metabolites

Staphylococcus aureus metabolic requirements during skin colonization

Project Summary Staphylococcus aureus causes 76% of all skin infections, and yet simultaneously this pathogen asymptomatically colonizes the skin of 8-22% of healthy adults. Since the majority of S. aureus disease is the result of autoinfection from the colonizing strain, and invasive infections often originate from the skin, there is an urgent need to understand colonization mechanisms. In colonizing the skin, S. aureus encounters abundant levels of amino acid derivatives like urocanic acid and 5-oxoproline (OP) that contribute to the skin’s “acid mantle” and have reported anti-Staphylococcal properties. The central hypothesis of this project is that amino acid transport and catabolism is a critical feature of S. aureus skin colonization. To model this environment, we developed a skin-like media (SLM) to assess S. aureus physiology on the human skin surface. We determined the S. aureus transcriptional response using RNAseq and performed metabolomics in SLM, both of which demonstrated that amino acid catabolism genes are upregulated and that amino acids are rapidly consumed. These findings indicate that S. aureus has a skin expression program that enables survival and growth in this harsh environment. In Specific Aim 1, we are investigating S. aureus metabolism of serine, the second most abundant amino acid on human skin. We hypothesize that serine transport and catabolism is critical for S. aureus skin colonization. We will assess growth of mutant strains disrupted in serine pathways in the SLM and during mouse skin colonization. With 13C-tracing experiments we will investigate serine flux in S. aureus using metabolomics. We will determine serine transport mechanisms using bioinformatic guided targets and serine analogues. In Specific Aim 2, we will assess S. aureus resistance to toxic skin metabolites. OP is abundant on human skin and is known to be deleterious to bacteria. Our preliminary metabolomics studies indicate that S. aureus metabolizes OP in SLM, and we have identified a putative oxoprolinase (genes SAUSA300_1566-1561) that is upregulated on skin. We hypothesize that the detoxification of OP contributes to S. aureus survival on the skin. We will construct mutants in the 1566-1561 locus and test their contributions to OP metabolism in SLM with growth and metabolomics experiments. We will also investigate OP transport and test mutant strains in our mouse skin colonization model. In Specific Aim 3, we will identify new determinants of S. aureus skin colonization using TnSeq. We have developed an improved TnSeq library preparation and analysis protocol, and in our preliminary studies we performed TnSeq in SLM and in our mouse skin colonization model. We will evaluate pathway hits, such as respiration and fermentation, and aspartate metabolism targets by testing constructed mutants during SLM growth and in the mouse model. Novel hits will be validated with follow-up genetic experiments and 13C-tracing experiments. Collectively, the proposed studies will advance our knowledge of S. aureus colonization and adaptation to the skin environment.

Investigating the nonlinear complex dynamics of the tuft cell-microbiome cross-talk: the impact of feedback loops on immune regulation, microbial modulation and response to tissue insults

Project Abstract Tuft cells (TCs) are specialized chemosensory epithelial cells that are emerging as critical regulators of intestinal homeostasis. Named over 70 years ago based on their distinct morphology, a defined function for TCs was only elucidated in the last decade. TCs in the small intestine sense succinate from helminths to initiate type 2 immune responses that mediate parasite expulsion. Recently, we discovered a novel physiologic function for TCs in the colon, where their role had been considered minimal. Succinate, a key microbial metabolite, is produced by colonic microbiota as both a precursor to other metabolites and a cross-feeding fuel source for pathogens. TCs respond to succinate by secreting interleukin-25 (IL-25), which activates type 2 cytokine- producing lymphocytes (T2Ls), amplifying TC expansion and reinforcing barrier function. We recently demonstrated that this SPB–TC–IL-25–T2L feedback loop is essential for protection against pathogen-induced colitis. Our preliminary data further suggest that TCs actively promote colonization by succinate-producing bacteria (SPBs), establishing positive feedback on TC-supporting microbes, while other epithelial cells such as goblet cells (GCs) and Paneth cells (PCs) may exert complementary or counterbalancing influences. Supported by new modeling insights, we hypothesize that these epithelial–immune–microbiome interactions form coordinated feedback loops that collectively optimize intestinal resilience. These loops may create a dynamic, multi-stable system that flexibly transitions between homeostatic and hyperplastic states, buffering against microbial fluctuations and pathogenic insults while preventing uncontrolled type 2 inflammation. Using a combination of mathematical modeling and experimental validation, we will develop a multi- layered systems framework to explore how epithelial–immune–microbial feedbacks shape resilience or breakdown in clinically relevant models of colonic infection and inflammation. Our three Aims will (1) develop, calibrate, and validate a mathematical model that integrates TCs, GCs, PCs, SPBs, and SCBs; (2) define the immunological circuits governing epithelial–microbiome equilibrium; and (3) determine how epithelial feedbacks regulate microbial community structure and resilience. In line with NIH’s new initiative to prioritize human-based research, our proposal combines computational modeling, human colonic organoids, and complementary mouse models. Organoid experiments will provide human-relevant data for model calibration, while in vivo studies validate systemic predictions, ensuring both rigor and translational relevance while minimizing reliance on animal models. This work will generate interoperable models that integrate epithelial, microbial, and immune networks, providing predictive insight into intestinal outcomes under homeostatic, infectious, and inflammatory conditions and informing therapeutic strategies for microbiome-targeted interventions.

Systems Biology of Early Atopy: Role of Human Milk (SunBEAm-Milk)

Surprisingly little is known about the effect of breastfeeding (BF) on infant immune system development besides an effect on the gut microbiome, but its impact on metabolites and Tregs could support protection against food allergy (FA). BF is currently recommended to prevent the development of allergic diseases, especially asthma/recurrent wheezing and AD in early childhood, but firm conclusions could not be drawn regarding FA due to high heterogeneity and low quality of studies. Reverse causation, recall bias and the poor accuracy of outcome assessment are significant limitations. Most are inadequately powered to specific FA; however, a recent study showed that exclusively BF infants had lower odds of egg, sesame, and peanut allergies. Importantly, immunomodulatory composition of HM varies between mothers, which has not been taken into consideration. For over two decades we have been developing methods to assess immunomodulatory factors in the complex matrix of HM and their association with infant FA. We have shown that high levels of HM total and specific IgA are associated with protection against cow’s milk allergy, but it is unclear whether HM IgA is responsible for or is a biomarker of the vertical transfer of protection. Infant fecal and systemic IgA levels during breastfeeding and after weaning are also elevated in infants at low risk for atopic disease raising the question of whether HM factors such as cytokines can promote IgA production in infants. Consistent with this, we showed that HM cytokines, such as APRIL, induce IgA production in naïve infant B cells, and infants receiving HM with higher levels of APRIL had lower incidence of allergic disease. Finally, lower levels of several HM fatty acids including short-chain fatty acids and DHA were associated with FA. While some these factors were are associated with maternal atopic disease, several of them are not and suggest a role for diet instead. The System Biology of Early Atopy (SunBEAm) population-based cohort of 2500 mother-infant pairs is >50% recruited and provides an unprecedented opportunity to assess association of HM feeding and immune factors in HM with development of infant immune system and FA/AD. The Common Sample comprises a subset of 100 dyads with FA, 100 with FA+AD, 100 with AD, 100 with no FA or AD and more extensively profiled biological data. Utilizing all 2-month HM samples available in the Common Sample, we will assess levels of immune factors in HM and their association with maternal/infant characteristics (Aim 1). Utilizing data from the whole cohort, we will assess the association between HM vs formula feeding on well-defined FA/AD further adjusted based on high vs low levels of HM immune components in the Common Sample (Aim 2b). Finally, we will examine the immune cell and epithelial effects of HM on infant immune markers and intestinal organoids (Aim 3). Key findings will be validated in an independent birth cohort. The ultimate goal is to uncover protective properties of BF and HM in FA and subsequent design of policies and prevention strategies to address the increasing rates of FA.

Understanding antiretroviral phosphorylation and dephosphorylation using mass spectrometry imaging-based enzyme histochemistry

PROJECT SUMMARY Our overall goal is to understand the mechanistic differences in the activation and deactivation of two widely used first-line antiretroviral drugs: tenofovir (TFV) and emtricitabine (FTC) in colonic tissues. HIV is a global health problem and roughly 1.3 million people became newly infected with HIV globally in 2022. Pre-exposure prophylaxis (PrEP) is an HIV prevention strategy where HIV-negative individuals use antiretrovirals to reduce the risk of HIV infection. Specifically, oral fixed-dose combinations of two antiretrovirals, namely, TFV (TFV; prescribed as TFV disoproxil fumarate or TFV alafenamide prodrugs) and FTC are FDA-approved for HIV PrEP. The pharmacologically active forms of TFV and FTC are TFV-diphosphate (TFV-DP) and FTC-triphosphate (FTC-TP), respectively, and these phosphorylated metabolites are found in cells. Unfortunately, high variability in the responses of TFV and FTC can lead to poor clinical outcomes, including therapeutic failure. However, the molecular mechanisms responsible for the observed variability in TFV and FTC responses are poorly understood. Although the observed variability in TFV and FTC drug responses is likely to be multifactorial, alterations in drug activation and deactivation can contribute to the observed variability in drug responses. Phosphorylation of TFV is known and recent studies suggest that nucleotidases may involve in the dephosphorylation of TFV metabolites. Although the kinases that phosphorylate FTC in peripheral blood mononuclear cells are known, the kinases that are responsible for the phosphorylation of FTC in putative sites of HIV infection such as colonic tissues are yet to be determined. Notably, unprotected receptive anal intercourse has a 20-fold higher risk of HIV transmission than vaginal intercourse. Thus, understanding the biotransformation of TFV and FTC in colonic tissue is important since it is a susceptible tissue to HIV infection. Recently, we have reported the enzymatic activities of nucleotidases toward the pharmacologically active metabolites of TFV and FTC in vitro. However, the mechanistic details of the biotransformation of the above drugs in HIV susceptible tissues such as colonic tissues are yet to be elucidated. Gaining a mechanistic understanding of the biotransformation of TFV and FTC in putative sites of HIV infection is important to improve their therapeutic efficacy. As such, in this application, we propose an innovative mass spectrometry imaging-based interdisciplinary approach to understand the biotransformation of TFV and FTC in the colon. Aim 1 will establish the role of nucleotide kinases and nucleotidases in regulating TFV and FTC metabolites in colonic cells mechanistically. Aim 2 will characterize the region- and cell-type-specific expression patterns, as well as enzymatic activities of nucleotide kinases and nucleotidases in situ. The proposed project will provide novel understandings of TFV and FTC activating and deactivating mechanisms that can be leveraged to optimize the therapeutic efficacy of the above drugs.

Magnetic resonance true temperature imaging with high spatial and temporal resolution

ABSTRACT The knowledge of temperature and temperature distribution within the brain can be critical to understanding the healthy and diseased brain, its response to acute injury, and in monitoring critically important thermal interventions. There are several temperature sensitive properties such relaxation rates and the proton resonance frequency shift (PRFS) that can be measured with magnetic resonance imaging (MRI) methods but these methods can only measure temperature change. The PRFS method, which provides the most accurate measurement of temperature change can only measure true tissue temperature if the starting true temperature distribution is known. Fortunately, MR spectroscopy (MRS) methods have been developed that show great promise in the measurement of true temperature. These methods rely on the detection of a temperature independent spectral peak of protons bound to carbon atoms in high concentration metabolites, such as N- acetylaspartate (NAA), creatine (Cr) and choline (Cho) which can be used as a reference for the temperature dependent spectral peak of water protons. Both single voxel spectroscopy (SVS) methods and MRS imaging (MRSI) methods have been described but are slow because of the long readout time needed to achieve adequate spectral resolution and the need to perform multiple averages due to the low signal being measured. Echo-planar spectroscopic imaging (EPSI) speeds up MRSI by interleaving an oscillating imaging gradient to spatially encode one of the imaging dimensions simultaneously with spectral readout. Unfortunately, SVS, MRSI, and even EPSI are unsuitable for clinical applications because of the low spatial resolution (voxel size 1 cm3) and temporal resolution (multiple minutes). The goal of this project is to develop an MRI technique that can measure true temperature in the whole brain at spatial and temporal resolutions that enable clinical utility for acutely assessing and longitudinally monitoring healthy and diseased brain tissue, and real time monitoring of thermal interventional therapies. This innovative true temperature measurement technique combines EPSI, for low resolution background field measurements, with PRFS for high spatial and temporal resolution water proton measurements. While conventional EPSI methods interleave volumetric acquisitions with and without water suppression, we propose an innovative modification to take advantage of the very strong water signal to obtain a very high resolution, dynamic method for true temperature measurements. The MRI pulse sequence will be refined, validated (Aim 1), applied to healthy subjects and post-surgery patients at risk for infections (Aim 2), and applied to essential tremor (ET) patients during the required delay between repeated focused ultrasound sonications (Aim 3). Successful completion of the aims of this study will result in a clinically practical method to obtain true temperature measurements in the brain with a spatial and temporal resolution sufficiently high to meet the needs of monitoring focal thermal therapy treatments as well as to provide true temperature measurements over the entire brain for assessment of the state of the brain with disease, infection, and injury.

Personalized medicine and predictive health and wellness: Adding the chemical component

Wearable sensors that detect and quantify biomarkers in retrievable biofluids (e.g., interstitial fluid, sweat, tears) provide information on human dynamic physiological and psychological states. This information can transform health and wellness by providing actionable feedback. Due to outdated and insufficiently sensitive technologies, current on-body sensing systems have capabilities limited to pH, and a few high-concentration electrolytes, metabolites, and nutrients. As such, wearable sensing systems cannot detect key low-concentration biomarkers indicative of stress, inflammation, metabolic, and reproductive status.  We are revolutionizing sensing. Our electronic biosensors detect virtually any signaling molecule or metabolite at ultra-low levels. We have monitored serotonin, dopamine, cortisol, phenylalanine, estradiol, progesterone, and glucose in blood, sweat, interstitial fluid, and tears. The sensors are based on modern nanoscale semiconductor transistors that are straightforwardly scalable for manufacturing. We are developing sensors for >40 biomarkers for personalized continuous monitoring (e.g., smartwatch, wearable patch) that will provide feedback for treating chronic health conditions (e.g., perimenopause, stress disorders, phenylketonuria). Moreover, our sensors will enable female fertility monitoring and the adoption of more healthy lifestyles to prevent disease and improve physical and cognitive performance.

Metabolic Remodelling in the Developing Forebrain in Health and Disease

Little is known about the critical metabolic changes that neural cells have to undergo during development and how temporary shifts in this program can influence brain circuitries and behavior. Motivated by the identification of autism-associated mutations in SLC7A5, a transporter for metabolically essential large neutral amino acids (LNAAs), we utilized metabolomic profiling to investigate the metabolic states of the cerebral cortex across various developmental stages. Our findings reveal significant metabolic restructuring occurring in the forebrain throughout development, with specific groups of metabolites exhibiting stage-specific changes. Through the manipulation of Slc7a5 expression in neural cells, we discovered an interconnected relationship between the metabolism of LNAAs and lipids within the cortex. Neuronal deletion of Slc7a5 influences the postnatal metabolic state, resulting in a shift in lipid metabolism and a cell-type-specific modification in neuronal activity patterns. This ultimately gives rise to enduring circuit dysfunction.

More than a beast growing in a passive brain: excitation and inhibition drive epilepsy and glioma progression

Gliomas are brain tumors formed by networks of connected tumor cells, nested in and interacting with neuronal networks. Neuronal activities interfere with tumor growth and occurrence of seizures affects glioma prognosis, while the developing tumor triggers seizures in the infiltrated cortex. Oncometabolites produced by tumor cells and neurotransmitters affect both the generation of epileptic activities by neurons and the growth of glioma cells through synaptic-related mechanisms, involving both GABAergic / Chloride pathways and glutamatergic signaling. From a clinical sight, epilepsy occurrence is beneficial to glioma prognosis but growing tumors are epileptogenic, which constitutes a paradox. This lecture will review how inhibitory and excitatory signaling drives glioma growth and how epileptic and oncological processes are interfering, with a special focus on the human brain.

Uncovering the molecular effectors of diet and exercise

Despite the profound effects of nutrition and physical activity on human health, our understanding of the molecules mediating the salutary effects of specific foods or activities remains remarkably limited. Here, we share our ongoing studies that use unbiased and high-resolution metabolomics technologies to uncover the molecules and molecular effectors of diet and exercise. We describe how exercise stimulates the production of Lac-Phe, a blood-borne signaling metabolite that suppresses feeding and obesity. Ablation of Lac-Phe biosynthesis in mice increases food intake and obesity after exercise. We also describe the discovery of an orphan metabolite, BHB-Phe. Ketosis-inducible BHB-Phe is a congener of exercise-inducible Lac-Phe, produced in CNDP2+ cells when levels of BHB are high, and functions to lower body weight and adiposity in ketosis. Our data uncover an unexpected and underappreciated signaling role for metabolic fuel derivatives in mediating the cardiometabolic benefits of diet and exercise. These data also suggest that diet and exercise may mediate their physiologic effects on energy balance via a common family of molecules and overlapping signaling pathways.

Role of the gut microbiota in the development of alcohol use disorder

The gut microbiota is composed of a very large number of bacteria, viruses, fungi and yeasts that play an important role in the body, through the production of a series of metabolites (including neurotransmitters), and through an essential role in the barrier function of the gut and the regulation of immunity and stress response. In this lecture I will present, based mainly on human studies but also on preclinical studies, the evidence for a role of the gut microbiota in the development of alcohol use disorder. I will show the first results of trials to test the effects of nutritional approaches to address these deficits.

Microbiota in the health of the nervous system and the response to stress

Microbes have shaped the evolution of eukaryotes and contribute significantly to the physiology and behavior of animals. Some of these traits are inherited by the progenies. Despite the vast importance of microbe-host communication, we still do not know how bacteria change short term traits or long-term decisions in individuals or communities. In this seminar I will present our work on how commensal and pathogenic bacteria impact specific neuronal phenotypes and decision making. The traits we specifically study are the degeneration and regeneration of neurons and survival behaviors in animals. We use the nematode Caenorhabditis elegans and its dietary bacteria as model organisms. Both nematode and bacteria are genetically tractable, simplifying the detection of specific molecules and their effect on measurable characteristics. To identify these molecules we analyze their genomes, transcriptomes and metabolomes, followed by functional in vivo validation. We found that specific bacterial RNAs and bacterially produced neurotransmitters are key to trigger a survival behavioral and neuronal protection respectively. While RNAs cause responses that lasts for many generations we are still investigating whether bacterial metabolites are capable of inducing long lasting phenotypic changes.

Parp mutations protect from mitochondrial toxicity in Alzheimer’s disease

Alzheimer’s disease is the most common age-related neurodegenerative disorder. Familial forms of Alzheimer’s disease associated with the accumulation of a toxic form of amyloid-β (Aβ) peptides are linked to mitochondrial impairment. The coenzyme nicotinamide adenine dinucleotide (NAD+) is essential for both mitochondrial bioenergetics and nuclear DNA repair through NAD+-consuming poly (ADP-ribose) polymerases (PARPs). Here, we analysed the metabolomic changes in flies over-expressing Aβ and showed a decrease of metabolites associated with nicotinate and nicotinamide metabolism, which is critical for mitochondrial function in neurons. We show that increasing the bioavailability of NAD+ protects against Aβ toxicity. Pharmacological supplementation using NAM, a form of vitamin B that acts as a precursor for NAD+ or a genetic mutation of PARP rescues mitochondrial defects, protects neurons against degeneration and reduces behavioural impairments in a fly model of Alzheimer’s disease. Next, we looked at links between PARP polymorphisms and vitamin B intake in patients with Alzheimer’s disease. We show that polymorphisms in the human PARP1 gene or the intake of vitamin B, are associated with a decrease in the risk and severity of Alzheimer’s disease. We suggest that enhancing the availability of NAD+ by either vitamin B supplements or the inhibition of NAD+-dependent enzymes, such as PARPs are potential therapies for Alzheimer’s disease.

A fresh look at the bird retina

I am working on the vertebrate retina, with a main focus on the mouse and bird retina. Currently my work is focused on three major topics: Functional and molecular analysis of electrical synapses in the retina Circuitry and functional role of retinal interneurons: horizontal cells Circuitry for light-dependent magnetoreception in the bird retina Electrical synapses Electrical synapses (gap junctions) permit fast transmission of electrical signals and passage of metabolites by means of channels, which directly connect the cytoplasm of adjoining cells. A functional gap junction channel consists of two hemichannels (one provided by each of the cells), each comprised of a set of six protein subunits, termed connexins. These building blocks exist in a variety of different subtypes, and the connexin composition determines permeability and gating properties of a gap junction channel, thereby enabling electrical synapses to meet a diversity of physiological requirements. In the retina, various connexins are expressed in different cell types. We study the cellular distribution of different connexins as well as the modulation induced by transmitter action or change of ambient light levels, which leads to altered electrical coupling properties. We are also interested in exploiting them as therapeutic avenue for retinal degeneration diseases. Horizontal cells Horizontal cells receive excitatory input from photoreceptors and provide feedback inhibition to photoreceptors and feedforward inhibition to bipolar cells. Because of strong electrical coupling horizontal cells integrate the photoreceptor input over a wide area and are thought to contribute to the antagonistic organization of bipolar cell and ganglion cell receptive fields and to tune the photoreceptor–bipolar cell synapse with respect to the ambient light conditions. However, the extent to which this influence shapes retinal output is unclear, and we aim to elucidate the functional importance of horizontal cells for retinal signal processing by studying various transgenic mouse models. Retinal circuitry for light-dependent magnetoreception in the bird We are studying which neuronal cell types and pathways in the bird retina are involved in the processing of magnetic signals. Likely, magnetic information is detected in cryptochrome-expressing photoreceptors and leaves the retina through ganglion cell axons that project via the thalamofugal pathway to Cluster N, a part of the visual wulst essential for the avian magnetic compass. Thus, we aim to elucidate the synaptic connections and retinal signaling pathways from putatively magnetosensitive photoreceptors to thalamus-projecting ganglion cells in migratory birds using neuroanatomical and electrophysiological techniques.

From function to cognition: New spectroscopic tools for studying brain neurochemistry in-vivo

In this seminar, I will present new methods in magnetic resonance spectroscopy (MRS) we’ve been working on in the lab. The talk will be divided into two parts. In the first, I will talk about neurochemical changes we observe in glutamate and GABA during various paradigms, including simple motors tasks and reinforcement learning. In the second part, I’ll present a new approach to MRS that focuses on measuring the relaxation times (T1, T2) of metabolites, which reflect changes to specific cellular microenvironments. I will explain why these can be exciting markers for studying several in-vivo pathologies, and also present some preliminary data from a cohort of mild cognitive impairment (MCI) patients, showing changes that correlate to cognitive decline.

Gut Feelings: The Microbiota-Gut-Brain Axis Across the Lifespan

The microbiota-gut-brain axis is emerging as a research area of increasing interest for those investigating the biological and physiological basis of brain development and behaviour during early life, adolescence & ageing. The routes of communication between the gut and brain include the vagus nerve, the immune system, tryptophan metabolism, via the enteric nervous system or by way of microbial metabolites such as short chain fatty acids. Studies in animal models have shown that the development of an appropriate stress response is dependent on the microbiota. Developmentally, a variety of factors can impact the microbiota in early life including mode of birth delivery, antibiotic exposure, mode of nutritional provision, infection, stress as well as host genetics. Recently, the gut microbiota has been implicated in regulating the stress response, and social behaviour. Moreover, fundamental brain processes from adult hippocampal neurogenesis to myelination to microglia activation have been shown to be regulated by the microbiome. Further studies will focus on understanding the mechanisms underlying such brain effects and how they can be exploited by microbiota-targeted interventions including ‘psychobiotics’ and diet

New Strategies and Approaches to Tackle and Understand Neurological Disorder

Broadly, the Mauro Costa-Mattioli laboratory (The MCM Lab) encompasses two complementary lines of research. The first one, more traditional but very important, aims at unraveling the molecular mechanisms underlying memory formation (e.g., using state-of-the-art molecular and cell-specific genetic approaches). Learning and memory disorders can strike the brain during development (e.g., Autism Spectrum Disorders and Down Syndrome), as well as during adulthood (e.g., Alzheimer’s disease). We are interested in understanding the specific circuits and molecular pathways that are primarily targeted in these disorders and how they can be restored. To tackle these questions, we use a multidisciplinary, convergent and cross-species approach that combines mouse and fly genetics, molecular biology, electrophysiology, stem cell biology, optogenetics and behavioral techniques. The second line of research, more recent and relatively unexplored, is focused on understanding how gut microbes control CNS driven-behavior and brain function. Our recent discoveries, that microbes in the gut could modulate brain function and behavior in a very powerful way, have added a whole new dimension to the classic view of how complex behaviors are controlled. The unexpected findings have opened new avenues of study for us and are currently driving my lab to answer a host of new and very interesting questions: - What are the gut microbes (and metabolites) that regulate CNS-driven behaviors? Would it be possible to develop an unbiased screening method to identify specific microbes that regulate different behaviors? - If this is the case, can we identify how members of the gut microbiome (and their metabolites) mechanistically influence brain function? - What is the communication channel between the gut microbiota and the brain? Do different gut microbes use different ways to interact with the brain? - Could disruption of the gut microbial ecology cause neurodevelopmental dysfunction? If so, what is the impact of disruption in young and adult animals? - More importantly, could specific restoration of selected bacterial strains (new generation probiotics) represent a novel therapeutic approach for the targeted treatment of neurodevelopmental disorders? - Finally, can we develop microbiota-directed therapeutic foods to repair brain dysfunction in a variety of neurological disorders?

Interactions between the microbiome and nervous system during early development

The gut microbiota is emerging as an important modulator of brain function and behavior, as several recent discoveries reveal substantial effects of the microbiome on neurophysiology, neuroimmunity and animal behavior. Despite these findings supporting a “microbiome-gut-brain axis”, the molecular and cellular mechanisms that underlie interactions between the gut microbiota and brain remain poorly understood. To uncover these, the Hsiao laboratory is mining the human microbiota for microbial modulators of host neuroactive molecules, investigating the impact of microbiota-immune system interactions on neurodevelopment and examining the microbiome as an interface between gene-environment interactions in neurological diseases. In particular, our research on effects of the maternal microbiome on offspring development in utero are revealing novel interactions between microbiome-dependent metabolites and fetal thalamocortical axonogenesis. Overall, we aim to dissect biological pathways for communication between the gut microbiota and nervous system, toward understanding fundamental interactions between physiological systems that impact brain and behavior.

Modulation of C. elegans behavior by gut microbes

We are interested in understanding how microbes impact the behavior of host animals. Animal nervous systems likely evolved in environments richly surrounded by microbes, yet the impact of bacteria on nervous system function has been relatively under-studied. A challenge has been to identify systems in which both host and microbe are amenable to genetic manipulation, and which enable high-throughput behavioral screening in response to defined and naturalistic conditions. To accomplish these goals, we use an animal host — the roundworm C. elegans, which feeds on bacteria — in combination with its natural gut microbiome to identify inter-organismal signals driving host-microbe interactions and decision-making. C. elegans has some of the most extensive molecular, neurobiological and genetic tools of any multicellular eukaryote, and, coupled with the ease of gnotobiotic culture in these worms, represents a highly attractive system in which to study microbial influence on host behavior. Using this system, we discovered that commensal bacterial metabolites directly modulate nervous system function of their host. Beneficial gut microbes of the genus Providencia produce the neuromodulator tyramine in the C. elegans intestine. Using a combination of behavioral analysis, neurogenetics, metabolomics and bacterial genetics we established that bacterially produced tyramine is converted to octopamine in C. elegans, which acts directly in sensory neurons to reduce odor aversion and increase sensory preference for Providencia. We think that this type of sensory modulation may increase association of C. elegans with these microbes, increasing availability of this nutrient-rich food source for the worm and its progeny, while facilitating dispersal of the bacteria.

Association of metabolites with cognitive decline and lipid pattern in Alzheimer's Disease

Gut-derived metabolites as modulators of brain inflammation

Acute stress, microbial metabolites and the microbiota-gut-brain axis: Focus on microbial regulation of barrier function and hippocampal plasticity

FENS Forum 2024

Alterations of specific metabolites during epileptogenesis in plasma of rats with lithium-pilocarpine-induced temporal lobe epilepsy

FENS Forum 2024

Gut microbiome metabolites and Alzheimer’s disease

FENS Forum 2024