Elaine Hsiao

The microbial metabolite imidazole propionate modulates hypothalamic activity and stress-induced behaviors Agirman et al. find that imidazole propionate, a microbiome-derived metabolite, reaches the brain, dampens hypothalamic activity, and promotes stress-related behaviors. Human data show that higher ImP...

Microbe-mediated stress?

Microbial metabolite Imidazole propionate reaches brain, dampens hypothalamic activity & promotes stress-related behaviors. In humans, higher ImP is associated w/reduced hypothalamic responses & emotional eating
@pipethero.bsky.social
www.cell.com/cell-host-mi...

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This work underscores how a single microbial metabolite can have profound effects on host neurobiology through direct access to the brain. A huge congratulations to Guli and coauthors for unraveling this pathway from the gut lumen to the hypothalamus!

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Importantly, these associations between high ImP, decreased hypothalamic activity, & maladaptive stress behaviors were reproduced in human subjects that were assessed for stress-related behavioral traits and underwent fMRI to measure hypothalamic reactivity to palatable food-related stimuli

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Instead, ImP specifically targets the hypothalamus. Guli saw decreased neuronal activation & increased GABA in the hypothalamus (but not amygdala). In primary neuronal cultures, supplementing ImP altered excitatory responses. This suggests that ImP tunes the brain's emotional circuitry directly. 🎯

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Is this due to neuroinflammation? Guli checked. Using snRNA-seq, immunostaining in the hypothalamus, and cytokine profiling, she found no evidence of ImP-induced neuroinflammation or mTOR activation. This suggests ImP acts via a different mechanism than general immune activation.

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What happens when ImP levels rise? Guli saw striking alterations in hypothalamic neurons for stress & E/I balance. ImP increased anxiety-like behaviors, seizure susceptibility, & stress-induced intake of palatable food. This was also seen with high ImP from E. lenta or ImP from HFD microbiota.

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She started by looking at how gut bacteria convert histidine into ImP. Using engineered B. theta and E. lenta, she confirmed that bacteria-derived ImP doesn’t stay in the gut. It enters systemic circulation and reaches multiple brain regions, including the hypothalamus.🩸🦠

We were inspired by metabolomic datasets showing that ImP is seen in the brain, as well human studies finding that high levels of serum ImP are seen in metabolic diseases like T2D and obesity. This made Guli wonder whether increased microbial production of ImP can account for high serum & brain ImP.

Excited to share new work by Guli Agirman + co that identifies a direct mechanism linking gut microbial imidazole propionate to stress! 🧠🦠 Btw this image was made by Nano Banana Pro 🍌. First time I've gotten a model to accurately generate a science graphic 🤯 authors.elsevier.com/a/1mA5M6t8JE...

Happy to share this paper in final form rdcu.be/eH8tj, with more info on neuronal responses and potential mechanism of actions! The results suggest that there is neural interoception of microbial metabolic state 🧠🦠 We hope they can inspire more work in this area!

Microbial regulation of serotonin and neuroimmune interactions Bidirectional communication between the gut microbiota and neuroimmune system is essential during host–microbiome interactions. Recent research has be…

Delighted to share this perspective piece by Lewis Yu on microbial regulation of serotonin and neuroimmune interactions. Looking forward to sharing more on this topic soon 🤞 www.sciencedirect.com/science/arti...

5/5 Awardee @chuchuzhang.bsky.social explores how different body states (eg, pregnancy) may change what neurons sense & how they respond. Her work may lead to new ways to address nausea associated w/ pregnancy🤰 & chemo.
🍾Congrats Dr. Zhang! @dgsomucla.bsky.social
🙏 #HFScout @pipethero.bsky.social

Extramural papers of the month

🧪our paper in @cp-cellhostmicrobe.bsky.social selected as NIEHS papers of the month! 🔥🔥 pubmed.ncbi.nlm.nih.gov/40315838/ @pipethero.bsky.social @scrippsocean.bsky.social

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Overall, this was an exciting proof of concept showing that i) a gut bacterium can be used to offset environmental risk for neurotoxicity and ii) bacterial treatment of pregnant mice has the capacity to protect the brains of their fetuses.

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To see if it reduces methylmercury to levels that are biologically meaningful, we tested it in pregnant mice. The bacterium reduced methylmercury bioaccumulation in maternal & fetal tissues, including brain, & reduced signs of toxicity in fetal brains from dams fed tuna or salmon

a man is talking to a woman and the words eliminate it are on the screen behind him ALT: a man is talking to a woman and the words eliminate it are on the screen behind him

To put it to the real test, Amina got a bluefin tuna from a fish market & processed it into a fine powder. The bacterium reduced fish methylmercury when in culture & when monocolonized in mice that were fed fish-based chow. It even worked by oral gavage to conventional mice!

a cartoon drawing of bacteria with the words party time written below them ALT: a cartoon drawing of bacteria with the words party time written below them

Kristie engineered the gut bacterium B. thetaiotaomicron to express enzymes that reduce methylmercury into forms that are less toxic & easily excreted, and showed the bacterium quickly reduces methylmercury in culture & in the guts of mice orally gavaged with methylmercury

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This made us wonder, if certain soil microbes survive by detoxifying methylmercury from their environment, could we use a microbe to detoxify methylmercury that enters the gut environment from eating mercury-containing fish?

Potential of Organic Mercury-resistant Bacteria Isolated from Mercury Contaminated Sites for Organic Mercury Remediation - PubMed The study suggested that there are four bacteria that have potentials to remediate organic mercury contamination sites.

We were inspired by work by Fatimawali, Kepel, and Tallei at Sam Ratulangi University that found mercury-resistant soil bacteria from a polluted gold mine
pubmed.ncbi.nlm.nih.gov/30796768/

We learned from Amina’s foundational research that levels of the neurotoxicant methylmercury are rising in fish, which poses a major issue for the billions of people iwho rely on fish as a major source of nutrition. www.nature.com/articles/s41...

This all began with a chance meeting at Scialog meeting by @RCSA1—think science speed-dating with rapid seed funding- a fun and impactful way to advance new ideas. Thanks to @RCSA1 for supporting collaborative, interdisciplinary research & making this work possible! newsroom.ucla.edu/releases/red...

An engineered gut bacterium protects against dietary methylmercury exposure in pregnant mice Yu and Chandra et al. engineered a commensal gut microbe, Bacteroides thetaiotaomicron, to detoxify methylmercury (MeHg). The engineered bacterium reduces MeHg in the intestinal lumen, limits its accu...

Thrilled to share this collaborative work by Kristie Yu, Francis Chandra, Amina Schartup and teams @Scripps_Ocean and @UCLA showing that an engineered gut bacterium can be used to reduce the neurotoxic effects of dietary methylmercury www.cell.com/cell-host-mi...

a green cartoon character is giving a thumbs up sign ALT: a green cartoon character is giving a thumbs up sign

Lots more to do and improve, but overall, this was an exciting proof of concept showing that i) a gut bacterium can be used to offset environmental risk for neurotoxicity and ii) bacterial treatment of pregnant mice has the capacity to protect the brains of their fetuses.

a robot says " if you go near this child , i will have no choice but to kill you " ALT: a robot says " if you go near this child , i will have no choice but to kill you "

To see if it reduces methylmercury to levels that are biologically meaningful, we tested it in pregnant mice. The bacterium reduced methylmercury bioaccumulation in maternal & fetal tissues, including brain, & reduced signs of toxicity in fetal brains from dams fed tuna or salmon

a man is talking to a woman and the words eliminate it are on the screen behind him ALT: a man is talking to a woman and the words eliminate it are on the screen behind him

To put it to the real test, Amina got a bluefin tuna from a fish market & processed it into a fine powder. The bacterium reduced fish methylmercury when in culture & when monocolonized in mice that were fed fish-based chow. It even worked by oral gavage to conventional mice!

a cartoon drawing of bacteria with the words party time written below them ALT: a cartoon drawing of bacteria with the words party time written below them

Kristie engineered the gut bacterium B. thetaiotaomicron to express enzymes that reduce methylmercury into forms that are less toxic & easily excreted, and showed the bacterium quickly reduces methylmercury in culture & in the guts of mice orally gavaged with methylmercury

a cartoon of spongebob with a question mark in a thought bubble ALT: a cartoon of spongebob with a question mark in a thought bubble

This made us wonder, if certain soil microbes survive by detoxifying methylmercury from their environment, could we use a microbe to detoxify methylmercury that enters the gut environment from eating mercury-containing fish?

Potential of Organic Mercury-resistant Bacteria Isolated from Mercury Contaminated Sites for Organic Mercury Remediation - PubMed The study suggested that there are four bacteria that have potentials to remediate organic mercury contamination sites.

We were inspired by work by Fatimawali, Kepel, and Tallei at Sam Ratulangi University that found mercury-resistant soil bacteria from a polluted gold mine
pubmed.ncbi.nlm.nih.gov/30796768/

Climate change and overfishing increase neurotoxicant in marine predators - Nature Overfishing and warming ocean temperature have caused an increase in methylmercury concentrations in some Atlantic predatory fish, and this trend is predicted to continue unless stronger mercury and c...

We learned from Amina’s foundational research that levels of the neurotoxicant methylmercury are rising in fish, which poses a major issue for the billions of people iwho rely on fish as a major source of nutrition. www.nature.com/articles/s41...

This all began with a chance meeting at Scialog meeting by RCSA — think science speed-dating with rapid seed funding- a fun and impactful way to advance new ideas. Thanks to RCSA for supporting collaborative, interdisciplinary research & making this work possible!