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Alzheimer Disease - gut connection

Periodic Reporting for period 3 - AD-gut (Alzheimer Disease - gut connection)

Reporting period: 2019-04-01 to 2020-03-31

Alzheimer’s disease (AD) is the leading cause of dementia in the Western world and to date, no cure nor any preventive strategy are available for this devastating, neurodegenerative disorder.

Bacterial 16S rRNA sequencing from fecal samples revealed a remarkable shift in the gut microbiota of conventionally-raised AD mice compared to healthy, wild-type mice. Based on these findings, we generated a germ-free Alzheimer (GF-AD) mouse model and discovered a drastic reduction of cerebral Aβ amyloid pathology when compared to control AD mice with natural intestinal microbiota. In contrast, fecal transplantation of GF-AD with harvested microbiota from conventionally-raised AD mice dramatically increased cerebral Aβ pathology.

These results strongly point to a microbial involvement in the development of AD and support the hypothesis that modulation of the gut microbiome may slow down and delay the onset of Alzheimer’s disease. This paves potentially a novel road for AD prevention, based on gut microbiota modulation through well designed probiotic cocktails.

Throughout the project, we have contributed significantly towards a better understanding of the microbiota-gut-brain axis, investigating this fascinating bidirectional communication system by examining neural, immune, endocrine, and metabolic pathways as a function of the microbiota diversity. The increased permeability of the gut and blood-brain barrier induced by microbiota dysbiosis may mediate or affect AD pathogenesis. Our studies highlighted the importance of microbiota diversity in the development of AD. Interesting future directions involve therapies that aim to reduce pathological bacteria and increase beneficial bacteria, via novel therapeutic strategies such as probiotic cocktails or through the balanced dietary intake.
"Based on these findings, AD-gut project aimed at designing and optimizing an efficient encapsulation strategy to guarantee the survival and delivery of probiotic strains in the gut as opposed to standard strategies targeting directly the brain. A successful accomplishment of these goals allowed us to derive potential AD risk factors and to establish an objective baseline setting for AD diagnosis. Ultimately, the present project will open new horizons in biomedical diagnostics and personalized medicine through the marketing of these technologies and therapeutic concepts.

The core of AD-gut integrates 3 subprojects: encapsulation of probiotics, deciphering the microbiome, and understanding induced microbiome alterations due to neurodegenerative disorders. The results gathered in the framework of the project are given for each scientific work package dedicated sections.

As shown by our dissemination and communication activities (described in the WP5), our project has been successfully disseminated through 29 peer-reviewed publications published in respected scientific journals.

At the launch of the project, a first EPFL press release has been published.

During the MAF 2017 conference, which took place from 10th to 13th September 2017 in Bruges, Belgium, our AD-gut project has been presented to the public. A booth was available for the participants.

Moreover, as part of our major scientific results promotion, an EPFL press release has been published at the acceptance of our publication “Combined multi-plane phase retrieval and super-resolution optical fluctuation imaging for 4D cell microscopy” in Nature Photonics. In addition, due to the importance of the work, it was as well covered by other media news and blogs.

Another EPFL press release has been published in relation to our publication in Nature Methods ""Parameter-free image resolution estimation based on decorrelation analysis"", partly linked to AD-gut project.

Finally, for our mid-term results, an additional EPFL press release has been published about our joint publication (KUL/EPFL), partly linked to AD-gut project, “Identifying microbial species by single-molecule DNA optical mapping and resampling statistics” accepted in Nucleic Acids Research (NAR) Genomics and Bioinformatics.

We are planning at least 3 more publications that will be related to AD-gut project (OPT imaging of the gut, benchmarking of optical mapping with other state of the art sequencing technologies, results related to the efficacy of prebiotic cocktails).

In addition, Consortium plans to exploit its cohesion and project results to apply to open calls from EU and to further develop approaches introduced within our project and hopefully lead to progress in new methods."
All three AD-gut pillars have progressed as planned during the project phases.

Within the scope of the WP1-Encapsulation, led by our partner MAINZ, different encapsulation strategies were evaluated regarding the survival of encapsulated bacteria and the oral administration route. Wet and dry formulations were designed according to the needs of the bacteria. Different drying methods were evaluated and high viabilities of bacteria were obtained after the encapsulation, storage, and release in wet and dry formulations. The commercially available capsules were tested and the filling of a commercially available capsules (mouse and human) with sufficient amount of bacteria in different formulations was achieved. The encapsulation formulations were optimized towards the use in capsules and the dissolution behavior of the capsules and the formulations were assessed in simulated juices.

The reader system for decoding the microbiome is built, ready for the first test runs. The bacteria of interest are partially available in culture. Brain imaging and biochemical control as a readout of the efficacy of administrated probiotics is advancing in parallel, ready in time for a first assessment of the underlying hypothesis: modulating the microbiome may entail a delay of neurodegenerative disorders. The automated microscopy reader exploits DNA mapping technology and offers longer read lengths while forgoing the need for complex library preparation and amplification, compared to state of the art 16s RNA sequencing. To fully enable mapping-based metagenomics, sensitivity, and specificity of DNA map analysis and identification need to be improved. Using detailed simulations and experimental data, we first demonstrate how fluorescence imaging of surface stretched, sequence specifically labeled DNA fragments can yield highly sensitive identification of targets. Second, a new analysis technique is introduced to increase specificity of the analysis, allowing even closely related species to be unambiguously resolved. Ultimately, the present project will open new horizons in biomedical diagnostics and personalized medicine through the marketing of these technologies and therapeutic concepts.

AD risk factors, the influence of the microbiota diversity on the progression of the AD pathology behavioral tests are in conventional and gnotobiotic environment Additionally as a part of longitudinal tests we traced metabolites using untargeted mass spectrometry, in parallel we performed histological assessment of the AD pathology in 16, 32 and 42 week-old mice in combination with. ELISA quantification of amyloid-beta 42. Lastly, we complemented our findings with targeted analysis of short-chain fatty acids and bile acids in brain and cecum samples from EPFL and Bern mice. To increase the throughput, sensitivity and speed up project metagenomics, we have developed a compact reader.
AD-gut project and its Work Packages fields