Mutual regulation between butyrate and hypoxia‐inducible factor‐1α in epithelial cell promotes expression of tight junction proteins

Abstract

Inflammatory bowel disease is a kind of multi-aetiological chronic disease that is driven by multidimensional factors. Hypoxia-inducible factor-1α (HIF-1α) plays an important role in anti-inflammatory and cellular responses to hypoxia. Previous studies have found that B or T-cell-specific HIF-1α knock out mice exhibit severe colonic inflammation. However, we know very little about other functions of HIF-1α in intestinal epithelial cells (IECs). In our study, HIF-1α ΔIEC mice were used to study the function of HIF-1α in IECs. HIF-1α was knocked down in Caco-2 cells by transfection with a small interfering (si) RNA. Immunohistochemical staining and western blotting were used to detect the expression of zonula occluden-1 (ZO-1) and Occludin. The content of colon was harvested for high-performance liquid chromatography analysis to examine the levels of butyrate in the gut. Our research found that HIF-1α played a protective role in dextran sulphate sodium-induced colitis, which was partly due to its regulation of tight junction (TJ) protein expression. Further study revealed that HIF-1α mediated TJ proteins levels by moderating the content of butyrate. Moreover, we found that butyrate regulated TJ protein expression, which is dependent on HIF-1α. These results indicated that there is a mutual regulatory mechanism between butyrate and HIF-1α, which has an important role in the maintenance of barrier function of the gastrointestinal tract.Abbreviations: CD, Crohn's disease; HIF-1α, hypoxia-inducible factor-1α; HPLC, high-performance liquid chromatography; IBD, inflammatory bowel disease; IEC, intestinal epithelial cell; IHC, immunohistochemical; UC, ulcerative colitis; ZO-1, zonula occluden-1 Jiuheng Yin and Chao Zhou are co-first authors.

Patient Derived Colonoids as Drug Testing Platforms–Critical Importance of Oxygen Concentration

“…While TNF/IL17 induced inflammatory responses at both 20% and 2% O 2, the effect on CXCL1 , CXCL2 , CXCL5 , CCL20 , CXCL10 and CXCL11 mRNA expression and protein release was less prominent at 2% O 2 . The overall assessment of our data is a reduction in TNF and TNF/IL17 induced responses in 2% O 2 , corresponding to the anti-inflammatory traits of hypoxia seen in other experimental systems ( Sun et al, 2019 ; Colgan et al, 2020 ; Yin et al, 2020 ). Thus, our results suggest that if correctly tuned, a HIF-response in the epithelium may partly normalize the chemokine levels seen in the inflamed mucosa.…”

“…Essential for the colonoid model, we found no differences in cell composition, morphology or cellular apoptosis suggesting that colonoids cultured under a physiological, low oxygen concentration were fully viable. Relevance to IBD is suggested by studies in experimental colitis models ( Sun et al, 2019 ; Colgan et al, 2020 ; Yin et al, 2020 ), and cell lines ( Muenchau et al, 2019 ; Vissenaekens et al, 2019 ), which indicate a protective stabilization of HIF1α, attenuating mucosal inflammation and promoting barrier formation. Moreover, reagents that activate HIF via inhibition of the prolyl hydroxylase enzymes, are suggested to induce hypoxia-mediated resolution in patients with intestinal mucosal inflammatory disease ( Glover and Colgan, 2011 ; Brown et al, 2020 ).…”

Role and mechanism of action of butyrate in atherosclerotic diseases: a review

“…Hypoxia-inducible factor-1 (HIF-1) is an important anti-inflammatory factor in lymphocytes. HIF-1 can regulate the expression of tight junction proteins by affecting the content of butyrate, thus playing a role in anti-inflammatory and cellular signalling (Yin et al 2020).…”

Is butyrate a natural alternative to dexamethasone in the management of CoVID-19?

“…Butyric acid is a potential inhibitor of pro-inflammatory molecule NF-κB [135][136][137] (Figure 1). Tight junction protein expression in intestinal epithelial cells is also influenced by butyrate mediated regulation 138 Butyrate also reduces the infiltration of proinflammatory Th9 cells and eosinophils into lungs 146 . Mice treated with butyrate exhibited a significant reduction of inflammatory infiltrates in the airways, tissue, and vascular disruption, and subsequently less haemorrhaging in the lungs induced by influenza infection 82 .…”

“…Butyric acid is a potential inhibitor of pro-inflammatory molecule NF-κB 135 – 137 ( Figure 1 ). Tight junction protein expression in intestinal epithelial cells is also influenced by butyrate mediated regulation 138 . Butyrate treatment on epithelial colon cells significantly downregulated the proinflammatory molecules including Toll-like receptor (TLR)2, TLR4, IL-6, IL-12A, IL-1β, IL-18, TNF, MAPK13, MAPK10, MAPK3, AKT1, AKT2, AKT3, NF-κB1A, NF-κB1, CXCL1, CXCL2, CXCL3, CXCL6, CXCL8, Chemokine ligands (CCL)2, Serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 1 (SERPINA1), SERPINA2, Colony Stimulating Factor (CSF) 3, Intercellular Adhesion Molecule 1 (ICAM1), Vascular Endothelial Growth Factor A (VEGFA), Major Vault Protein (MVP), Cathelicidin Antimicrobial Peptide (CAMP) and insulin-like growth factor binding protein (IGFBP)3, along with inhibition of proinflammatory pathways, including (i) triggering receptor expressed on myeloid cells (TREM-1) signalling, (ii) production of nitric oxide (NO) and ROS, (iii) high-mobility group box-1 (HMGB1) signalling, (iv) IL-6 signalling, and (v) acute phase response signalling 25 .…”