TY - JOUR
T1 - Dietary wheat amylase trypsin inhibitors exacerbate CNS inflammation in experimental multiple sclerosis
AU - Zevallos, Victor
AU - Yogev, Nir
AU - Hauptmann, Judith
AU - Nikolaev, Alexei
AU - Pickert, Geethanjali
AU - Heib, Valeska
AU - Fittler, Nicola
AU - Steven, Sebastian
AU - Luessi, Felix
AU - Neerukonda, Manjusha
AU - Janoschka, Claudia
AU - Tobinski, Ann-Marie
AU - Klotz, Luisa
AU - Waisman, Ari
AU - Schuppan, Detlef
N1 - Funding information: This work was supported by the German Research Foundation (DFG), Collaborative Research Center on Multiple Sclerosis (SFB TR128/3, projects A03, A07 and A08) and SFB TR355/1 (project number 490846870) to DS and AW. DS received project-related support by DFG grant Schu 646/20-1/2 (Allergy), Pic/Schu SPP 1656 (Intestinal microbiota, to GP and DS), Schu 646/17-1 (ATI) and by the Leibniz Foundation (Wheatscan, SAW-2016-DFA-2).
PY - 2024/1/1
Y1 - 2024/1/1
N2 - Objective: Wheat has become a main staple globally. We studied the effect of defined pro-inflammatory dietary proteins, wheat amylase trypsin inhibitors (ATI), activating intestinal myeloid cells via toll-like receptor 4, in experimental autoimmune encephalitis (EAE), a model of multiple sclerosis (MS). Design: EAE was induced in C57BL/6J mice on standardised dietary regimes with defined content of gluten/ATI. Mice received a gluten and ATI-free diet with defined carbohydrate and protein (casein/zein) content, supplemented with: (a) 25% of gluten and 0.75% ATI; (b) 25% gluten and 0.19% ATI or (c) 1.5% purified ATI. The effect of dietary ATI on clinical EAE severity, on intestinal, mesenteric lymph node, splenic and central nervous system (CNS) subsets of myeloid cells and lymphocytes was analysed. Activation of peripheral blood mononuclear cells from patients with MS and healthy controls was compared. Results: Dietary ATI dose-dependently caused significantly higher EAE clinical scores compared with mice on other dietary regimes, including on gluten alone. This was mediated by increased numbers and activation of pro-inflammatory intestinal, lymph node, splenic and CNS myeloid cells and of CNS-infiltrating encephalitogenic T-lymphocytes. Expectedly, ATI activated peripheral blood monocytes from both patients with MS and healthy controls. Conclusions: Dietary wheat ATI activate murine and human myeloid cells. The amount of ATI present in an average human wheat-based diet caused mild intestinal inflammation, which was propagated to extraintestinal sites, leading to exacerbation of CNS inflammation and worsening of clinical symptoms in EAE. These results support the importance of the gut-brain axis in inflammatory CNS disease.
AB - Objective: Wheat has become a main staple globally. We studied the effect of defined pro-inflammatory dietary proteins, wheat amylase trypsin inhibitors (ATI), activating intestinal myeloid cells via toll-like receptor 4, in experimental autoimmune encephalitis (EAE), a model of multiple sclerosis (MS). Design: EAE was induced in C57BL/6J mice on standardised dietary regimes with defined content of gluten/ATI. Mice received a gluten and ATI-free diet with defined carbohydrate and protein (casein/zein) content, supplemented with: (a) 25% of gluten and 0.75% ATI; (b) 25% gluten and 0.19% ATI or (c) 1.5% purified ATI. The effect of dietary ATI on clinical EAE severity, on intestinal, mesenteric lymph node, splenic and central nervous system (CNS) subsets of myeloid cells and lymphocytes was analysed. Activation of peripheral blood mononuclear cells from patients with MS and healthy controls was compared. Results: Dietary ATI dose-dependently caused significantly higher EAE clinical scores compared with mice on other dietary regimes, including on gluten alone. This was mediated by increased numbers and activation of pro-inflammatory intestinal, lymph node, splenic and CNS myeloid cells and of CNS-infiltrating encephalitogenic T-lymphocytes. Expectedly, ATI activated peripheral blood monocytes from both patients with MS and healthy controls. Conclusions: Dietary wheat ATI activate murine and human myeloid cells. The amount of ATI present in an average human wheat-based diet caused mild intestinal inflammation, which was propagated to extraintestinal sites, leading to exacerbation of CNS inflammation and worsening of clinical symptoms in EAE. These results support the importance of the gut-brain axis in inflammatory CNS disease.
KW - small intestine
KW - nutrition
KW - autoimmunity
KW - brain/gut interaction
KW - gluten free diet
UR - http://www.scopus.com/inward/record.url?scp=85169894926&partnerID=8YFLogxK
U2 - 10.1136/gutjnl-2023-329562
DO - 10.1136/gutjnl-2023-329562
M3 - Article
C2 - 37595983
SN - 0017-5749
VL - 73
SP - 92
EP - 104
JO - Gut
JF - Gut
IS - 1
M1 - gutjnl-2023-329562
ER -