Biology subjects

Morigny, P.

Publications and source records attributed to Morigny, P..

3 recordsLinked to original sources

bioRxiv2026

Mixed acid fermentation products from Lachnospira eligens counteract myotube atrophy

IntroductionAcute myeloid leukemia (AML) is a hematological malignancy associated with muscle wasting. As the relative abundance of Lachnospira eligens was reduced in patients with AML compared to healthy individuals and correlated positively with muscle strength, we hypothesized that L. eligens positively impacts the muscle through the production of small metabolites reaching the systemic circulation. MethodsL. eligens levels were analyzed in two additional independent cohorts. Six L. eligens isolates were characterized through whole-genome sequencing to select clinically relevant strains. The composition of their culture supernatant was analyzed by metabolomics. The impact of L. eligens supernatant on dexamethasone- and interleukin-6-atrophied murine myotubes was assessed. Bioactive metabolites and their production mechanism were identified using among others bioactivity-guided fractionation. The underlying mechanism was also explored on the host side through myotubes transcriptome analysis and metabolic flux analysis. The relevance of bioactive metabolites and their production mechanism was evaluated through clinical data and samples analyses and in a mouse model of leukemia. ResultsThe levels of L. eligens are reduced in independent cohorts of patients with AML and its supernatant counteracts myotube atrophy. This anti-atrophic effect, conserved between strains of the same species, depends on the occurrence of mixed acid fermentation (MAF) in anoxic culture conditions and the presence of its acid end-products acetate, formate and D-lactate. Consistent with those results, blood levels of acetate are decreased and the relative abundance of fecal bacteria capable of performing aerobic respiration is increased in patients with AML. However, bacterial supernatant failed to prevent muscle atrophy and weakness in leukemic mice, likely due to insufficient sustained elevation of acid end-products in the blood. ConclusionThis work reveals the anti-atrophic effect of MAF end-products on myotubes and suggests the importance of considering gut electron acceptor levels (e.g. O2) in disorders affecting muscle health. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=133 SRC="FIGDIR/small/729780v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@112529eorg.highwire.dtl.DTLVardef@1ee1929org.highwire.dtl.DTLVardef@b5f389org.highwire.dtl.DTLVardef@187bc40_HPS_FORMAT_FIGEXP M_FIG Mixed acid fermentation products from Lachnospira eligens counteract myotube atrophy. Our study suggests that gut anaerobiosis is disrupted in treatment-naive patients with acute myeloid leukemia (AML), leading to decreased circulating acetate levels and a reduced relative abundance of L. eligens, which significantly correlated with muscle strength. In line with this framework, in vitro experiments demonstrate that the culture supernatant of L. eligens, which contains mixed acid fermentation (MAF) end-products such as acetate, effectively counteracts C2C12 myotube atrophy in the presence of pro-atrophying stimuli. Further mechanistic experiments indicate a causal role for MAF end-products in this anti-atrophying effect. Created with BioRender.com. Legend: solid frames: experimental results; dashed frames: hypothetical conclusions derived from results; black solid arrow: established correlation; black dashed arrows: hypothetical causation. C_FIG

microbiology↗

bioRxiv2024

Deep Learning and 3D Imaging Reveal Whole-Body Alterations in Obesity

Many diseases, such as obesity, have systemic effects that impact multiple organ systems throughout the body. However, tools for comprehensive, high-resolution analysis of disease-associated changes at the whole-body scale have been lacking. Here, we developed a suite of deep learning-based image analysis algorithms (MouseMapper) and integrated it with tissue clearing and light-sheet microscopy to enable a comprehensive analysis of diseases impacting diverse systems across the mouse body. This approach enables the quantitative analysis of cellular and structural changes across the entire mouse body at unprecedented resolution and scale, including tracking nerves over several centimeters in whole animal bodies. To demonstrate its power, we applied MouseMapper to study nervous and immune systems in high-fat diet induced obesity. We uncovered widespread changes in both immune cell distribution and nerve structures, including alterations in the trigeminal nerve characterized by a reduced number of nerve endings in obese mice. These structural abnormalities were associated with functional deficits of whisker sensing and proteomic changes in the trigeminal ganglion, primarily affecting pathways related to axon growth and the complement system. Additionally, we found heterogeneity in obesity-induced whole-body inflammation across different tissues and organs. Our study demonstrates MouseMappers capability to discover and quantify pathological alterations at the whole-body level, offering a powerful approach for investigating the systemic impacts of various diseases. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=187 SRC="FIGDIR/small/608300v1_ufig1.gif" ALT="Figure 1"> View larger version (74K): org.highwire.dtl.DTLVardef@17d2601org.highwire.dtl.DTLVardef@14a2d3dorg.highwire.dtl.DTLVardef@e04114org.highwire.dtl.DTLVardef@d0b8b5_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIWe developed MouseMapper: AI-driven pipeline for whole-body structural analysis in mice C_LIO_LIMouseMapper revealed obesity-induced changes in nerves and immune cells across multiple organs C_LIO_LIMouseMapper identified facial nerve alterations in obesity linked to impaired whisker sensitivity C_LIO_LIMouseMapper has the potential for holistic 3D analysis of systemic diseases C_LI Supplementary Videos can be seen at: http://discotechnologies.org/MouseMapper/

systems biology↗

bioRxiv2023

Virtual reality empowered deep learning analysis of brain activity

Tissue clearing and fluorescent microscopy are powerful tools for unbiased organ-scale protein expression studies. Critical for interpreting expression patterns of large imaged volumes are reliable quantification methods. Here, we present DELiVR a deep learning pipeline that uses virtual reality (VR)-generated training data to train deep neural networks, and quantify c-Fos as marker for neuronal activity in cleared mouse brains and map its expression at cellular resolution. VR annotation significantly accelerated the speed of generating training data compared to conventional 2D slice based annotation. DELiVR detects cells with much higher precision than current threshold-based pipelines, and provides an extensive toolbox for data visualization, inspection and comparison. We applied DELiVR to profile cancer-related mouse brain activity, and discovered a novel activation pattern that distinguishes between weight-stable cancer and cancer-associated weight loss. Thus, DELiVR provides a robust mouse brain analysis pipeline at cellular scale that can be used to study brain activity patterns in health and disease. The DELiVR software, Fiji plugin and documentation can be found at https://www.DISCOtechnologies.org/DELiVR/. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=169 SRC="FIGDIR/small/540970v1_ufig1.gif" ALT="Figure 1"> View larger version (66K): org.highwire.dtl.DTLVardef@172d5bforg.highwire.dtl.DTLVardef@2f1d80org.highwire.dtl.DTLVardef@139e7a0org.highwire.dtl.DTLVardef@95dce1_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIDELiVR detects labelled cells in cleared brains with deep learning C_LIO_LIDELiVR is trained by annotating ground-truth data in virtual reality (VR) C_LIO_LIDELiVR is launched via a FIJI plugin anywhere from PCs to clusters C_LIO_LIUsing DELiVR, we found new brain activity patterns in weight-stable vs. cachectic cancer C_LI Supplementary Videos can be seen at: https://www.DISCOtechnologies.org/DELiVR/

bioinformatics↗