Chronic inflammatory disease features
Many characteristics of CIDs are consistent with the PHM hypothesis.
Given the diversity of exposures, the PHM hypothesis suggests that PHMs
are numerous and each patient has a unique mix of PHMs colonizing varied
tissues. Consequently, comorbidities among CIDs would be expected to be
common and allergic, autoimmune and other inflammation-related diseases
would have significant overlap. And this is increasingly being found.
Allergy is being found in autoimmune and other CIDs. For example, in a
large retrospective analysis of a UK population, Krishna et al[109]
found a significantly higher rate of at least one of 3 allergic diseases
(allergic rhinoconjunctivitis, atopic eczema and asthma) in almost all
of the 11 CIDs that they examined. Allergic disorders or sensitization
have been found to be associated with Type 1 diabetes[110–112] and
with diabetes associated autoantibodies[113]. A recent analysis
indicated that celiac disease and HLA-related autoimmune disease
susceptibility was associated with IgE sensitization in young
children[114].
Autoantibodies are common and occur even in people who are
healthy[115,116]. It has been proposed that autoantibodies might
only become a problem when there is a source of chronic immune
activation, e.g. from chronic infection, causing a higher level of
autoimmunity than usual[115].
Autoantibodies have been detected in non-autoimmune diseases such as
asthma[117], chronic rhinosinusitis[118], idiopathic pulmonary
fibrosis[119] and COPD[120]. IgE antibodies targeting
self-antigens (auto allergy) are found in many autoimmune/inflammatory
diseases[121], including systemic lupus erythematosus (SLE), Graves’
disease, multiple sclerosis and rheumatoid arthritis. According to the
PHM hypothesis, auto allergy could be the result of cross-reactions
between colonizing PHMs and self-tissue.
The respiratory tract has been found to be involved in a number of
autoimmune diseases, including rheumatoid arthritis, SLE and systemic
sclerosis[122]. Epidemiological research shows that inflammatory
bowel disease (IBD) is often preceded by airway diseases[123]. These
findings are consistent with a connection between inhaled microbes and
non-respiratory diseases.
Evidence linking stress to autoimmune diseases[8,9,124] and allergic
diseases[38,125] has been accumulating. Elevated resting heart rate
and low heart rate variability occur with increased stress[126,127]
and have been associated with all-cause mortality[128–132]. Sleep
disturbances, which may be related to stress, may predispose to the
development of autoimmune disease[86].
Other components of the PHM hypothesis are also found commonly in CIDs.
Specifically, opportunistic pathogens[5,24,133,134] and/or
dysbiosis[24,134,135] have been documented in many CIDs. Dietary
alterations that would tend to reduce PHM exposure are showing benefit,
as will be discussed in more detail in a later section.
An example of a CID that potentially fits the PHM hypothesis is
sarcoidosis, a systemic disease marked by chronic granulomatous lung
inflammation. It has been linked to mold exposure in damp buildings, and
these damp buildings likely would have elevated PHM levels. A
study[136] found evidence for increased sensitivity to fungal and
bacterial antigens in sarcoidosis patients. There has also been research
suggesting a causal role for bacterial infection[137,138].
Antifungal[139] and antibacterial[140,141] approaches in
sarcoidosis have shown promise. Their limited success might result at
least partly from some PHMs being less susceptible to most
antimicrobials. This could be due to the potentially polyextremotolerant
nature of PHMs, polymicrobial infections (e.g., requiring multiple
antimicrobials), PHM-induced immune dysregulation and possible chronic
PHM exposure. Although non-PHMs might also be involved, the PHM
hypothesis predicts that the initiators of the disease process would be
PHMs. Secondary opportunistic infections also occur[142].
Many IBD findings also appear to be consistent with the PHM hypothesis.
IBD patients tend to have increased oxygen in their intestinal tract,
resulting from inflammatory processes[143]. This leads to a greater
abundance of oxygen-tolerant Proteobacteria and lower levels of
microbial diversity[143,144]. The family Enterobacteriaceae, within
the Proteobacteria, includes many pathogenic bacteria[144]. A
reduction of species associated with anti-inflammatory effects is also
observed[145]. An immune reaction to commensal microbes can occur as
well, which might be due to the intestinal permeability and immune
activation that develops[146]. Immunosuppressive drugs, an elemental
diet and fecal microbiota transplants are approaches that shown some
benefit in treating IBD[145].
It is not yet known what initiates the inflammatory processes and the
other features of IBD. In one of the IBDs, Crohn’s disease, an
antibiotic combination targeting Mycobacterium avian subspecies
paratuberculosis (MAP) infection has been reported to lead to long-term
disease remission[147–151]. Agrawal et al[149] discuss recent
promising data and addresses several common objections regarding MAP’s
role, making a compelling case for the involvement of MAP or similar
species. It has also been suggested that other CIDs might be caused by
MAP[152].
How MAP is acquired is still uncertain[153]. If its acquisition is
related to a westernized diet or lifestyle it might itself be considered
to be a PHM.
There has also been increasing evidence for the cold chain hypothesis
for Crohn’s disease, which postulates an inflammation-provoking role for
Yersinia spp ingested from refrigerated food[41]. Substantiation of
the MAP and cold chain hypotheses is hampered by the difficulty of
detecting the implicated microbes and their relatively low
pathogenicity.
Diverse IBD hypotheses could be seen as unified and explained by the PHM
hypothesis. Both MAP and Yersinia spp could be viewed as opportunistic
pathogens that take advantage of PHM-induced immune system
dysregulation. Other microbes could contribute to disease as well (e.g.,
fungi[154]), and the particular species/strains involved could vary
among individuals.
The anti-mycobacterial antibiotic approach targeting MAP shows signs of
working best early in disease[151]. Perhaps this is because fewer
PHMs and opportunistic infections that dysregulate/suppress the immune
system have colonized and increased.
PHM-induced immune dysregulation or suppression postulated by the PHM
hypothesis might be thought of as analogous to HIV weakening the immune
system and leading to secondary infections. But in this case, the PHMs’
effects on the immune system are proposed to be typically more subtle
and the opportunistic infections may be harder to detect.
The PHM hypothesis can also explain the connection of IBD with a
westernized diet[11], food reactions[155,156], allergic
diseases[109,157–159] stress[160,161] and microbe-rich
environment associated lung diseases[123,162]. The periodic
exacerbations in IBD may often be due to variations in exposure to
inhaled/ingested PHMs and/or stress from PHM reactions, sometimes
combined with psychological stress[2]. Seasonal variation in IBD
disease activity that appears to be linked to inhalant allergies has
been found[158]. The implicated foods and inhalants may be
associated with PHMs or might cross-react with PHMs. The PHM hypothesis
can also potentially explain the reported effectiveness of varied
dietary interventions in IBD (see diet section below).
Thus, looking at diverse types of observations, it appears that many
CIDs are compatible with the PHM hypothesis. The evidence supporting the
PHM hypothesis for a number of other CIDs is discussed in more detail
elsewhere[2].