A Pilot Clinical Study on Post-Operative Recurrence Provides Biological Clues for a Role of Candida Yeasts and Fluconazole in Crohn’s Disease
Abstract
:1. Introduction
2. Methods
2.1. Study Design and Patient Population
2.2. Mycological Analysis
2.3. Serological Analysis
2.3.1. Serum Markers of Inflammation
2.3.2. Serological Markers of IBD
2.3.3. Markers of Invasive Candidiasis
2.3.4. Innate Immunity Lectins Sensing C. albicans
2.4. Statistical Analysis
3. Results
3.1. Qualitative and Quantitative Evolution of Yeast Gut Colonization over the 6-Month Post-Operative Period
3.2. Evolution of C-Reactive Protein (CRP) and Serum Calprotectin Levels
3.3. Evolution of Anti-Glycan Antibody Markers of CD
3.4. Evolution of Biomarkers of Invasive Candidiasis
3.5. Level and Evolution of Sensing of C. albicans by the Innate Immunity Lectins Gal-3 and MBL
3.6. Integration of the Biomarkers Tested in Diagnostic and Prognostic Models
4. Discussion
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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FCZ Group (n = 14) | Placebo Group (n = 15) | |
---|---|---|
Sex (male) | 5 (35.7) | 4 (26.7) |
Age at CD diagnosis (years) | 20.3 (19.4–21.8) | 23.4 (20.5–31.7) |
Age at inclusion | 26.7 (22.8–34.2) | 29.5 (23.6–40.8) |
Disease duration (years) | 4.9 (1.9–14.1) | 3.9 (0.5–9.1) |
Disease type | ||
Penetrating | 4 (28.6) | 6 (40.0) |
Stenosing | 9 (64.3) | 9 (60.0) |
Unclassified | 1 (7.1) | 0 (0.0) |
Previous surgery | 0 | 0 |
ASCA titer at inclusion | 86.5 (F70.3–114.8] | 108.4 (78.4–134.3) |
CDAI at inclusion | 135 (86–217) | 104 (68–127) |
Type of Serum Biomarker Analyzed/Abbreviation | General Features | Molecular Characteristics | Rationale for Longitudinal Analysis in Relation with Crohn’s Disease Evolution | Rationale for Longitudinal Analysis in Relation with Candida Colonization/Infection |
---|---|---|---|---|
Markers of inflammation | ||||
Calprotectin | Described as biomarker of systemic inflammation [33,43]. Detection of feacal calprotectin in stools is recommended for IBD diagnosis and treatment follow up [44,45] | Protein from PMNs (S100 A8/A9 Family) | High levels suggested as being informative for diagnosis and disease outcome [33,43,44] | None current indication for the diagnosis of Candidiasis. |
Serum Antibodies | ||||
ASCA | Anti-Saccharomyces cerevisiae antibodies | Anti-oligomannose antibodies (Epitope present in S. cerevisiae and C. albicans mannan) Epitope with Man α-1,3 linked at the non reducing end of tetra or trimannose α-1,2 linked [3]. | The most potent marker of Crohn’s disease in terms of prevalence and prediction of onset [8,9] | Generated during a C. albicans invasive infection [13] In CD patients healthy relatives their presence correlates with C. albicans carriage [10]. |
ALCA | Anti-Laminaribioside Carbohydrate Antibodies | Disaccharide sequence of α-1,3 glucans(Epitope present in S. cerevisiae and C. albicans glucans) | Adjunct of ASCA for CD diagnosis [12] | Generated during a C. albicans invasive infection [13] Antibodies targeting molecules interacting with Dectin-1, a major receptor of C. albicans innate immunity triggering IL17 pathway [46] |
ACCA | Anti-Chitobioside Carbohydrate Antibodies | Disaccharide sequence of chitin (Epitope present in S. cerevisiae and C. albicans chitin) | Adjunct of ASCA for CD diagnosis [12,47] | Generated during a C. albicans invasive infection [13] The target of these antibodies (chitin) binding to FIBCD1 dampen Intestinal inflammation [48] |
Platelia test® C.albManAb | Anti-Candida albicans mannan Antibodies | Detection of human polyclonal antibody response to mannan oligomannose repertoire | Levels increased [10,49] | Marker of C. albicans invasive infection used for diagnosis [13,34] |
Anti-Hwp1 Antibodies/C.albProtAb | Anti-Hyphal Protein 1 antibody Hwp1 is a molecule specific for C. albicans hyphal (invasive) form [50] | Peptidic epitope [35] | Never explored in this setting | Marker of C. albicans invasive infection used for diagnosis [35] |
Fungitel Assay(TM) /BDG | Circulating β-1,3 D Glucan [36] | Polymer of β-1,3 D glucan Recognized by Dectin-1 activating the Th17 pathway [29,51] | Described as circulating during CD [37] | Widely used for the diagnosis of systemic candidiasis [36] |
Innate Immunity Lectins | ||||
Galectin-3/Gal-3 | C-Lectin member of Galactose binding lectins Expressed on cells of the macrophage lineage [39]. Expressed on intestinal cells. Associates with dectin-1 for Fungal recognition [52] associates with TLR2 [15]. | Receptor for C. albicans β-1,2 mannoses, immunomodulatory adhesins, expressed on C. albicans mannan mannoproteins and glycolipids [14,15] | Increased during inflammatory diseases [40,53] | Increased during Candida infection [40] |
Mannose Binding Lectin MBL | Produced by hepatic and intestinal cells [54] Combines with MASP for activating complement lectin pathway | Reacts with α-D-mannose N-acetyl-D Glucosamine L-Fucose | Role in Crohn’s disease: Impaired MBL-MASP functional activity in CD [55] Levels inversely correlates with ASCA [56,57] | Role in mucosal and systemic Candidiasis, participates to clearance of circulating C. albicans mannan in patient sera [41,42,54] |
Biological Parameter | Visit | All Patients (n = 23) | p iV vs. V6.mo |
---|---|---|---|
Calprotectin | iV | 4.2 (3.3–8.7) | 0.002 |
V6.mo | 2.2 (1.2–3.4) | ||
ASCA | iV | 109.2 (76.7–159.0) | <0.0001 |
V6.mo | 80.6 (67.4–125.1) | ||
ALCA | iV | 62.6 (45.3–97.7) | 0.113 |
V6.mo | 53.0 (45.0–82.8) | ||
ACCA | iV | 51.6 (34.3–69.7) | 0.04 |
V6.mo | 37.6 (23.2–63.0) | ||
AMCA | iV | 57.3 (45.1–85.0) | 0.327 |
V6.mo | 47.4 (38.9–79.8) | ||
C.albManAb | iV | 6.8 (2.7–9.5) | <0.0001 |
V6.mo | 3.3 (1.0–6.3) | ||
C.albProtAb | iV | 0.6 (0.3–2.4) | <0.0001 |
V6.mo | 0.4 (0.3–0.8) | ||
Galectin-3 | iV | 10.3 (6.7–11.8) | <0.0001 |
V6.mo | 6.2 (4.2–9.1) | ||
MBL | iV | 1032.4 (271.5–2697.2) | 0.283 |
V6.mo | 1216.0 (304.9–2271.4) |
No Recurrence | Recurrence | Total | p(χ2) | |
---|---|---|---|---|
Gal-3 + MBL + Calprotectin | ||||
Response to treatment | ||||
FCZ (+) | 27 | 12 | 39 | |
Placebo (−) | 14 | 22 | 36 | |
Total | 41 | 34 | 75 | 0.007 |
No response to treatment | ||||
FCZ (−) | 7 | 13 | 20 | |
Placebo (+) | 4 | 3 | 7 | |
Total | 11 | 16 | 27 | |
Overall total | 52 | 50 | 102 | |
ACCA + CaManAb + MBL + Calprotectin | ||||
Response to treatment | ||||
FCZ (+) | 24 | 9 | 33 | |
Placebo (−) | 14 | 23 | 37 | |
Total | 38 | 32 | 70 | 0.016 |
No response to treatment | ||||
FCZ (−) | 10 | 16 | 26 | |
Placebo (+) | 4 | 2 | 6 | |
Total | 14 | 18 | 32 | |
Overall total | 52 | 50 | 102 |
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Sendid, B.; Salvetat, N.; Sarter, H.; Loridant, S.; Cunisse, C.; François, N.; Aijjou, R.; Gelé, P.; Leroy, J.; Deplanque, D.; et al. A Pilot Clinical Study on Post-Operative Recurrence Provides Biological Clues for a Role of Candida Yeasts and Fluconazole in Crohn’s Disease. J. Fungi 2021, 7, 324. https://doi.org/10.3390/jof7050324
Sendid B, Salvetat N, Sarter H, Loridant S, Cunisse C, François N, Aijjou R, Gelé P, Leroy J, Deplanque D, et al. A Pilot Clinical Study on Post-Operative Recurrence Provides Biological Clues for a Role of Candida Yeasts and Fluconazole in Crohn’s Disease. Journal of Fungi. 2021; 7(5):324. https://doi.org/10.3390/jof7050324
Chicago/Turabian StyleSendid, Boualem, Nicolas Salvetat, Helène Sarter, Severine Loridant, Catherine Cunisse, Nadine François, Rachid Aijjou, Patrick Gelé, Jordan Leroy, Dominique Deplanque, and et al. 2021. "A Pilot Clinical Study on Post-Operative Recurrence Provides Biological Clues for a Role of Candida Yeasts and Fluconazole in Crohn’s Disease" Journal of Fungi 7, no. 5: 324. https://doi.org/10.3390/jof7050324
APA StyleSendid, B., Salvetat, N., Sarter, H., Loridant, S., Cunisse, C., François, N., Aijjou, R., Gelé, P., Leroy, J., Deplanque, D., Jawhara, S., Weissmann, D., Desreumaux, P., Gower-Rousseau, C., Colombel, J. F., & Poulain, D. (2021). A Pilot Clinical Study on Post-Operative Recurrence Provides Biological Clues for a Role of Candida Yeasts and Fluconazole in Crohn’s Disease. Journal of Fungi, 7(5), 324. https://doi.org/10.3390/jof7050324