probability of Treatment Weighing (IPTW) fitted multivariable Cox regression confirmed the significantly decreased risk of death (HR 0.55, 95%CI: 0.34-0.90) and treatment discontinuation (HR 0.61, 95%CI: 0.40-0.91) for patients from PROVIDENCE cohort 1 in comparison to the control cohort. In the context of longer treatment exposure, the cumulative incidence of any grade immune-related adverse events (irAEs) was higher in the PROVIDENCE cohort 1 compared to the control cohort. Nevertheless, patients from cohort 1 experienced a significantly decreased risk of all grade thyroid irAEs than the control cohort (OR 0.16, 95%CI: 0.03-0.85). Conclusion: The PROVIDENCE study suggests the potential positive impact of early systematic vitamin D supplementation on outcomes of patients with advanced cancer receiving ICIs and support adequate repletion as a possible prophylaxis for thyroid irAEs.
... Additionally, studies uncovered the widespread distribution and expression of the vitamin D receptor and its related metabolic enzymes in fat, pancreas, pituitary, and thyroid cells, indicating vitamin D's pleiotropic functions in health and diseases [3]. Previous studies have demonstrated that low 25(OH)D levels are related to infection [4,5], autoimmune diseases [6,7], and endocrine metabolic disorders such as diabetes [8], adrenal diseases [9], and polycystic ovary syndrome [10]. Recent evidence indicated a relationship between vitamin D concentrations and thyroid diseases, including autoimmune thyroid disease and thyroid cancer [11]. ...
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The relationship between vitamin D deficiency and sensitivity to thyroid hormones was unclear. We aimed to explore the association of 25-hydroxyvitamin D (25(OH)D) levels with thyroid hormone sensitivity in euthyroid adults. A total of 3143 subjects were included. The serum 25(OH)D, free thyroxine (FT3), free thyrotropin (FT4), thyroid-stimulating hormone (TSH), and other clinical variables were measured. Vitamin D deficiency was defined as 25(OH)D < 20 ng/mL. Thyroid feedback quantile-based index (TFQI), parametric thyroid feedback quantile-based index (PTFQI), thyroid-stimulating hormone index (TSHI), thyrotrophic thyroxine resistance index (TT4RI), and FT3/FT4 were calculated to assess thyroid hormone sensitivity. Results showed that 58.8% of the participants had vitamin D deficiency. They had significantly higher levels of triglyceride, insulin, FT3, FT4, TSH, TFQI, PTFQI, TSHI, and TT4RI and lower levels of high-density lipoprotein cholesterol than those with sufficient vitamin D (all p < 0.05). Logistic regression analysis showed that the risk of impaired sensitivity to thyroid hormones evaluated by TFIQ, PTFQI, TSHI, and TT4RI increased by 68% (OR: 1.68; 95%CI: 1.45–1.95; and p < 0.001), 70% (OR: 1.70; 95%CI: 1.46–1.97; and p < 0.001), 66% (OR: 1.66; 95%CI: 1.43–1.92; and p < 0.001), and 50% (OR: 1.50; 95%CI: 1.30–1.74; and p < 0.001), respectively, in participants with vitamin D deficiency compared with those with sufficient vitamin D after adjusting for multiple confounders. In conclusion, in euthyroid populations, vitamin D deficiency was associated with impaired sensitivity to thyroid hormones.
... A low vitamin D status most likely occurs in the winter season, in particular in the about 15% of the world's population living above a latitude of 38 • N [71,72], i.e., when there is low or no endogenous vitamin D 3 production. High vitamin D responders better tolerate these conditions and should suffer less frequently from autoimmune diseases [73], infections [74], and/or cancer [75] because vitamin D contributes to the prevention of these diseases. In contrast, low vitamin D responders represent a vulnerable part of society that requires higher vitamin D 3 supplementation doses than suggested by population-based recommendations and guidelines that may serve primarily mid vitamin D responders. ...
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Vitamin D intervention studies are designed to evaluate the impact of the micronutrient vitamin D3 on health and disease. The appropriate design of studies is essential for their quality, successful execution, and interpretation. Randomized controlled trials (RCTs) are considered the “gold standard” for intervention studies. However, the most recent large-scale (up to 25,000 participants), long-term RCTs involving vitamin D3 did not provide any statistically significant primary results. This may be because they are designed similarly to RCTs of a therapeutic drug but not of a nutritional compound and that only a limited set of parameters per individual were determined. We propose an alternative concept using the segregation of study participants into different groups of responsiveness to vitamin D3 supplementation and in parallel measuring a larger set of genome-wide parameters over multiple time points. This is in accordance with recently developed mechanistic modeling approaches that do not require a large number of study participants, as in the case of statistical modeling of the results of a RCT. Our experience is based on the vitamin D intervention trials VitDmet, VitDbol, and VitDHiD, which allowed us to distinguish the study participants into high, mid, and low vitamin D responders. In particular, investigating the vulnerable group of low vitamin D responders will provide future studies with more conclusive results both on the clinical and molecular benefits of vitamin D3 supplementation. In conclusion, our approach suggests a paradigm shift towards detailed investigations of transcriptome and epigenome-wide parameters of a limited set of individuals, who, due to a longitudinal design, can act as their own controls.
... Interestingly, increased α-1,25(OH)2D 3 and normal 25(OH)D levels have been found in PD patients under sustained inflammation and elevated inflammatory cytokine levels. Inflammation and low VD are somewhat believed to have a cause-effect relationship with each other (Mangin et al., 2014). VD also decreased the mRNA expression of proinflammatory cytokines in specific areas of the brain, thereby T A B L E 3 : GC (vitamin D binding protein) polymorphisms and association with vitamin D level of Parkinson's disease patients. ...
Parkinson's disease (PD) and vitamin D share a unique link as vitamin D deficiency (VDD) prevails in PD. Thus, an in-depth understanding of vitamin D biology in PD might be crucial for therapeutic strategies emphasising vitamin D. Specifically, explicating the effect of VDD and genetic polymorphisms of vitamin D-associated genes in PD, like VDR (vitamin D receptor) or GC (vitamin D binding protein) may aid the process along with polymorphisms of vitamin D metabolising genes (e.g., CYP2R1 and CYP27A1) in PD. Literature review of single nucleotide polymorphisms (SNPs) related to vitamin D levels [GC (GC1-rs7041 and GC2-rs4588), CYP2R1, CYP24A1 and CYP27B1] and vitamin D function [VDR (FokI - rs2228570 and rs10735810; ApaI - rs7976091, rs7975232BsmI and rs1544410; and TaqI - rs731236)] was conducted to explore their relationship with PD severity globally. VDR-FokI polymorphism was reported to be significantly associated with PD in Hungarian, Chinese and Japanese populations, whereas VDR-ApaI polymorphism was found to affect PD in the Iranian population. However, VDR-TaqI and BsmI polymorphisms had no significant association with PD severity. Conversely, GC1 polymorphisms reportedly affected vitamin D levels without influencing the disease severity. CYP2R1 (excluding rs1993116) was also reportedly linked to clinical manifestations of PD. Genetic polymorphisms might cause VDD despite enough sunlight exposure and vitamin D-rich food intake, enhancing inflammation, there by influencing PD pathophysiology. Knowledge of the polymorphisms associated with VDD appears promising for developing precision vitamin D-dosing therapeutic strategies against PD.
... 18 Because the vitamin D metabolites are implicated in the induction of antimicrobial activity and have anti-inflammatory and immune-system modulating properties. 19,20 Failure to eradicate H. pylori may be associated with vitamin D deficiency, necessitating vitamin D supplementation prior to H. pylori eradication. 21 VDR has a role in the immune-modulating abilities of active vitamin D. 22 Vitamin D receptor gene polymorphisms (ApaI and TaqI) lead to decreased vitamin D level which associated with the response to treatment. ...
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Background & aims: This research aimed to determine how variations in the vitamin D receptor gene affected the response of H. pylori infections to eradication therapy. Patients and methods: On 105 adult H. Pylori-positive patients, a prospective cohort study was carried out. PCR was used to genotype all patients' VDR gene polymorphisms. The patients in the study received standard triple eradication medication (clarithromycin 500 mg, amoxicillin 1000 mg, and omeprazole 20 mg) twice daily for 14 days. A stool test for H. pylori Ag was conducted 4 weeks following the end of treatment. Results: In our study, the usual triple therapy's H. pylori eradication rate was 75.2%. The successful eradication of H. pylori and VDR rs 2228570 gene polymorphisms was more prevalent in CT gene polymorphism (64.6%) compared to non-responders (19.2%), while treatment failure was more prevalent in CC gene polymorphism (73.1% in non-responders compared to responders 24.1%), which is statistically significant. In regards to the eradication of H. pylori and VDR rs7975232 gene polymorphisms, the success of eradication was more prevalent in AC gene polymorphism (54.4%) vs non-responders (30.4%), while all patients (14) with gene AA (17.7%) are responders to standard treatment, while the failure of treatment was more prevalent in CC gene polymorphism (69.2% in non-responder vs 27.8% in responders) which is statistically significant. Our findings demonstrated a strong correlation between patients' responses to H. pylori treatment and polymorphisms in the VDR gene (ApaI and TaqI) (P 0.05). Conclusion: As far as we are aware, this is the first study to identify a potential link between the FokI and Apal VDR polymorphism and treatment response in H pylori-positive patients. To evaluate the findings, more research with larger number of patients and different population is required.
Colorectal cancer (CRC) is one of the most life‐threatening neoplasias in terms of incidence and mortality worldwide. Vitamin D deficiency has been associated with an increased risk of CRC. 1α,25‐dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ], the most active vitamin D metabolite, is a pleiotropic hormone that, through its binding to a transcription factor of the nuclear receptor superfamily, is a major regulator of the human genome. 1,25(OH) 2 D 3 acts on colon carcinoma and stromal cells and displays tumor protective actions. Here, we review the variety of molecular mechanisms underlying the effects of 1,25(OH) 2 D 3 in CRC, which affect multiple processes that are dysregulated during tumor initiation and progression. Additionally, we discuss the epidemiological data that associate vitamin D deficiency and CRC, and the most relevant randomized controlled trials of vitamin D 3 supplementation conducted in both healthy individuals and CRC patients.
Vitamin D exerts its antiviral effect through vitamin D receptor (VDR)/retinoid X receptor-mediated host immunomodulation. Besides the downregulation of VDR expression, its polymorphism was also observed among hepatitis B virus (HBV)-positive patients. To understand the possible link between VDR polymorphism and its altered expression during HBV infection and disease progression, VDR Apa-I [rs7975232 (C>A)] single nucleotide polymorphism (SNP) was analyzed in a case-control manner. VDR Apa-I (rs7975232, C>A) polymorphism was studied using 340 HBV patients and 102 healthy controls. Genotype analysis and gene expression study was performed using restriction fragment length polymorphism and quantitative polymerase chain reaction, respectively. Statistical analysis was performed using SPSS (IBM) considering p-value <0.05 as significant for comparing the differences between the groups. Significant mean difference in VDR expression was observed between HBV-positive patients (1.6 ± 0.94) and controls (0.69 ± 0.73). Furthermore, the mean fold change of Healthy control with CC genotype (1.92 ± 0.99) was found to be marginally significant compared with mutant genotype (CA/AA) (1.08 ± 0.43/0.59 ± 0.56, p = 0.045). In HBV+ patients, the mean fold change in the CC genotype was 0.88 ± 0.38, which exhibits a significant mean difference upon comparison with other genotypes (0.52 ± 0.49, 0.113 ± 0.34; p = 0.018, p = 0.048). However, the fold change value does not differ between CA and AA genotypes. Further comparative analysis of VDR expression between the control and case also exhibits significant differences (p = 0.001) among allelic variants. Observed genotype distribution frequency exhibits a significant association with disease type. The mutant genotype was found to be significantly associated with HBV infection and disease progression, (odds ratio = 0.730, 95% confidence interval = 0.462-1.152, p = 0.06). VDR SNP rs7975232 (C>A) may affect VDR expression by controlling several other variables and suggest that deviation from wild-type genotype (CC) is associated with downregulation of expression, which in turn involved in host immunomodulation in favor of HBV infection and disease progression.
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Nutritional rickets remains a public health problem in many countries, despite dramatic declines in the prevalence of the condition in many developed countries since the discoveries of vitamin D and the role of ultraviolet light in prevention. The disease continues to be problematic among infants in many communities, especially among infants who are exclusively breast-fed, infants and children of dark-skinned immigrants living in temperate climates, infants and their mothers in the Middle East, and infants and children in many developing countries in the tropics and subtropics, such as Nigeria, Ethiopia, Yemen, and Bangladesh. Vitamin D deficiency remains the major cause of rickets among young infants in most countries, because breast milk is low in vitamin D and its metabolites and social and religious customs and/or climatic conditions often prevent adequate ultraviolet light exposure. In sunny countries such as Nigeria, South Africa, and Bangladesh, such factors do not apply. Studies indicated that the disease occurs among older toddlers and children and probably is attributable to low dietary calcium intakes, which are characteristic of cereal-based diets with limited variety and little access to dairy products. In such situations, calcium supplements alone result in healing of the bone disease. Studies among Asian children and African American toddlers suggested that low dietary calcium intakes result in increased catabolism of vitamin D and the development of vitamin D deficiency and rickets. Dietary calcium deficiency and vitamin D deficiency represent 2 ends of the spectrum for the pathogenesis of nutritional rickets, with a combination of the 2 in the middle.
Precise maintenance of the physiologic levels of both extracellular and intracellular ionized calcium is essential to life. Calcium and phosphate homeostasis is complex, yet three important hormones are responsible for modulating most of the extracellular control of these minerals. Parathyroid hormone acts directly on bone and kidney and indirectly on the intestine to maintain or restore the serum calcium level. The signal for increased PTH synthesis and secretion is a decrease in the serum ionized calcium concentration and a decrease in serum levels of l,25(OH)2-D. Calcitonin is produced in parafollicular cells of the thyroid and inhibits bone resorption in pharmacologic doses. These cells recognize the calcium signal in a different way. A diminution in serum calcium decreases calcitonin production and release. The role of calcitonin in normal human physiology, however, remains in dispute. Finally, the biologically potent metabolite of vitamin D, l,25(OH)2-D, stimulates intestinal absorption of calcium and phosphate. It also probably plays a role in the orderly mineralization and resorption of bone and has some influence on renal resorption of filtered calcium and phosphorus. A major stimulus to its production by proximal renal tubule cells is elevated PTH and decreased serum levels of calcium and phosphate. The absence of PTH as well as high serum calcium and phosphate levels can reduce its synthesis and secretion. These three hormones along with other mediators and messengers work in concert to maintain the normal calcium homeostasis.¹⁸ A disturbance at any level in this intricate regulatory network will result in a host of compensatory changes that may lead to clinical disease. A complete understanding of these normal mechanisms is a prerequisite to investigating the etiology and treatment of the various pathologic responses seen with many of the metabolic bone disorders.
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 pathogenic. This review includes details on the diverse forms and functions of individual bacteria and attempts to make this information relevant to the care of patients. A series of experimental studies involving host-bacterium interactions illustrates the probability that most bacteria exposed to a deleterious host environment can assume a form quite different from that of a free-living bacterium. A hypothesis is offered for a kind of reproductive cycle of morphologically aberrant bacteria as a means to relate their diverse tissue forms to each other. Data on the basic biology of persistent bacteria are correlated with expression of disease and particularly the mechanisms of both latency and chronicity that typify certain infections. For example, in certain streptococcal and nocardial infections, it has been clearly established that wall-defective forms can be induced in a suitable host. These organisms can survive and persist in a latent state within the host, and they can cause pathologic responses compatible with disease. A series of cases illustrating idiopathic conditions in which cryptic bacteria have been implicated in the expression of disease is presented. These conditions include nephritis, rheumatic fever, aphthous stomatitis, idiopathic hematuria, Crohn's disease, and mycobacterial infections. By utilizing PCR, previously nonculturable bacilli have been identified in patients with Whipple's disease and bacillary angiomatosis. Koch's postulates may have to be redefined in terms of molecular data when dormant and nonculturable bacteria are implicated as causative agents of mysterious diseases.
Vitamin D deficiency is now recognized as a pandemic. The major cause of vitamin D deficiency is the lack of appreciation that sun exposure in moderation is the major source of vitamin D for most humans. Very few foods naturally contain vitamin D, and foods that are fortified with vitamin D are often inadequate to satisfy either a child's or an adult's vitamin D requirement. Vitamin D deficiency causes rickets in children and will precipitate and exacerbate osteopenia, osteoporosis, and fractures in adults. Vitamin D deficiency has been associated with increased risk of common cancers, autoimmune diseases, hypertension, and infectious diseases. A circulating level of 25-hydroxyvitamin D of >75 nmol/L, or 30 ng/mL, is required to maximize vitamin D's beneficial effects for health. In the absence of adequate sun exposure, at least 800–1000 IU vitamin D3/d may be needed to achieve this in children and adults. Vitamin D2 may be equally effective for maintaining circulating concentrations of 25-hydroxyvitamin D when given in physiologic concentrations.
Background: Studies suggest that vitamin D supplementation may reduce cancer and fracture risks. Purpose: To examine the benefits and harms of vitamin D with or without calcium supplementation on clinical outcomes of cancer and fractures in adults. Data sources: English-language studies identified from MEDLINE and the Cochrane Central Register of Controlled Trials through July 2011. Study selection: Randomized, controlled trials (RCTs), prospective cohort studies, and nested case-control studies reporting incidence of or death from cancer and fracture outcomes. Data extraction: Multiple reviewers extracted details about participant characteristics, including baseline vitamin D status and use of supplements; details of statistical analyses, including adjustments for confounding; and methodological quality. Differences were resolved by consensus. Data synthesis: 19 RCTs (3 for cancer and 16 for fracture outcomes) and 28 observational studies (for cancer outcomes) were analyzed. Limited data from RCTs suggested that high-dose (1000 IU/d) vitamin D supplementation can reduce the risk for total cancer, and data from observational studies suggested that higher blood 25-hydroxyvitamin D (25-[OH]D) concentrations might be associated with increased risk for cancer. Mixed-effects dose-response meta-analyses showed that each 10-nmol/L increase in blood 25-(OH)D concentration was associated with a 6% (95% CI, 3% to 9%) reduced risk for colorectal cancer but no statistically significant dose-response relationships for prostate and breast cancer. Random-effects model meta-analysis showed that combined vitamin D and calcium supplementation reduced fracture risk (pooled relative risk, 0.88 [CI, 0.78 to 0.99]) in older adults, but the effects differed according to study setting: institution (relative risk, 0.71 [CI, 0.57 to 0.89]) versus community-dwelling (relative risk, 0.89 [CI, 0.76 to 1.04]). One RCT showed adverse outcomes associated with supplementation, including increased risk for renal and urinary tract stones. Limitations: Most trial participants were older (aged≥65 years) postmenopausal women. Observational studies were heterogeneous and were limited by potential confounders. Conclusion: Combined vitamin D and calcium supplementation can reduce fracture risk, but the effects may be smaller among community-dwelling older adults than among institutionalized elderly persons. Appropriate dose and dosing regimens, however, require further study. Evidence is not sufficiently robust to draw conclusions regarding the benefits or harms of vitamin D supplementation for the prevention of cancer. Primary funding source: Agency for Healthcare Research and Quality.
Low serum concentrations of 25-hydroxyvitamin D (25[OH]D) have been associated with many non-skeletal disorders. However, whether low 25(OH)D is the cause or result of ill health is not known. We did a systematic search of prospective and intervention studies that assessed the effect of 25(OH)D concentrations on non-skeletal health outcomes in individuals aged 18 years or older. We identified 290 prospective cohort studies (279 on disease occurrence or mortality, and 11 on cancer characteristics or survival), and 172 randomised trials of major health outcomes and of physiological parameters related to disease risk or inflammatory status. Investigators of most prospective studies reported moderate to strong inverse associations between 25(OH)D concentrations and cardiovascular diseases, serum lipid concentrations, inflammation, glucose metabolism disorders, weight gain, infectious diseases, multiple sclerosis, mood disorders, declining cognitive function, impaired physical functioning, and all-cause mortality. High 25(OH)D concentrations were not associated with a lower risk of cancer, except colorectal cancer. Results from intervention studies did not show an effect of vitamin D supplementation on disease occurrence, including colorectal cancer. In 34 intervention studies including 2805 individuals with mean 25(OH)D concentration lower than 50 nmol/L at baseline supplementation with 50 mug per day or more did not show better results. Supplementation in elderly people (mainly women) with 20 mug vitamin D per day seemed to slightly reduce all-cause mortality. The discrepancy between observational and intervention studies suggests that low 25(OH)D is a marker of ill health. 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. In elderly people, restoration of vitamin D deficits due to ageing and lifestyle changes induced by ill health could explain why low-dose supplementation leads to slight gains in survival.