Page 154 - MI-2-3

Microbes & Immunity Hyphae and healthspan

of the gut microbiome is now recognized as a primary Periodontitis is also linked to ASCVD and obesity.
15
16
determinant of overall health. Data from long COVID Gut profiling revealed an elevated abundance and diversity
(LC) research may have elevated Candida from a mere of Candida species among people who are obese. Indeed,
17
opportunist to a key player in healthspan. Traditionally periodontitis is associated with systemic disease in
considered incidental or opportunistic, more recent general and specifically with the NOD-, LRR-, and pyrin
18
findings suggest that invasive Candida plays a critical domain-containing protein 3 (NLRP3) inflammasome
19
and wide-ranging pathogenic role, even in individuals and transglutaminase, both CO markers. Periodontitis
20
21
who are not overtly immunocompromised. Candida has is directly related to COVID-19 severity and is also linked
22
now been identified as a collaborator with numerous to LC. Candida is directly associated with periodontitis,
23
other pathogens. The overconsumption of refined dysphagia, and hyposalivation. CO may precede and
24
carbohydrates and alcohol has unleashed Candida, potentiate P. gingivalis in addition to Treponema denticola,
25
the primary hyphae-producing gut fungus, which Tannerella forsythia, and other periodontopathic bacteria,
is normally present as a commensal organism in its inducing periodontitis. Refined carbohydrates increase
26
yeast form. These hyphae release candidalysin, a toxin the risk of periodontitis and CO. CO can be both the cause
27
capable of inducing autoantibodies. As Hippocrates and effect of xerostomia, a frequent oral complaint in LC.
28
29
observed, “All diseases begin in the gut,” and the gut, Candida and periodontitis are also linked to zonulin,
30
in turn, begins in the mouth. In this context, Candida the primary determinant of intestinal and endothelial
potentiates pathogenic bacteria, and it is unsurprising permeability. In a study of 33 patients with various
that periodontitis (and Candida) has been linked to inflammatory and autoimmune diseases, 60% of those with
pervasive health issues, including autoimmune diseases, high zonulin levels tested positive for yeast overgrowth.
31
cancer, dementia, atherosclerotic cardiovascular disease Additional links between zonulin, autoimmune disease,
(ASCVD), and other systemic conditions. Candida and Candida have recently been reported. Zonulin is a
overgrowth (CO)-induced periodontitis may serve as biomarker for the development of celiac disease and
32
a pre-cursor to a shortened healthspan; however, the is elevated in inflammatory bowel disease (IBD). CO
33
precise mechanisms remain unclear. Several distinct but has recently been implicated in the etiology of ulcerative
overlapping mechanisms have been proposed: colitis. It may be a primary determinant of chronic disease
34
1) Hyphal aspartyl protease induces the release of zonulin because invading hyphae present mannan epitopes that
2) Hyphal epitopes generate autoantibodies appear to elicit Gq proteins coupled to G-protein coupled
3) Candidalysin induces the production of citrullinated receptor (GPCR) antibodies. Gq is one of the four types
35
peptide antibodies of G alpha protein, which also include Gi, Gs, and G12/13.
4) Citrullinated autoantibodies facilitate Epstein–Barr Gq proteins are associated with chronic diseases. They
36
virus (EBV) escape can also induce pain 37,38 and loss of taste/smell. The
39
5) Hyphae stimulate mast cells to release histamine and effects of histamine and bradykinin are also dependent
41
40
tryptase on Gq-coupled GPCRs. These interconnecting linkages are
6) Altered tryptophan metabolism (ATM) results from shown in Figure 1.
fungal indoleamine dioxygenase (IDO)
7) Candida-induced acetaldehyde suppresses methionine 3. Hyphal protease and zonulin
synthase Candida hyphae secrete aspartyl protease, which
8) Histone deacetylase release is triggered by Candida. activates the protease-activated receptor 2, leading to
42
43
2. Inflammaging, Candida, and periodontitis zonulin release from intestinal epithelial cells. Zonulin
is directly associated with increased intestinal and
Aging is characterized by systemic chronic inflammation, endothelial permeability. Yeast overgrowth is reported
1
known as inflammaging, and is associated with in most individuals with elevated zonulin levels.
31
3
4
autoimmunity, dementia, and cancer. Periodontitis Aspartyl protease facilitates hyphae development, biofilm
2
5
triggers inflammaging and is directly linked to cancer formation, host invasion, and immune evasion. Biofilm
6
risk, dementia, and autoimmune diseases, including formation contributes to cancer progression, dementia,
7,8
45
44
systemic lupus erythematosus (SLE), systemic sclerosis, periodontitis, ASCVD, and autoimmune diseases. 47
9,10
11
46
Hashimoto’s disease, and multiple sclerosis. 13
12
Porphyromonas gingivalis has been implicated in the 4. Hyphal epitopes and autoantibodies
generation of anti-citrullinated protein antibodies (ACPAs) Candida hyphal epitopes include a hyphal wall protein
in patients with rheumatoid arthritis (RA), indicating a that mimics gliadin, associated with celiac disease.
direct biological link between periodontitis and RA. 14 Mannan is another hyphal epitope that may bind lectins
Volume 2 Issue 3 (2025) 146 doi: 10.36922/mi.4736