Candida albicans is a fungus commonly encountered in chronically ill individuals. Recent research provides a more complete picture of how c. albicans fits into the picture of the persons immune dysregulation and gives us a clearer understanding of what the body needs when there is candida overgrowth.
The ability of candida albicans to upregulate NLRP3 inflammasome activation means that candida can be enormously pro-inflammatory in susceptible individuals. Eliminating candida can be of great importance to help reduce inflammation, histamine and improve chronic inflammation as a whole.
Below is a list of some common but not well known side-effects of candida overgrowth.
Candida toxins
Candidalysin is a cytolytic peptide fungal toxin secreted by c. albicans. Nature (2016) states that “This secreted toxin directly damages epithelial membranes, triggers a danger response signaling pathway and activates epithelial immunity.” C. albicans damages epithelia by direct penetrating damage and by induction of NLRP3-mediated inflammation, through mechanisms that involve candidalysin. This toxin causes cellular damage and chronic inflammation, meaning if you have candida overgrowth, they are secreting this toxin which will damage not just the cells in the gut but the whole body and elevate gut and whole body inflammation.
Elevates Chronic inflammation and Th2 dominance
Nature Communications (2018) discusses multiple methods by which c. albicans destroys macrophages, including activation of the NLRP3 inflammasome which causes production of inflammatory cytokines and promotes Th2 dominance, meaning you will have chronic inflammation which will affect the gut, skin, joints, brain and entire body.
Decreases Th1 Immunity
Gut Microbes (2022) paper describes autophagy as an essential protective mechanism by which epithelial cells protect themselves against damage by c. albicans. This is particularly interesting, given that c. albicans is known to promote Th2 dominance in the host, in order to avoid being killed by the host’s adequate Th1 response (Infection and Immunity, 2012). So what this means is that candida causes an increase Th2 production and decrease in Th1 immune cell production. This decreases Interferon Gamma which decreases autophagy and this causes a loss of epithelial defense repair against candida albicans.
In a susceptible host, C. albicans is able to translocate through the gut barrier, promoting its dissemination into deeper organs. C. albicans hyphae can invade human epithelial cells by two well-documented mechanisms: epithelial-driven endocytosis and C. albicans-driven active penetration. One mechanism by which host cells protect themselves against intracellular C. albicans is termed autophagy.
Causes Autoimmune flares and increase Autoimmune intensity
“Candida albicans is both the most common fungal commensal microorganism in healthy individuals and the major fungal pathogen causing high mortality in at-risk populations, especially immunocompromised patients.”
Cell Host & Microbe (2015) paper describes some fascinating interconnections in which c. albicans vaginal infection drives pathogenic inflammation via NLRP3 activation that drives IL-1β generation. However, IL-22, serving as a mucosal barrier protector, “restrains NLRP3 activity,” via production of IL-1 receptor antagonist (IL-1Ra). There are two important points to take from this. The first is that IL-22 has an important protective role in mucosal barrier immunity. However, as with most things in immunology, something that works well at a low level as part of housekeeping can become problematic if the need to evoke the mechanism becomes chronic. In other words, a little upregulation of IL-22 beyond baseline, when needed, can be fine. But, evoking that process in a chronic illness setting can lead to issues. Too much of something is never a good thing. Persistence of c. albicans infection would be expected to over-promote IL-22 as a defense mechanism. If this influences tissue beyond the local epithelia where the infection is occurring, or if autoimmunity involves those tissues (as in Crohn’s disease or Ulcerative Colitis, for example), the IL-22 might be expected to increase antibody glycation, including glycation of auto-reactive antibodies, making existing autoimmunity worse. This is why people with autoimmune disease should never go with untreated dysbiosis. If they keep evoking IL-22, they’ll risk glycating anti-self antibodies and that will make their antibodies more aggressive causing more aggressive flares.
The second notable thing is that the TNFα that’s part of maturing naïve T cells into Th22 cells will also participate in the NFkB/TNFα & IL-1β loop activation. So, while TNFα is driving IL22 production, the IL-22 that gets made will drive production of IL-1Ra (IL-1 receptor antagonist) which will take some of the momentum out of the autocrine loop activation of NFkB. This is a good example of the immune system regulating itself. The inflammatory activation and glycation of antibodies that is useful to kill the candida also creates elements of its own resolution, when things are going well. When the process works, candida is killed and you get resolution. When it doesn’t, the patient is chronically inflamed and Th2 dominant.
This also sharpens the need to identify single nucleotide polymorphisms (genetic SNPs) related to TNFα (rs1800629) and IL-6 (rs1800795). In individuals who are non-wild-type, particularly those homozygous for the defect for one or both of these snp’s, the upregulation of IL-22 might be expected to be more significant, tipping the balance toward an overly exuberant inflammatory response to c. albicans infection. This sharpened response might be expected to more effectively recruit an early immune response that eradicates the infection. However, if that doesn’t occur, the result could simply be more inflammation. Given the c. albicans is commensal in 30-50% of the population, this could yield a low level smoldering inflammation.
Possibility to develop Sjogren’s Syndrome with Candida overgrowth
Frontiers in Medicine (2022) discusses the increased odds of developing Sjogren’s syndrome in patients with c. albicans. The numbers of patients for whom this manifestation occurs is small, so it’s not suitable to think that everyone with candida is at risk for Sjogren’s (remember, 30-50% of humans have c. albicans as a commensal…). But, it’s interesting to see the connection that Sjogren’s syndrome may form in some individuals a as result of candida.
Cancer risk with candida
Several papers discuss c. albicans and cancer risk. Given that the Th1 cell system (Th1 cells, NK cells, CTL’s, and M1 macs) are known to do key surveillance against cancer, and given that c. albicans is known to promote Th2 dominance in the host, this is not surprising that having candida can increase cancer risk as Th1 immunity decreases and Th2 dominance increases. The promotion by candidalysin of Th17 effector cytokine activation along with GM-CSF activation, increase cancer risk and can also be expected to make autoimmunity worse.
“Oral squamous cell carcinoma is associated with many known risk factors including tobacco smoking, chronic alcoholism, poor oral hygiene, unhealthy dietary habits and microbial infection. Previous studies have highlighted Candida albicans host tissue infection as a risk factor in the initiation and progression of oral cancer. C albicans invasion induces several cancerous hallmarks, such as activation of proto-oncogenes, induction of DNA damage and overexpression of inflammatory signaling pathways. Candidalysin has a clear role in inflammasome activation and induction of cell damage. Several inflammatory molecules such as IL-6, IL-17, NLRP3 and GM-CSF have been linked to carcinogenesis. Chronic inflammatory infiltration also arises from severe damage of the epithelial cell layer (dysplasia). The initial cell injury leads to a pre-cancerous lesion, to the formation of the malignant neoplasm, which may develop into cancer… Candidalysin has been reported to excite granulocyte-macrophage colony-stimulating factor GM-CSF, an essential molecule in carcinogenesis… GM-CSF can also stimulate the proliferation of a number of tumour cell lines, including breast cancer cell lines.”
The Research
Candidalysin is a fungal peptide toxin critical for mucosal infection
Nature. 2016 Apr 7;532(7597):64-8. Moyes DI, Wilson D, Richardson JP, et al.
The fungal peptide toxin Candidalysin activates the NLRP3 inflammasome and causes cytolysis in mononuclear phagocytes
Nat Commun. 2018 Oct 15;9(1):4260. Kasper L, König A, Koenig P, et al.
Membrane protective role of autophagic machinery during infection of epithelial cells by Candida albicans
Gut Microbes. Jan-Dec 2022;14(1):2004798. Lapaquette P, Ducreux A, Basmaciyan L, et al.
Interplay between Candida albicans and the mammalian innate host defense
Infect Immun. 2012 Apr;80(4):1304-13. Cheng C, Joosten LAB, Kullberg B, Netea MG.
Candida Infection as an Early Sign of Subsequent Sjögren’s Syndrome: A Population-Based Matched Cohort Study
Front Med (Lausanne). 2022 Jan 21;8:796324. Chen C, Chang F, Hung Y, et al.
Candida albicans and candidalysin in inflammatory disorders and cancer
Immunology. 2021 Jan;162(1):11-16. Ho J, Camilli G, Griffiths JS, et al.
The role of Candida albicans candidalysin ECE1 gene in oral carcinogenesis
J Oral Pathol Med. 2020 Oct;49(9):835-841. Fariha EA, Satiman EN, Ahmad H, et al.