Chemical Impacts of the Microbiome Across Scales Reveal Novel Conjugated Bile Acids

Ra, Quinn; Vrbanac, Alison; Av, Melnik; Ka, Patras; Christy, Mitchell P.; At, Nelson; Aksenov, Alexander A.; Tripathi, Anupriya; Humphrey, Gregory; R, da Silva; Bussell, Robert H.; Thron, Taren; Wang, M; Vargas, Fernando; Jm, Gauglitz; Mj, Meehan; Poulsen, Orit; Bs, Boland; Jt, Chang; Wj, Sandborn; Lim, Megan S.; Garg, Neha; Lumeng, Julie C.; Bi, Kazmierczak; Jain, Rishi K.; Egan, M.G.; Rhee, Kyung E.; Gg, Haddad; Siegel, Dionicio; Mazmanian, Sarkis K.; Nizet,; Knight, Rob; Pc, Dorrestein

doi:10.1101/654756

Cited by 8 publications

(10 citation statements)

References 33 publications

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“…Indeed, we showed that Clostridium spp. were found to produce this bile acid [36]. This result demonstrates mmvec's ability to streamline the discovery of microbes that produce specific molecules of interest in vivo.…”

Section: Effects Of High Fat Diet In Murine Model Case Studymentioning

confidence: 72%

“…We then tested whether mmvec could determine the microbial origin of specific molecules in a complex biological system. We recently discovered a new kind of bile acid, where cholate is conjugated to amino acids other than glycine and taurine [36]. These molecules increased in abundance with high-fat diet in humans.…”

Section: Effects Of High Fat Diet In Murine Model Case Studymentioning

confidence: 99%

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Learning representations of microbe–metabolite interactions

et al. 2019

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Integrating multi-omics datasets is critical for microbiome research, but multiple statistical challenges can confound traditional correlation techniques. We solve this problem by using neural networks to estimate the conditional probability that each molecule is present given the presence of each specific microbe. We show with known environmental (desert biological soil crust wetting) and clinical (cystic fibrosis lung) examples, our ability to recover microbe-metabolite relationships, and demonstrate how the method can discover relationships between microbially-produced metabolites and inflammatory bowel disease.

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Section: Effects Of High Fat Diet In Murine Model Case Studymentioning

confidence: 72%

Section: Effects Of High Fat Diet In Murine Model Case Studymentioning

confidence: 99%

Learning representations of microbe–metabolite interactions

et al. 2019

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“…The 3D mouse model was generated as described previously (Quinn et al 2019). In brief, MRI images were acquired at the UCSD Center for Functional MRI from a euthanized 8-wk-old female C57BL/6 mouse with a Bruker 7T/20 MRI scanner using a quadrature birdcage transceiver.…”

Section: D Mouse Modelmentioning

confidence: 99%

Organ-level protein networks as a reference for the host effects of the microbiome

et al. 2020

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Connections between the microbiome and health are rapidly emerging in a wide range of diseases. However, a detailed mechanistic understanding of how different microbial communities are influencing their hosts is often lacking. One method researchers have used to understand these effects are germ-free (GF) mouse models. Differences found within the organ systems of these model organisms may highlight generalizable mechanisms that microbiome dysbioses have throughout the host. Here, we applied multiplexed, quantitative proteomics on the brains, spleens, hearts, small intestines, and colons of conventionally raised and GF mice, identifying associations to colonization state in over 7000 proteins. Highly ranked associations were constructed into protein–protein interaction networks and visualized onto an interactive 3D mouse model for user-guided exploration. These results act as a resource for microbiome researchers hoping to identify host effects of microbiome colonization on a given organ of interest. Our results include validation of previously reported effects in xenobiotic metabolism, the innate immune system, and glutamate-associated proteins while simultaneously providing organism-wide context. We highlight organism-wide differences in mitochondrial proteins including consistent increases in NNT, a mitochondrial protein with essential roles in influencing levels of NADH and NADPH, in all analyzed organs of conventional mice. Our networks also reveal new associations for further exploration, including protease responses in the spleen, high-density lipoproteins in the heart, and glutamatergic signaling in the brain. In total, our study provides a resource for microbiome researchers through detailed tables and visualization of the protein-level effects of microbial colonization on several organ systems.

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“…Understanding how the gut microbiota influence the brain, and the complex network of molecules and neurotransmitters that mediate this influence, is a significant challenge requiring novel tools and approaches. Mass spectrometry imaging (MSI) is a molecular imaging tool that can be applied to understand and map biological systems with recent successes in mapping microbial interactions with their environment ( 36 – 38 ). MSI maps the distribution of small molecules across a tissue section independent of any label, so no prior knowledge of the molecules present is required.…”

Section: Introductionmentioning

confidence: 99%

Mapping the influence of the gut microbiota on small molecules in the brain through mass spectrometry imaging

Wall

Hulme

Meikle

et al. 2020

Preprint

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27Background: The gut microbiota is known to influence virtually all facets of human health. 28Recent work has highlighted a potential role for the gut microbiota in neurological health 29 through the microbiome-gut-brain axis. Microbes can influence the brain both directly and 30 indirectly; through neurotransmitter production, induction of host immunomodulators, or 31 through the release or induction of other microbial or host molecules. 32Methods: Here we used mass spectrometry imaging (MSI), a label-free imaging tool, to map 33 the molecular changes that occur in the murine gut and brain in germ-free, antibiotic-treated 34 and control mice. 35Results: We determined the spatial distribution and relative quantification of 36 neurotransmitters and their precursors across brain and gut sections in response to the 37 microbiome. Using untargeted MSI of small molecules, we detected a significant change in 38 the levels of four identified metabolites in the brains of germ-free animals compared to 39 controls; vitamin B5, 3-hydroxy-3-methylglutaric acid, 3-methyl-4- 40(trimethylammonio)butanoate and 4-(trimethylammonio)pentanoate. However, antibiotic 41 treatment induced no significant changes in these metabolites in the brain after one week of 42 treatment. 43Conclusions: This work exemplifies the utility of MSI as a tool in determining the spatial 44 distribution and quantification of bacterial and host metabolites in the gut and brain whilst also 45 offering the potential for discovery of novel mediators of microbiome-gut-brain axis 46 communication.47 48 49 50 Background 51Deciphering the complex bi-directional communication across the microbiome gut brain 52 (MGB) axis remains a challenging prospect. The composition and stability of the gut 53 microbiome is now proposed to be a significant contributor to human health with changes in 54 its composition suggested as a contributing factor in a number of neurological conditions. 55Diverse human neurological disorders, ranging from autism spectrum disorders (ASDs) and 56 attention-deficit/hyperactivity disorder (ADHD) to Alzheimer's and Parkinson's disease, have 57 linked gastrointestinal abnormalities or changes in the gut microbiome (1-6). Similarly, 58 altered levels of certain bacterial species in the gut have been linked with depression (7, 8). 59Despite the deficiencies of germ free (GF) animal models, their use for investigating links 60 between the gut microbiota and the brain have proved informative and are helping to uncover 61 the influence of bacteria on neurotransmitter levels alongside other bacterial and host 62 metabolites. Their neuro-developmental abnormalities including increased blood-brain-barrier 63 (BBB) permeability, alterations in abundance and maturity of microglia cells, and reduced 64 myelination (9-11) have been well documented but their use, alongside antibiotic treated 65 (ABX) mice, have provided further evidence that supports the importance of a stable and 66 healthy gut microbiota in maintaining normal cognitive function and developm...

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Chemical Impacts of the Microbiome Across Scales Reveal Novel Conjugated Bile Acids

Cited by 8 publications

References 33 publications

Learning representations of microbe–metabolite interactions

Learning representations of microbe–metabolite interactions

Organ-level protein networks as a reference for the host effects of the microbiome

Mapping the influence of the gut microbiota on small molecules in the brain through mass spectrometry imaging

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