Abstract
Wheat amylase trypsin inhibitors (ATIs) represent a common dietary protein component of gluten-containing cereals (wheat, rye, and barley). They act as toll-like receptor 4 ligands, and are largely resistant to intestinal proteases, eliciting a mild inflammatory response within the intestine after oral ingestion. Importantly, nutritional ATIs exacerbated inflammatory bowel disease and features of fatty liver disease and the metabolic syndrome in mice. For Alzheimer’s disease (AD), both inflammation and altered insulin resistance are major contributing factors, impacting onset as well as progression of this devastating brain disorder in patients. In this study, we evaluated the impact of dietary ATIs on a well-known rodent model of AD (5xFAD). We assessed metabolic, behavioral, inflammatory, and microbial changes in mice consuming different dietary regimes with and without ATIs, consumed ad libitum for eight weeks. We demonstrate that ATIs, with or without a gluten matrix, had an impact on the metabolism and gut microbiota of 5xFAD mice, aggravating pathological hallmarks of AD. If these findings can be translated to patients, an ATI-depleted diet might offer an alternative therapeutic option for AD and warrants clinical intervention studies.
Highlights
About 30 million people worldwide suffer from Alzheimer’s disease (AD) and for the vast majority, the sporadic cases, the origin of the disease stays still enigmatic
Underlying mechanisms are still not fully understood. Nutritional compounds such as linoleic acid, vitamins or polyunsaturated fatty acids have been discussed as being preventive for decades,. Many of these nutritional substances are correlated to immune modulatory probabilities and AD patients have been demonstrated to show altered immune stimulation [4,5] as well as mutations in microglial genes such as triggering receptor expressed on myeloid cells 2 (TREM2; [6])
The role toll-like receptor 4 (TLR4) plays in AD is not fully deciphered; a recent report found the minor allele of the rs4986790 polymorphism (G) of TLR4 to be associated with a reduced risk of developing AD and higher cortical thickness in human patients [14]
Summary
About 30 million people worldwide suffer from Alzheimer’s disease (AD) and for the vast majority, the sporadic cases, the origin of the disease stays still enigmatic. Underlying mechanisms are still not fully understood Nutritional compounds such as linoleic acid, vitamins or polyunsaturated fatty acids have been discussed as being preventive for decades, (for example: [3]). An increasing body of evidence suggests that the inflammatory status in the brain might be relevant and peripheral inflammation In this regard, the gut might play an outstanding role with a large surface exposed to a plethora of microbial organisms and nutritional substances. Amylase trypsin inhibitors (ATI) are commonly ingested immune stimulatory proteins, mostly present in dietary wheat, rye and barley. They appear to be more relevant than the abundant gluten itself as triggers of the multifaceted nonceliac wheat sensitivity (NCWS) syndrome. The four groups of animals were subsequently analyzed for intestinal morphometry, inflammatory markers, gut microbial composition, behavioral deficits, and plaque deposition
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