Greco, Antonio; (2025) Impact of IL10 family members and gut microbial metabolites on Intestinal epithelial integrity in Health & Disease. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is treatment used for haematological malignancies. 30-70% of patients treated can get graft versus host disease (GVHD) which leads to morbidity and mortality post-treatment. Increased intestinal permeability and microbial dysbiosis are correlated to the disease. The current study assessed the intestinal permeability and cytokine profile in allo-HSCT paediatric patients (GVHD+ and GVHD-) and healthy controls. Next, the impact of IL10 cytokine family members (IL10, IL22, IL19, IL20 and IL24), butyrate (microbial metabolite) and “pro-inflammatory” cytokines (IFNγ and IL1β) on gut barrier function (e.g., permeability, wound healing capacity, proliferation and necrosis-apoptosis) were studied in T84 cell line used as an in-vitro model. The results of this investigation demonstrated increased permeability in allo-HSCT patients compared to healthy controls, with GVHD+ patients exhibiting similar intestinal permeability levels during the pre-conditioning period, compared to GVHD-. IFNγ increased IL22RA1 expression, the receptor subunit of IL22 cytokine, which is known to protect from GVHD in vivo. The majority of IL10 cytokine family members did not demonstrate a significant effect in the assessments performed. IL22 increased permeability through claudin 2 upregulation. IL10-induced cell proliferation of non-differentiated T84 cells. Notably, IL10 failed to activate STAT3 in differentiated cells. Butyrate induced a decrease in permeability followed by a subsequent strong increase. 24-hour stimulation affected the expression of the majority of tight junction proteins, increased human beta-defensins 1 and 3, increased wound healing rate, increased early apoptosis and reduced late apoptosis/necrosis. Importantly, butyrate reduced IL20RA mRNA and protein levels. Finally, an IL10RB KO T84 cell line was generated to elucidate the indirect effect of IL10 on butyrate-induced outcomes. In conclusion, intestinal barrier function is influenced by immune modulators and microbiome, which may affect the initiation and progression of GVHD.

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