The Impact of Candida rugosa Lipase in the Gut Microbiome in Health and Alzheimer’s Disease and Identification of Allosteric Modulators

Menden, Ariane (2021). The Impact of Candida rugosa Lipase in the Gut Microbiome in Health and Alzheimer’s Disease and Identification of Allosteric Modulators. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.000130ff

Abstract

Alzheimer’s disease (AD) affects more than 50 million people worldwide. Despite the continual identification of new disease features, treatment options are limited due to failure of clinical trials to identify effective treatments. Consequently, novel therapeutic strategies arising from other areas of research, such as the gut microbiome, are being considered due to their potential to modulate AD pathology. The gut microbiome is regarded as a symbiotic physiological regulator of human health via the bidirectional gut–brain axes. Several studies have revealed a persistent compositional imbalance in the gut microbiome of both AD patients and in animal models of AD potentially contributing to AD pathology. Conversely, it has been suggested that normalization of the gut microbial composition might ameliorate AD pathology in animal models and in humans. In healthy individuals, shifts of the gut microbiota primarily occur in response to dietary changes such as administration of exogenous enzymes. These enzymes can evoke shifts in the composition of the gut microbiota by increasing enzymatic activity in the digestive tract and therefore the release of metabolites from dietary macromolecules. Lipases are one subclass of digestive enzymes which can elevate gut availability of fatty acids and glycerol. Some of these cleavage products can promote growth and metabolite production of specific bacterial species changing the gut microbial composition. Hence, we hypothesized that
“Oral administration of an exogenous lipase in AP/PS1 mice normalizes gut microbiome and metabolite composition, and rescues AD pathology and aberrant behavior”.
To this end, three hypotheses were examined: (1) Oral lipase administration in C67BL/6J (Wt) mice will alter free fatty acid and glycerol release in the gut; (2) oral lipase administration in APPsw/PS1-de9 (APP/PS1) mice will normalize the gut microbiota and metabolite composition that correlates with improved AD-like pathology; and (3) that a combined use of a positive allosteric modulator with the exogenous lipase will enhance the expected effects from hypotheses (1) and (2).

The studies revealed that exogenous lipase administration is correlated with normalization of gut microbiome and metabolite composition in Wt and APP/PS1 animals. Furthermore, administration of exogenous lipase correlated with reduced AD-like pathology and behavior in APP/PS1 animals. In addition, we provided evidence that the treatment-dependent shifts in the gut microbiome and metabolite composition of APP/PS1 mice caused the observed improvement of memory in these animals. Collectively, this work advances our understanding of how CRL could be used to reduce AD pathology and might present novel treatment options for AD patients.

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