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].