Maayan Levy

All Publications

• Effect of obesity on the acute response to SARS-CoV-2 infection and development of post-acute sequelae of COVID-19 (PASC) in nonhuman primates. PLoS pathogens Sauter, K. A., Webb, G. M., Bader, L., Kreklywich, C. N., Takahashi, D. L., Zaro, C., McGuire, C. M., Lewis, A. D., Colgin, L. M., Kirigiti, M. A., Blomenkamp, H., Pessoa, C., Humkey, M., Hulahan, J., Sleeman, M., Zweig, R. C., Thomas, S., Thomas, A., Gao, L., Hirsch, A. J., Levy, M., Cherry, S., Kahn, S. E., Slifka, M. K., Streblow, D. N., Sacha, J. B., Kievit, P., Roberts, C. T. 2025; 21 (7): e1012988

  Abstract

  Long-term adverse consequences of SARS-CoV-2 infection, termed "long COVID" or post-acute sequelae of COVID (PASC), are a major component of overall COVID-19 disease burden. Prior obesity and metabolic disease increase the severity of acute disease, but SARS-CoV-2 infection also contributes to the development of new-onset metabolic disease. Since the COVID pandemic occurred in the context of the global obesity epidemic, an important question is the extent to which pre-existing obesity modifies long-term responses to SARS-CoV-2 infection. We utilized a nonhuman primate model to compare the effects of infection with the SARS-CoV-2 delta variant in lean and obese/insulin-resistant adult male rhesus macaques over a 6-month time course. While some longitudinal responses to SARS-CoV-2 infection, including overall viral dynamics, SARS-CoV-2-specific IgG induction, cytokine profiles, and tissue persistence of viral RNA, did not appreciably differ between lean and obese animals, other responses, including neutralizing Ab dynamics, lung pathology, body weight, degree of insulin sensitivity, adipocytokine profiles, body temperature, and nighttime activity levels were significantly different in lean versus obese animals. Furthermore, several parameters in lean animals were altered following SARS-CoV-2 infection to resemble those in obese animals. Notably, persistent changes in multiple parameters were present in most animals, suggesting that PASC may be more prevalent than estimated from self-reported symptoms in human studies.

  View details for DOI 10.1371/journal.ppat.1012988

  View details for PubMedID 40705709

• Gut metagenomes reveal interactions between dietary restriction, ageing and the microbiome in genetically diverse mice. Nature microbiology Litichevskiy, L., Considine, M., Gill, J., Shandar, V., Cox, T. O., Descamps, H. C., Wright, K. M., Amses, K. R., Dohnalová, L., Liou, M. J., Tetlak, M., Galindo-Fiallos, M. R., Wong, A. C., Lundgren, P., Kim, J., Uhr, G. T., Rahman, R. J., Mason, S., Merenstein, C., Bushman, F. D., Raj, A., Harding, F., Chen, Z., Prateek, G. V., Mullis, M., Deighan, A. G., Robinson, L., Tanes, C., Bittinger, K., Chakraborty, M., Bhatt, A. S., Li, H., Barnett, I., Davenport, E. R., Broman, K. W., Levy, M., Cohen, R. L., Botstein, D., Freund, A., Di Francesco, A., Churchill, G. A., Li, M., Thaiss, C. A. 2025

  Abstract

  The gut microbiome changes with age and has been proposed to mediate the benefit of lifespan-extending interventions such as dietary restriction. However, the causes and consequences of microbiome ageing and the potential of such interventions remain unclear. Here we analysed 2,997 metagenomes collected longitudinally from 913 deeply phenotyped, genetically diverse mice to investigate interactions between the microbiome, ageing, dietary restriction (caloric restriction and fasting), host genetics and a range of health parameters. Among the numerous age-associated microbiome changes that we find in this cohort, increased microbiome uniqueness is the most consistent parameter across a second longitudinal mouse experiment that we performed on inbred mice and a compendium of 4,101 human metagenomes. Furthermore, cohousing experiments show that age-associated microbiome changes may be caused by an accumulation of stochastic environmental exposures (neutral theory) rather than by the influence of an ageing host (selection theory). Unexpectedly, the majority of taxonomic and functional microbiome features show small but significant heritability, and the amount of variation explained by host genetics is similar to ageing and dietary restriction. We also find that more intense dietary interventions lead to larger microbiome changes and that dietary restriction does not rejuvenate the microbiome. Lastly, we find that the microbiome is associated with multiple health parameters, including body composition, immune components and frailty, but not lifespan. Overall, this study sheds light on the factors influencing microbiome ageing and aspects of host physiology modulated by the microbiome.

  View details for DOI 10.1038/s41564-025-01963-3

  View details for PubMedID 40164832

  View details for PubMedCentralID 4547605

• Ketogenic Diet Enhances CAR T Cell Antitumor Function Via β-Hydroxybutyrate Liu, S., Guruprasad, P., Han, K., Paruzzo, L., Shestov, A., Kelly, A., Amses, K. R., Afriat, A., Madhu, B., Litichevskiy, L., Dubowitz, E., Tangal, N., Mcsween, A., Tan, M., Carturan, A., Lee, A., Zhang, Y., Gabrielli, G., Pajarillo, R., Patel, R. P., Ghilardi, G., Porazzi, P., Schuster, S. J., O'Connor, R. S., Milone, M. C., Rabinowitz, J., Levy, M., Ruella, M. ELSEVIER. 2024: 4-5

  View details for DOI 10.1182/blood-2024-208913

  View details for Web of Science ID 001412528300004

• Microbial colonization programs are structured by breastfeeding and guide healthy respiratory development. Cell Shenhav, L., Fehr, K., Reyna, M. E., Petersen, C., Dai, D. L., Dai, R., Breton, V., Rossi, L., Smieja, M., Simons, E., Silverman, M. A., Levy, M., Bode, L., Field, C. J., Marshall, J. S., Moraes, T. J., Mandhane, P. J., Turvey, S. E., Subbarao, P., Surette, M. G., Azad, M. B. 2024; 187 (19): 5431-5452.e20

  Abstract

  Breastfeeding and microbial colonization during infancy occur within a critical time window for development, and both are thought to influence the risk of respiratory illness. However, the mechanisms underlying the protective effects of breastfeeding and the regulation of microbial colonization are poorly understood. Here, we profiled the nasal and gut microbiomes, breastfeeding characteristics, and maternal milk composition of 2,227 children from the CHILD Cohort Study. We identified robust colonization patterns that, together with milk components, predict preschool asthma and mediate the protective effects of breastfeeding. We found that early cessation of breastfeeding (before 3 months) leads to the premature acquisition of microbial species and functions, including Ruminococcus gnavus and tryptophan biosynthesis, which were previously linked to immune modulation and asthma. Conversely, longer exclusive breastfeeding supports a paced microbial development, protecting against asthma. These findings underscore the importance of extended breastfeeding for respiratory health and highlight potential microbial targets for intervention.

  View details for DOI 10.1016/j.cell.2024.07.022

  View details for PubMedID 39303691

  View details for PubMedCentralID PMC11531244

• From intestinal metabolites to the brain: Investigating the mysteries of Long COVID CLINICAL AND TRANSLATIONAL MEDICINE Liu, S., Devason, A. S., Levy, M. 2024; 14 (3): e1608

  View details for DOI 10.1002/ctm2.1608

  View details for Web of Science ID 001182323400001

  View details for PubMedID 38468492

  View details for PubMedCentralID PMC10928348

• Serotonin reduction in post-acute sequelae of viral infection. Cell Wong, A. C., Devason, A. S., Umana, I. C., Cox, T. O., Dohnalová, L., Litichevskiy, L., Perla, J., Lundgren, P., Etwebi, Z., Izzo, L. T., Kim, J., Tetlak, M., Descamps, H. C., Park, S. L., Wisser, S., McKnight, A. D., Pardy, R. D., Kim, J., Blank, N., Patel, S., Thum, K., Mason, S., Beltra, J. C., Michieletto, M. F., Ngiow, S. F., Miller, B. M., Liou, M. J., Madhu, B., Dmitrieva-Posocco, O., Huber, A. S., Hewins, P., Petucci, C., Chu, C. P., Baraniecki-Zwil, G., Giron, L. B., Baxter, A. E., Greenplate, A. R., Kearns, C., Montone, K., Litzky, L. A., Feldman, M., Henao-Mejia, J., Striepen, B., Ramage, H., Jurado, K. A., Wellen, K. E., O'Doherty, U., Abdel-Mohsen, M., Landay, A. L., Keshavarzian, A., Henrich, T. J., Deeks, S. G., Peluso, M. J., Meyer, N. J., Wherry, E. J., Abramoff, B. A., Cherry, S., Thaiss, C. A., Levy, M. 2023; 186 (22): 4851-4867.e20

  Abstract

  Post-acute sequelae of COVID-19 (PASC, "Long COVID") pose a significant global health challenge. The pathophysiology is unknown, and no effective treatments have been found to date. Several hypotheses have been formulated to explain the etiology of PASC, including viral persistence, chronic inflammation, hypercoagulability, and autonomic dysfunction. Here, we propose a mechanism that links all four hypotheses in a single pathway and provides actionable insights for therapeutic interventions. We find that PASC are associated with serotonin reduction. Viral infection and type I interferon-driven inflammation reduce serotonin through three mechanisms: diminished intestinal absorption of the serotonin precursor tryptophan; platelet hyperactivation and thrombocytopenia, which impacts serotonin storage; and enhanced MAO-mediated serotonin turnover. Peripheral serotonin reduction, in turn, impedes the activity of the vagus nerve and thereby impairs hippocampal responses and memory. These findings provide a possible explanation for neurocognitive symptoms associated with viral persistence in Long COVID, which may extend to other post-viral syndromes.

  View details for DOI 10.1016/j.cell.2023.09.013

  View details for PubMedID 37848036

  View details for PubMedCentralID PMC11227373

• Single-cell analysis and spatial resolution of the gut microbiome FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY Madhu, B., Miller, B. M., Levy, M. 2023; 13: 1271092

  Abstract

  Over the past decade it has become clear that various aspects of host physiology, metabolism, and immunity are intimately associated with the microbiome and its interactions with the host. Specifically, the gut microbiome composition and function has been shown to play a critical role in the etiology of different intestinal and extra-intestinal diseases. While attempts to identify a common pattern of microbial dysbiosis linked with these diseases have failed, multiple studies show that bacterial communities in the gut are spatially organized and that disrupted spatial organization of the gut microbiome is often a common underlying feature of disease pathogenesis. As a result, focus over the last few years has shifted from analyzing the diversity of gut microbiome by sequencing of the entire microbial community, towards understanding the gut microbiome in spatial context. Defining the composition and spatial heterogeneity of the microbiome is critical to facilitate further understanding of the gut microbiome ecology. Development in single cell genomics approach has advanced our understanding of microbial community structure, however, limitations in approaches exist. Single cell genomics is a very powerful and rapidly growing field, primarily used to identify the genetic composition of microbes. A major challenge is to isolate single cells for genomic analyses. This review summarizes the different approaches to study microbial genomes at single-cell resolution. We will review new techniques for microbial single cell sequencing and summarize how these techniques can be applied broadly to answer many questions related to the microbiome composition and spatial heterogeneity. These methods can be used to fill the gaps in our understanding of microbial communities.

  View details for DOI 10.3389/fcimb.2023.1271092

  View details for Web of Science ID 001085416000001

  View details for PubMedID 37860069

  View details for PubMedCentralID PMC10582963

• A subpopulation of lipogenic brown adipocytes drives thermogenic memory NATURE METABOLISM Lundgren, P., Sharma, P. V., Dohnalova, L., Coleman, K., Uhr, G. T., Kircher, S., Litichevskiy, L., Bahnsen, K., Descamps, H. C., Demetriadou, C., Chan, J., Chellappa, K., Cox, T. O., Heyman, Y., Pather, S. R., Shoffler, C., Petucci, C., Shalem, O., Raj, A., Baur, J. A., Snyder, N. W., Wellen, K. E., Levy, M., Seale, P., Li, M., Thaiss, C. A. 2023; 5 (10): 1691-+

  Abstract

  Sustained responses to transient environmental stimuli are important for survival. The mechanisms underlying long-term adaptations to temporary shifts in abiotic factors remain incompletely understood. Here, we find that transient cold exposure leads to sustained transcriptional and metabolic adaptations in brown adipose tissue, which improve thermogenic responses to secondary cold encounter. Primary thermogenic challenge triggers the delayed induction of a lipid biosynthesis programme even after cessation of the original stimulus, which protects from subsequent exposures. Single-nucleus RNA sequencing and spatial transcriptomics reveal that this response is driven by a lipogenic subpopulation of brown adipocytes localized along the perimeter of Ucp1hi adipocytes. This lipogenic programme is associated with the production of acylcarnitines, and supplementation of acylcarnitines is sufficient to recapitulate improved secondary cold responses. Overall, our data highlight the importance of heterogenous brown adipocyte populations for 'thermogenic memory', which may have therapeutic implications for leveraging short-term thermogenesis to counteract obesity.

  View details for DOI 10.1038/s42255-023-00893-w

  View details for Web of Science ID 001073676200002

  View details for PubMedID 37783943

  View details for PubMedCentralID PMC11309804

• The enteric nervous system relays psychological stress to intestinal inflammation. Cell Schneider, K. M., Blank, N., Alvarez, Y., Thum, K., Lundgren, P., Litichevskiy, L., Sleeman, M., Bahnsen, K., Kim, J., Kardo, S., Patel, S., Dohnalová, L., Uhr, G. T., Descamps, H. C., Kircher, S., McSween, A. M., Ardabili, A. R., Nemec, K. M., Jimenez, M. T., Glotfelty, L. G., Eisenberg, J. D., Furth, E. E., Henao-Mejia, J., Bennett, F. C., Pierik, M. J., Romberg-Camps, M., Mujagic, Z., Prinz, M., Schneider, C. V., Wherry, E. J., Bewtra, M., Heuckeroth, R. O., Levy, M., Thaiss, C. A. 2023; 186 (13): 2823-2838.e20

  Abstract

  Mental health profoundly impacts inflammatory responses in the body. This is particularly apparent in inflammatory bowel disease (IBD), in which psychological stress is associated with exacerbated disease flares. Here, we discover a critical role for the enteric nervous system (ENS) in mediating the aggravating effect of chronic stress on intestinal inflammation. We find that chronically elevated levels of glucocorticoids drive the generation of an inflammatory subset of enteric glia that promotes monocyte- and TNF-mediated inflammation via CSF1. Additionally, glucocorticoids cause transcriptional immaturity in enteric neurons, acetylcholine deficiency, and dysmotility via TGF-β2. We verify the connection between the psychological state, intestinal inflammation, and dysmotility in three cohorts of IBD patients. Together, these findings offer a mechanistic explanation for the impact of the brain on peripheral inflammation, define the ENS as a relay between psychological stress and gut inflammation, and suggest that stress management could serve as a valuable component of IBD care.

  View details for DOI 10.1016/j.cell.2023.05.001

  View details for PubMedID 37236193

  View details for PubMedCentralID PMC10330875

• Hierarchical contribution of individual lifestyle factors and their interactions on adenomatous and serrated polyp risk JOURNAL OF GASTROENTEROLOGY Kim, J., Nath, K., Schmidlin, K., Schaufelberger, H., Quattropani, C., Vannini, S., Mossi, S., Thumshirn, M., Manz, M., Litichevskiy, L., Fan, J., Dmitrieva-Posocco, O., Li, M., Levy, M., Schar, P., Zwahlen, M., Thaiss, C. A., Truninger, K. 2023; 58 (9): 856-867

  Abstract

  Individual colorectal polyp risk factors are well characterized; however, insights into their pathway-specific interactions are scarce. We aimed to identify the impact of individual risk factors and their joint effects on adenomatous (AP) and serrated polyp (SP) risk.We collected information on 363 lifestyle and metabolic parameters from 1597 colonoscopy participants, resulting in over 521,000 data points. We used multivariate statistics and machine-learning approaches to assess associations of single variables and their interactions with AP and SP risk.Individual factors and their interactions showed common and polyp subtype-specific effects. Abdominal obesity, high body mass index (BMI), metabolic syndrome, and red meat consumption globally increased polyp risk. Age, gender, and western diet associated with AP risk, while smoking was associated with SP risk. CRC family history was associated with advanced adenomas and diabetes with sessile serrated lesions. Regarding lifestyle factor interactions, no lifestyle or dietary adjustments mitigated the adverse smoking effect on SP risk, whereas its negative effect was exacerbated by alcohol in the conventional pathway. The adverse effect of red meat on SP risk was not ameliorated by any factor, but was further exacerbated by western diet along the conventional pathway. No modification of any factor reduced the negative impact of metabolic syndrome on AP risk, whereas increased fatless fish or meat substitutes' intake mitigated its effect on SP risk.Individual risk factors and their interactions for polyp formation along the adenomatous and serrated pathways are strongly heterogeneous. Our findings may facilitate tailored lifestyle recommendations and contribute to a better understanding of how risk factor combinations impact colorectal carcinogenesis.

  View details for DOI 10.1007/s00535-023-02004-8

  View details for Web of Science ID 001004091600001

  View details for PubMedID 37300599

  View details for PubMedCentralID PMC10423128

• Preterm birth is associated with xenobiotics and predicted by the vaginal metabolome NATURE MICROBIOLOGY Kindschuh, W. F. F., Baldini, F., Liu, M. C. C., Liao, J., Meydan, Y., Lee, H. H. H., Heinken, A., Thiele, I., Thaiss, C. A. A., Levy, M., Korem, T. 2023; 8 (2): 246-+

  Abstract

  Spontaneous preterm birth (sPTB) is a leading cause of maternal and neonatal morbidity and mortality, yet its prevention and early risk stratification are limited. Previous investigations have suggested that vaginal microbes and metabolites may be implicated in sPTB. Here we performed untargeted metabolomics on 232 second-trimester vaginal samples, 80 from pregnancies ending preterm. We find multiple associations between vaginal metabolites and subsequent preterm birth, and propose that several of these metabolites, including diethanolamine and ethyl glucoside, are exogenous. We observe associations between the metabolome and microbiome profiles previously obtained using 16S ribosomal RNA amplicon sequencing, including correlations between bacteria considered suboptimal, such as Gardnerella vaginalis, and metabolites enriched in term pregnancies, such as tyramine. We investigate these associations using metabolic models. We use machine learning models to predict sPTB risk from metabolite levels, weeks to months before birth, with good accuracy (area under receiver operating characteristic curve of 0.78). These models, which we validate using two external cohorts, are more accurate than microbiome-based and maternal covariates-based models (area under receiver operating characteristic curve of 0.55-0.59). Our results demonstrate the potential of vaginal metabolites as early biomarkers of sPTB and highlight exogenous exposures as potential risk factors for prematurity.

  View details for DOI 10.1038/s41564-022-01293-8

  View details for Web of Science ID 000913115100006

  View details for PubMedID 36635575

  View details for PubMedCentralID PMC9894755

• A microbiome-dependent gut-brain pathway regulates motivation for exercise. Nature Dohnalová, L., Lundgren, P., Carty, J. R., Goldstein, N., Wenski, S. L., Nanudorn, P., Thiengmag, S., Huang, K. P., Litichevskiy, L., Descamps, H. C., Chellappa, K., Glassman, A., Kessler, S., Kim, J., Cox, T. O., Dmitrieva-Posocco, O., Wong, A. C., Allman, E. L., Ghosh, S., Sharma, N., Sengupta, K., Cornes, B., Dean, N., Churchill, G. A., Khurana, T. S., Sellmyer, M. A., FitzGerald, G. A., Patterson, A. D., Baur, J. A., Alhadeff, A. L., Helfrich, E. J., Levy, M., Betley, J. N., Thaiss, C. A. 2022; 612 (7941): 739-747

  Abstract

  Exercise exerts a wide range of beneficial effects for healthy physiology1. However, the mechanisms regulating an individual's motivation to engage in physical activity remain incompletely understood. An important factor stimulating the engagement in both competitive and recreational exercise is the motivating pleasure derived from prolonged physical activity, which is triggered by exercise-induced neurochemical changes in the brain. Here, we report on the discovery of a gut-brain connection in mice that enhances exercise performance by augmenting dopamine signalling during physical activity. We find that microbiome-dependent production of endocannabinoid metabolites in the gut stimulates the activity of TRPV1-expressing sensory neurons and thereby elevates dopamine levels in the ventral striatum during exercise. Stimulation of this pathway improves running performance, whereas microbiome depletion, peripheral endocannabinoid receptor inhibition, ablation of spinal afferent neurons or dopamine blockade abrogate exercise capacity. These findings indicate that the rewarding properties of exercise are influenced by gut-derived interoceptive circuits and provide a microbiome-dependent explanation for interindividual variability in exercise performance. Our study also suggests that interoceptomimetic molecules that stimulate the transmission of gut-derived signals to the brain may enhance the motivation for exercise.

  View details for DOI 10.1038/s41586-022-05525-z

  View details for PubMedID 36517598

  View details for PubMedCentralID PMC11162758

• Ketogenic Diet and Beta-Hydroxybutyrate in Colorectal Cancer DNA AND CELL BIOLOGY Khoziainova, S., Rozenberg, G., Levy, M. 2022; 41 (12): 1007-1011

  Abstract

  Colorectal cancer (CRC) is one of the leading causes of cancer-related death in the United States. Although certain genetic predispositions may contribute to one's risk for developing CRC, dietary and lifestyle factors may play an important role as well. In a recent study in Nature, Dmitrieva-Posocco et al, reveal a potential protective role of the ketogenic diet in colorectal cancer growth and progression. Administration of a ketogenic diet to CRC-bearing mice demonstrated a tumor-suppressive effect. Specifically, the ketone body β-hydroxybutyrate (BHB) exhibited the ability to suppress epithelial cell proliferation and inhibit tumor growth. BHB acts on cancer cells through regulation of homeodomain-only protein Hopx, known regulator of CRC. Furthermore, BHB requires a surface receptor Hcar to induce Hopx expression and suppress proliferation of intestinal epithelial cells. Taken together, these results describe a new therapeutic approach of using dietary intervention for the prevention and treatment of colorectal cancer.

  View details for DOI 10.1089/dna.2022.0486

  View details for Web of Science ID 000892699300001

  View details for PubMedID 36454261

  View details for PubMedCentralID PMC10162116

• Editorial: Women in microbiome in health and disease 2021 FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY Pereira, M., Levy, M., Nissapatorn, V., de Oliveira, G. 2022; 12: 1054190

  View details for DOI 10.3389/fcimb.2022.1054190

  View details for Web of Science ID 000876505500001

  View details for PubMedID 36304933

  View details for PubMedCentralID PMC9593082

• Second trimester short cervix is associated with decreased abundance of cervicovaginal lipid metabolites AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY Gerson, K. D., Yang, N., Anton, L., Levy, M., Ravel, J., Elovitz, M. A., Burris, H. H. 2022; 227 (2): 273.e1-273.e18

  Abstract

  A short cervix is a risk factor for preterm birth. The molecular drivers of a short cervix remain elusive. Metabolites may function as mediators of pathologic processes.We sought to determine if a distinct cervicovaginal metabolomic profile is associated with a short cervix (<25 mm) to unveil the potential mechanisms by which premature cervical remodeling leads to a short cervix.This was a secondary analysis of a completed prospective pregnancy cohort. Cervicovaginal fluid was obtained between 20 and 24 weeks' gestation. The participants selected for metabolomic profiling were frequency-matched by birth outcome and cervicovaginal microbiota profile. This analysis included 222 participants with cervical length measured. A short cervix was defined as one having length <25 mm, as measured by transvaginal ultrasound. Unpaired t-tests were performed with a Bonferroni correction for multiple comparisons.There were 27 participants with a short cervix, and 195 with normal cervical length. Of the 637 metabolites detected, 26 differed between those with a short cervix and those with normal cervical lengths; 22 were decreased, of which 21 belonged to the lipid metabolism pathway (all P<.000079). Diethanolamine, erythritol, progesterone, and mannitol or sorbitol were increased in the cases of short cervix. Among participants with Lactobacillus-deficient microbiota, only diethanolamine and mannitol or sorbitol differed between short cervix (n=17) and normal cervical length (n=75), both increased.A short cervix is associated with decreased cervicovaginal lipid metabolites, particularly sphingolipids. This class of lipids stabilizes cell membranes and protects against environmental exposures. Increased diethanolamine-an immunostimulatory xenobiotic-is associated with a short cervix. These observations begin to identify the potential mechanisms by which modifiable environmental factors may invoke cell damage in the setting of biological vulnerability, thus promoting premature cervical remodeling in spontaneous preterm birth.

  View details for DOI 10.1016/j.ajog.2022.04.031

  View details for Web of Science ID 000836681800030

  View details for PubMedID 35469813

  View details for PubMedCentralID PMC9382664

• β-Hydroxybutyrate suppresses colorectal cancer. Nature Dmitrieva-Posocco, O., Wong, A. C., Lundgren, P., Golos, A. M., Descamps, H. C., Dohnalová, L., Cramer, Z., Tian, Y., Yueh, B., Eskiocak, O., Egervari, G., Lan, Y., Liu, J., Fan, J., Kim, J., Madhu, B., Schneider, K. M., Khoziainova, S., Andreeva, N., Wang, Q., Li, N., Furth, E. E., Bailis, W., Kelsen, J. R., Hamilton, K. E., Kaestner, K. H., Berger, S. L., Epstein, J. A., Jain, R., Li, M., Beyaz, S., Lengner, C. J., Katona, B. W., Grivennikov, S. I., Thaiss, C. A., Levy, M. 2022; 605 (7908): 160-165

  Abstract

  Colorectal cancer (CRC) is among the most frequent forms of cancer, and new strategies for its prevention and therapy are urgently needed1. Here we identify a metabolite signalling pathway that provides actionable insights towards this goal. We perform a dietary screen in autochthonous animal models of CRC and find that ketogenic diets exhibit a strong tumour-inhibitory effect. These properties of ketogenic diets are recapitulated by the ketone body β-hydroxybutyrate (BHB), which reduces the proliferation of colonic crypt cells and potently suppresses intestinal tumour growth. We find that BHB acts through the surface receptor Hcar2 and induces the transcriptional regulator Hopx, thereby altering gene expression and inhibiting cell proliferation. Cancer organoid assays and single-cell RNA sequencing of biopsies from patients with CRC provide evidence that elevated BHB levels and active HOPX are associated with reduced intestinal epithelial proliferation in humans. This study thus identifies a BHB-triggered pathway regulating intestinal tumorigenesis and indicates that oral or systemic interventions with a single metabolite may complement current prevention and treatment strategies for CRC.

  View details for DOI 10.1038/s41586-022-04649-6

  View details for PubMedID 35477756

  View details for PubMedCentralID PMC9448510

• A non-optimal cervicovaginal microbiota in pregnancy is associated with a distinct metabolomic signature among non-Hispanic Black individuals SCIENTIFIC REPORTS Gerson, K. D., Liao, J., McCarthy, C., Burris, H. H., Korem, T., Levy, M., Ravel, J., Elovitz, M. A. 2021; 11 (1): 22794

  Abstract

  Biomechanical and molecular processes of premature cervical remodeling preceding spontaneous preterm birth (sPTB) likely result from interactions between the cervicovaginal microbiota and host immune responses. A non-optimal cervicovaginal microbiota confers increased risk of sPTB. The cervicovaginal space is metabolically active in pregancy; microbiota can produce, modify, and degrade metabolites within this ecosystem. We establish that cervicovaginal metabolomic output clusters by microbial community in pregnancy among Black individuals, revealing increased metabolism within the amino acid and dipeptide pathways as hallmarks of a non-optimal microbiota. Few differences were detected in metabolomic profiles when stratified by birth outcome. The study raises the possibility that metabolites could distinguish women with greater risk of sPTB among those with similar cervicovaginal microbiota, and that metabolites within the amino acid and carbohydrate pathways may play a role in this distinction.

  View details for DOI 10.1038/s41598-021-02304-0

  View details for Web of Science ID 000722007100020

  View details for PubMedID 34815499

  View details for PubMedCentralID PMC8611022

• Microbial memories IMMUNITY Wong, A. C., Levy, M. 2021; 54 (2): 201-204

  Abstract

  The microbiota impedes pathogen invasion of the intestinal ecosystem, a phenomenon termed colonization resistance. In an upcoming issue of Cell, Stacy et al. describe host-initiated metabolite pathways that functionally alter the microbiota after primary infection, thereby augmenting colonization resistance to subsequent infection.

  View details for DOI 10.1016/j.immuni.2021.01.009

  View details for Web of Science ID 000627407700005

  View details for PubMedID 33567260

• High-Throughput Screen Identifies Host and Microbiota Regulators of Intestinal Barrier Function GASTROENTEROLOGY Grosheva, I., Zheng, D., Levy, M., Polansky, O., Lichtenstein, A., Golani, O., Dori-Bachash, M., Moresi, C., Shapiro, H., Del Mare-Roumani, S., Valdes-Mas, R., He, Y., Karbi, H., Chen, M., Harmelin, A., Straussman, R., Yissachar, N., Elinav, E., Geiger, B. 2020; 159 (5): 1807-1823

  Abstract

  The intestinal barrier protects intestinal cells from microbes and antigens in the lumen-breaches can alter the composition of the intestinal microbiota, the enteric immune system, and metabolism. We performed a screen to identify molecules that disrupt and support the intestinal epithelial barrier and tested their effects in mice.We performed an imaging-based, quantitative, high-throughput screen (using CaCo-2 and T84 cells incubated with lipopolysaccharide; tumor necrosis factor; histamine; receptor antagonists; and libraries of secreted proteins, microbial metabolites, and drugs) to identify molecules that altered epithelial tight junction (TJ) and focal adhesion morphology. We then tested the effects of TJ stabilizers on these changes. Molecules we found to disrupt or stabilize TJs were administered mice with dextran sodium sulfate-induced colitis or Citrobacter rodentium-induced intestinal inflammation. Colon tissues were collected and analyzed by histology, fluorescence microscopy, and RNA sequencing.The screen identified numerous compounds that disrupted or stabilized (after disruption) TJs and monolayers of epithelial cells. We associated distinct morphologic alterations with changes in barrier function, and identified a variety of cytokines, metabolites, and drugs (including inhibitors of actomyosin contractility) that prevent disruption of TJs and restore TJ integrity. One of these disruptors (putrescine) disrupted TJ integrity in ex vivo mouse colon tissues; administration to mice exacerbated colon inflammation, increased gut permeability, reduced colon transepithelial electrical resistance, increased pattern recognition receptor ligands in mesenteric lymph nodes, and decreased colon length and survival times. Putrescine also increased intestine levels and fecal shedding of viable C rodentium, increased bacterial attachment to the colonic epithelium, and increased levels of inflammatory cytokines in colon tissues. Colonic epithelial cells from mice given putrescine increased expression of genes that regulate metal binding, oxidative stress, and cytoskeletal organization and contractility. Co-administration of taurine with putrescine blocked disruption of TJs and the exacerbated inflammation.We identified molecules that disrupt and stabilize intestinal epithelial TJs and barrier function and affect development of colon inflammation in mice. These agents might be developed for treatment of barrier intestinal impairment-associated and inflammatory disorders in patients, or avoided to prevent inflammation.

  View details for DOI 10.1053/j.gastro.2020.07.003

  View details for Web of Science ID 000591420700022

  View details for PubMedID 32653496

• Weak Microbial Metabolites: a Treasure Trove for Using Biomimicry to Discover and Optimize Drugs MOLECULAR PHARMACOLOGY Dvorak, Z., Klapholz, M., Burris, T. P., Willing, B. P., Gioiello, A., Pellicciari, R., Galli, F., March, J., O'Keefe, S. J., Sartor, R., Kim, C. H., Levy, M., Mani, S. 2020; 98 (4): 343-349

  Abstract

  For decades, traditional drug discovery has used natural product and synthetic chemistry approaches to generate libraries of compounds, with some ending as promising drug candidates. A complementary approach has been to adopt the concept of biomimicry of natural products and metabolites so as to improve multiple drug-like features of the parent molecule. In this effort, promiscuous and weak interactions between ligands and receptors are often ignored in a drug discovery process. In this Emerging Concepts article, we highlight microbial metabolite mimicry, whereby parent metabolites have weak interactions with their receptors that then have led to discrete examples of more potent and effective drug-like molecules. We show specific examples of parent-metabolite mimics with potent effects in vitro and in vivo. Furthermore, we show examples of emerging microbial ligand-receptor interactions and provide a context in which these ligands could be improved as potential drugs. A balanced conceptual advance is provided in which we also acknowledge potential pitfalls-hyperstimulation of finely balanced receptor-ligand interactions could also be detrimental. However, with balance, we provide examples of where this emerging concept needs to be tested. SIGNIFICANCE STATEMENT: Microbial metabolite mimicry is a novel way to expand on the chemical repertoire of future drugs. The emerging concept is now explained using specific examples of the discovery of therapeutic leads from microbial metabolites.

  View details for DOI 10.1124/molpharm.120.000035

  View details for Web of Science ID 000571821800006

  View details for PubMedID 32764096

  View details for PubMedCentralID PMC7485585

• Small molecules, big effects: microbial metabolites in intestinal immunity AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY Glotfelty, L. G., Wong, A. C., Levy, M. 2020; 318 (5): G907-G911

  Abstract

  The mammalian intestine is host to a vast number of microbial organisms. The immune system must balance tolerance with innate and adaptive defense mechanisms to maintain homeostasis with the microbial community. Interestingly, microbial metabolites have been shown to play a role in shaping the host immune response, thus assisting with adaptations that have significant implications for human health and disease. New investigations have uncovered roles for metabolites in modulating almost every aspect of the immune system. In this minireview, we survey these recent findings, which taken together reveal nuanced interactions that we are just beginning to understand.

  View details for DOI 10.1152/ajpgi.00263.2019

  View details for Web of Science ID 000535703100005

  View details for PubMedID 32249590

  View details for PubMedCentralID PMC7395478

• The bidirectional nature of microbiome-epithelial cell interactions CURRENT OPINION IN MICROBIOLOGY Solis, A. G., Klapholz, M., Zhao, J., Levy, M. 2020; 56: 45-51

  Abstract

  The biogeography of the mammalian intestine is remarkable in that a vast microbial consortium exists inside the organism, surrounded by intestinal epithelial cells. The microbiome and the intestinal epithelium have developed a complex network of interactions that maintain intestinal homeostasis. We now recognize that functions of the epithelium are compartmentalized in specific intestinal epithelial cell subtypes. Furthermore, we are beginning to understand the ways in which microbes and their metabolic products impact the specific epithelial subsets. Here, we survey the mechanisms utilized by the microbiome to regulate intestinal epithelial function, and inversely, how different epithelial cell subtypes cooperate in regulating the microbiome.

  View details for DOI 10.1016/j.mib.2020.06.007

  View details for Web of Science ID 000601212200009

  View details for PubMedID 32653776

  View details for PubMedCentralID PMC7744412

• The biogeography of colonization resistance NATURE MICROBIOLOGY Solis, A. G., Levy, M. 2020; 5 (2): 234-235

  View details for DOI 10.1038/s41564-019-0660-x

  View details for Web of Science ID 000511211600004

  View details for PubMedID 31992893

• The gut microbiota regulates white adipose tissue inflammation and obesity via a family of microRNAs SCIENCE TRANSLATIONAL MEDICINE Virtue, A. T., McCright, S. J., Wright, J. M., Jimenez, M. T., Mowel, W. K., Kotzin, J. J., Joannas, L., Basavappa, M. G., Spencer, S. P., Clark, M. L., Eisennagel, S. H., Williams, A., Levy, M., Manne, S., Henrickson, S. E., Wherry, E., Thaiss, C. A., Elinav, E., Henao-Mejia, J. 2019; 11 (496)

  Abstract

  The gut microbiota is a key environmental determinant of mammalian metabolism. Regulation of white adipose tissue (WAT) by the gut microbiota is a process critical to maintaining metabolic fitness, and gut dysbiosis can contribute to the development of obesity and insulin resistance (IR). However, how the gut microbiota regulates WAT function remains largely unknown. Here, we show that tryptophan-derived metabolites produced by the gut microbiota controlled the expression of the miR-181 family in white adipocytes in mice to regulate energy expenditure and insulin sensitivity. Moreover, dysregulation of the gut microbiota-miR-181 axis was required for the development of obesity, IR, and WAT inflammation in mice. Our results indicate that regulation of miR-181 in WAT by gut microbiota-derived metabolites is a central mechanism by which host metabolism is tuned in response to dietary and environmental changes. As we also found that MIR-181 expression in WAT and the plasma abundance of tryptophan-derived metabolites were dysregulated in a cohort of obese human children, the MIR-181 family may represent a potential therapeutic target to modulate WAT function in the context of obesity.

  View details for DOI 10.1126/scitranslmed.aav1892

  View details for Web of Science ID 000471200300004

  View details for PubMedID 31189717

  View details for PubMedCentralID PMC7050429

• New Approaches to Microbiome-Based Therapies MSYSTEMS Wong, A. C., Levy, M. 2019; 4 (3)

  Abstract

  Over the last decade, our understanding of the composition and functions of the gut microbiota has greatly increased. To a large extent, this has been due to the development of high-throughput genomic analyses of microbial communities, which have identified the critical contributions of the microbiome to human health. Consequently, the intestinal microbiota has emerged as an attractive therapeutic target. The large majority of microbiota-targeted therapies aim at engineering the intestinal ecosystem by means of probiotics or prebiotics. Recently, a novel therapeutic approach has emerged which focuses on molecules that are secreted, modulated, or degraded by the microbiome and act directly on the host. Here, we discuss the advantages and challenges associated with the metabolite-based "postbiotic" approach, highlighting recent progress and the areas that need intensive attention and investigation over the next 5 years. The time is ripe for postbiotic therapies to be developed in the near future.

  View details for DOI 10.1128/mSystems.00122-19

  View details for Web of Science ID 000482619800030

  View details for PubMedID 31164406

  View details for PubMedCentralID PMC6584878