Christoph Thaiss

All Publications

• Author Correction: Resolving tissue complexity by multimodal spatial omics modeling with MISO. Nature methods Coleman, K., Schroeder, A., Loth, M., Zhang, D., Park, J. H., Sung, J. Y., Blank, N., Cowan, A. J., Qian, X., Chen, J., Jiang, J., Yan, H., Samarah, L. Z., Clemenceau, J. R., Jang, I., Kim, M., Barnfather, I., Rabinowitz, J. D., Deng, Y., Lee, E. B., Lazar, A., Gao, J., Furth, E. E., Hwang, T. H., Wang, L., Thaiss, C. A., Hu, J., Li, M. 2025

  View details for DOI 10.1038/s41592-025-02645-y

  View details for PubMedID 40050700

• Author Correction: Resolving tissue complexity by multimodal spatial omics modeling with MISO. Nature methods Coleman, K., Schroeder, A., Loth, M., Zhang, D., Park, J. H., Sung, J. Y., Blank, N., Cowan, A. J., Qian, X., Chen, J., Jiang, J., Yan, H., Samarah, L. Z., Clemenceau, J. R., Jang, I., Kim, M., Barnfather, I., Rabinowitz, J. D., Deng, Y., Lee, E. B., Lazar, A., Gao, J., Furth, E. E., Hwang, T. H., Wang, L., Thaiss, C. A., Hu, J., Li, M. 2025; 22 (3): 635

  View details for DOI 10.1038/s41592-025-02600-x

  View details for PubMedID 39856234

• Resolving tissue complexity by multimodal spatial omics modeling with MISO. Nature methods Coleman, K., Schroeder, A., Loth, M., Zhang, D., Park, J. H., Sung, J. Y., Blank, N., Cowan, A. J., Qian, X., Chen, J., Jiang, J., Yan, H., Samarah, L. Z., Clemenceau, J. R., Jang, I., Kim, M., Barnfather, I., Rabinowitz, J. D., Deng, Y., Lee, E. B., Lazar, A., Gao, J., Furth, E. E., Hwang, T. H., Wang, L., Thaiss, C. A., Hu, J., Li, M. 2025; 22 (3): 530-538

  Abstract

  Spatial molecular profiling has provided biomedical researchers valuable opportunities to better understand the relationship between cellular localization and tissue function. Effectively modeling multimodal spatial omics data is crucial for understanding tissue complexity and underlying biology. Furthermore, improvements in spatial resolution have led to the advent of technologies that can generate spatial molecular data with subcellular resolution, requiring the development of computationally efficient methods that can handle the resulting large-scale datasets. MISO (MultI-modal Spatial Omics) is a versatile algorithm for feature extraction and clustering, capable of integrating multiple modalities from diverse spatial omics experiments with high spatial resolution. Its effectiveness is demonstrated across various datasets, encompassing gene expression, protein expression, epigenetics, metabolomics and tissue histology modalities. MISO outperforms existing methods in identifying biologically relevant spatial domains, representing a substantial advancement in multimodal spatial omics analysis. Moreover, MISO's computational efficiency ensures its scalability to handle large-scale datasets generated by subcellular resolution spatial omics technologies.

  View details for DOI 10.1038/s41592-024-02574-2

  View details for PubMedID 39815104

  View details for PubMedCentralID 4662681

• Dietary manipulation of intestinal microbes prolongs survival in a mouse model of Hirschsprung disease. bioRxiv : the preprint server for biology Tjaden, N. E., Liou, M. J., Sax, S. E., Lassoued, N., Lou, M., Schneider, S., Beigel, K., Eisenberg, J. D., Loeffler, E., Anderson, S. E., Yan, G., Litichevskiy, L., Dohnalová, L., Zhu, Y., Jin, D. M., Raab, J., Furth, E. E., Thompson, Z., Rubenstein, R. C., Pilon, N., Thaiss, C. A., Heuckeroth, R. O. 2025

  Abstract

  Enterocolitis is a common and potentially deadly manifestation of Hirschsprung disease (HSCR) but disease mechanisms remain poorly defined. Unexpectedly, we discovered that diet can dramatically affect the lifespan of a HSCR mouse model ( Piebald lethal , sl/sl ) where affected animals die from HAEC complications. In the sl/sl model, diet alters gut microbes and metabolites, leading to changes in colon epithelial gene expression and epithelial oxygen levels known to influence colitis severity. Our findings demonstrate unrecognized similarity between HAEC and other types of colitis and suggest dietary manipulation could be a valuable therapeutic strategy for people with HSCR.Hirschsprung disease (HSCR) is a birth defect where enteric nervous system (ENS) is absent from distal bowel. Bowel lacking ENS fails to relax, causing partial obstruction. Affected children often have "Hirschsprung disease associated enterocolitis" (HAEC), which predisposes to sepsis. We discovered survival of Piebald lethal ( sl/sl ) mice, a well-established HSCR model with HAEC, is markedly altered by two distinct standard chow diets. A "Protective" diet increased fecal butyrate/isobutyrate and enhanced production of gut epithelial antimicrobial peptides in proximal colon. In contrast, "Detrimental" diet-fed sl/sl had abnormal appearing distal colon epithelium mitochondria, reduced epithelial mRNA involved in oxidative phosphorylation, and elevated epithelial oxygen that fostered growth of inflammation-associated Enterobacteriaceae . Accordingly, selective depletion of Enterobacteriaceae with sodium tungstate prolonged sl/sl survival. Our results provide the first strong evidence that diet modifies survival in a HSCR mouse model, without altering length of distal colon lacking ENS.Two different standard mouse diets alter survival in the Piebald lethal ( sl/sl ) mouse model of Hirschsprung disease, without impacting extent of distal colon aganglionosis (the region lacking ENS). Piebald lethal mice fed the "Detrimental" diet had many changes in colon epithelial transcriptome including decreased mRNA for antimicrobial peptides and genes involved in oxidative phosphorylation. Detrimental diet fed sl/sl also had aberrant-appearing mitochondria in distal colon epithelium, with elevated epithelial oxygen that drives lethal Enterobacteriaceae overgrowth via aerobic respiration. Elimination of Enterobacteriaceae with antibiotics or sodium tungstate improves survival of Piebald lethal fed the "Detrimental diet".

  View details for DOI 10.1101/2025.02.10.637436

  View details for PubMedID 39990395

  View details for PubMedCentralID PMC11844371

• Spatiotemporal dynamics during niche remodeling by super-colonizing microbiota in the mammalian gut. Cell systems Urtecho, G., Moody, T., Huang, Y., Sheth, R. U., Richardson, M., Descamps, H. C., Kaufman, A., Lekan, O., Zhang, Z., Velez-Cortes, F., Qu, Y., Cohen, L., Ricaurte, D., Gibson, T. E., Gerber, G. K., Thaiss, C. A., Wang, H. H. 2024; 15 (11): 1002-1017.e4

  Abstract

  While fecal microbiota transplantation (FMT) has been shown to be effective in reversing gut dysbiosis, we lack an understanding of the fundamental processes underlying microbial engraftment in the mammalian gut. Here, we explored a murine gut colonization model leveraging natural inter-individual variations in gut microbiomes to elucidate the spatiotemporal dynamics of FMT. We identified a natural "super-donor" consortium that robustly engrafts into diverse recipients and resists reciprocal colonization. Temporal profiling of the gut microbiome showed an ordered succession of rapid engraftment by early colonizers within 72 h, followed by a slower emergence of late colonizers over 15-30 days. Moreover, engraftment was localized to distinct compartments of the gastrointestinal tract in a species-specific manner. Spatial metagenomic characterization suggested engraftment was mediated by simultaneous transfer of spatially co-localizing species from the super-donor consortia. These results offer a mechanism of super-donor colonization by which nutritional niches are expanded in a spatiotemporally dependent manner. A record of this paper's transparent peer review process is included in the supplemental information.

  View details for DOI 10.1016/j.cels.2024.10.007

  View details for PubMedID 39541983

• Dietary restriction impacts health and lifespan of genetically diverse mice. Nature Di Francesco, A., Deighan, A. G., Litichevskiy, L., Chen, Z., Luciano, A., Robinson, L., Garland, G., Donato, H., Vincent, M., Schott, W., Wright, K. M., Raj, A., Prateek, G. V., Mullis, M., Hill, W. G., Zeidel, M. L., Peters, L. L., Harding, F., Botstein, D., Korstanje, R., Thaiss, C. A., Freund, A., Churchill, G. A. 2024; 634 (8034): 684-692

  Abstract

  Caloric restriction extends healthy lifespan in multiple species1. Intermittent fasting, an alternative form of dietary restriction, is potentially more sustainable in humans, but its effectiveness remains largely unexplored2-8. Identifying the most efficacious forms of dietary restriction is key for developing interventions to improve human health and longevity9. Here we performed an extensive assessment of graded levels of caloric restriction (20% and 40%) and intermittent fasting (1 and 2 days fasting per week) on the health and survival of 960 genetically diverse female mice. We show that caloric restriction and intermittent fasting both resulted in lifespan extension in proportion to the degree of restriction. Lifespan was heritable and genetics had a larger influence on lifespan than dietary restriction. The strongest trait associations with lifespan included retention of body weight through periods of handling-an indicator of stress resilience, high lymphocyte proportion, low red blood cell distribution width and high adiposity in late life. Health effects differed between interventions and exhibited inconsistent relationships with lifespan extension. 40% caloric restriction had the strongest lifespan extension effect but led to a loss of lean mass and changes in the immune repertoire that could confer susceptibility to infections. Intermittent fasting did not extend the lifespan of mice with high pre-intervention body weight, and two-day intermittent fasting was associated with disruption of erythroid cell populations. Metabolic responses to dietary restriction, including reduced adiposity and lower fasting glucose, were not associated with increased lifespan, suggesting that dietary restriction does more than just counteract the negative effects of obesity. Our findings indicate that improving health and extending lifespan are not synonymous and raise questions about which end points are the most relevant for evaluating aging interventions in preclinical models and clinical trials.

  View details for DOI 10.1038/s41586-024-08026-3

  View details for PubMedID 39385029

  View details for PubMedCentralID PMC11485257

• 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

• Aging disrupts circadian gene regulation and function in macrophages. Nature immunology Blacher, E., Tsai, C., Litichevskiy, L., Shipony, Z., Iweka, C. A., Schneider, K. M., Chuluun, B., Heller, H. C., Menon, V., Thaiss, C. A., Andreasson, K. I. 1800

  Abstract

  Aging is characterized by an increased vulnerability to infection and the development of inflammatory diseases, such as atherosclerosis, frailty, cancer and neurodegeneration. Here, we find that aging is associated with the loss of diurnally rhythmic innate immune responses, including monocyte trafficking from bone marrow to blood, response to lipopolysaccharide and phagocytosis. This decline in homeostatic immune responses was associated with a striking disappearance of circadian gene transcription in aged compared to young tissue macrophages. Chromatin accessibility was significantly greater in young macrophages than in aged macrophages; however, this difference did not explain the loss of rhythmic gene transcription in aged macrophages. Rather, diurnal expression of Kruppel-like factor 4 (Klf4), a transcription factor (TF) well established in regulating cell differentiation and reprogramming, was selectively diminished in aged macrophages. Ablation of Klf4 expression abolished diurnal rhythms in phagocytic activity, recapitulating the effect of aging on macrophage phagocytosis. Examination of individuals harboring genetic variants of KLF4 revealed an association with age-dependent susceptibility to death caused by bacterial infection. Our results indicate that loss of rhythmic Klf4 expression in aged macrophages is associated with disruption of circadian innate immune homeostasis, a mechanism that may underlie age-associated loss of protective immune responses.

  View details for DOI 10.1038/s41590-021-01083-0

  View details for PubMedID 34949832