Altered Gut Microbiome Composition and Tryptic Activity of the 5xFAD Alzheimer’s Mouse Model

Abstract

The regulation of physiological gut functions such as peristalsis or secretion of digestive enzymes by the central nervous system via the Nervus vagus is well known. Recent investigations highlight that pathological conditions of neurological or psychiatric disorders might directly interfere with the autonomous neuronal network of the gut - the enteric nervous system, or even derive from there. By using a murine Alzheimer's disease model, we investigated a potential influence of disease-associated changes on gastrointestinal properties. 5xFAD mice at three different ages were compared to wild type littermates in regard to metabolic parameters and enzymes of the gut by fluorimetric enzyme assay and western blotting. Overexpression of human amyloid-β protein precursor (AβPP) within the gut was assessed by qPCR and IHC; fecal microbiome analysis was conducted by 16SrRNA quantitation of selected phyla and species. While general composition of fecal samples, locomotion, and food consumption of male 5xFAD animals were not changed, we observed a reduced body weight occurring at early pathological stages. Human AβPP was not only expressed within the brain of these mice but also in gut tissue. Analysis of fecal proteins revealed a reduced trypsin amount in the 5xFAD model mice as compared to the wild type. In addition, we observed changes in fecal microbiota composition along with age. We therefore suggest that the presence of the mutated transgenes (AβPP and PS1), which are per se the basis for the genetic form of Alzheimer's disease in humans, directly interferes with gut function as shown here for the disease model mice.

Gut microbiota, cognitive frailty and dementia in older individuals: a systematic review

“…These mice also show dramatically increased gut mucosa permeability, with several bacteria-derived membrane vesicles that can be found in the blood and could influence amyloid plaque deposition in the brain 45. Interestingly, amyloid deposition was also observed in the gut tissue of murine AD models and it correlated with dysbiosis 46. In a recent observational study, mice genetically prone to AD exhibited a distinct fecal microbiota composition than healthy controls, with reduced biodiversity and altered functionality 47.…”

Secretory Products of the Human GI Tract Microbiome and Their Potential Impact on Alzheimer's Disease (AD): Detection of Lipopolysaccharide (LPS) in AD Hippocampus

“…Consisting of about ~4 × 10 13 microorganisms, the human GI tract microbiome forms a highly complex, symbiotic and dynamic ecosystem within the host and dietary factors and host genetics appear to have a strong influence on microbial abundance, speciation and complexity, and their ability to influence CNS functions (Foster et al, 2016; Li et al, 2016; Richards et al, 2016; Brandscheid et al, 2017; Tremlett et al, 2017). We sincerely hope that this “Perspectives” article has effectively highlighted recent findings on microbial-derived endotoxins, exotoxins, LOSs and LPSs, amyloids and sncRNAs and has stimulated interest in the potential contribution of these neurotoxic and pro-inflammatory microbial exudates to age-related inflammatory neurodegeneration, amyloidogenesis, and AD-relevant pathology (Figure 1).…”

The role of gut microbiota in pathogenesis of Alzheimer's disease

“…) and neurodegenerative diseases (Brandscheid et al . ; Parashar and Udayabanu ) that can affect the intestinal system. In this paper, I reviewed substantial live studies presenting compelling evidence for the interaction between impaired gut microbial diversity and AD, which is a stepping‐stone for proposing a hypothesis on the pathogenesis of AD.…”