Selected Grantee Publications
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- Rodent Models
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Reduced Alcohol Preference and Intake after Fecal Transplant in Patients with Alcohol Use Disorder Is Transmissible to Germ-Free Mice
Wolstenholme et al., Nature Communications. 2022.
https://www.doi.org/10.1038/s41467-022-34054-6
Alcohol use disorder is a major cause of reduced life expectancy worldwide, and this misuse has increased exponentially during the COVID-19 pandemic. Fecal microbiota transplant has been shown previously to reduce alcohol craving in humans with cirrhosis. Here, the investigators report that the reduction in craving and alcohol preference is transmissible to male germ-free mice only when live bacteria—and not germ-free supernatants—are used for colonization. This differential colonization was associated with alterations in the gut immune–inflammatory response through short-chain fatty acids. Supported by ORIP (P40OD010995), NIAAA, NIDDK, and NIMH.
Promoting Validation and Cross-Phylogenetic Integration in Model Organism Research
Cheng et al., Disease Models & Mechanisms. 2022.
https://www.doi.org/10.1242/dmm.049600
Model organisms are essential for biomedical research and therapeutic development, but translation of such research to the clinic is low. The authors summarized discussions from an NIH virtual workshop series, titled “Validation of Animal Models and Tools for Biomedical Research,” held from 2020 to 2021. They described challenges and opportunities for developing and integrating tools and resources and provided suggestions for improving the rigor, validation, reproducibility, and translatability of model organism research. Supported by ORIP (R01OD011116, R24OD031447, R03OD030597, R24OD018559, R24OD017870, R24OD026591, R24OD022005, U42OD026645, U42OD012210, U54OD030165, UM1OD023221, P51OD011107), NIAMS, NIDDK, NIGMS, NHGRI, and NINDS.
X Chromosome Agents of Sexual Differentiation
Arnold et al., Nature Reviews Endocrinology. 2022.
https://www.doi.org/10.1038/s41574-022-00697-0
Many diseases affect one sex disproportionately. A major goal of biomedical research is to understand which sex-biasing factors influence disease severity and to develop therapeutic strategies to target these factors. Two groups of such agents are sex chromosome genes and gonadal hormones. Researchers use the “four core genotypes” model to enable comparisons among animals with different sex chromosomes but the same type of sex hormones, which allows investigators to distinguish disease mechanisms influenced by the sex chromosomes. Supported by ORIP (R01OD030496, R21OD026560), NICHD, NIDDK, and NHLBI.
Targeted Suppression of Human IBD-Associated Gut Microbiota Commensals by Phage Consortia for Treatment of Intestinal Inflammation
Federici et al., Cell. 2022.
https://www.doi.org/10.1016/j.cell.2022.07.003
Human gut commensals increasingly are suggested to affect noncommunicable diseases, such as inflammatory bowel disease (IBD), yet their targeted suppression remains an unmet challenge. In this report, investigators identified a clade of Klebsiella pneumoniae (Kp) strains—featuring a unique antibiotic resistance and mobilome signature—that is associated strongly with disease exacerbation and severity. Transfer of clinical IBD-associated Kp strains into colitis-prone, germ-free, and colonized mice of both sexes enhances intestinal inflammation. An orally administered combination phage therapy targeting sensitive and resistant IBD-associated Kp clade members enables effective Kp suppression, suggesting the feasibility of avoiding antibiotic resistance while effectively inhibiting noncommunicable disease–contributing pathobionts. Supported by ORIP (P40OD010995) and NIDDK.
Obesity Alters Pathology and Treatment Response in Inflammatory Disease
Bapat et al., Nature. 2022.
https://www.doi.org/10.1038/s41586-022-04536-0
Obesity and metabolic disease have been shown to affect immunotherapeutic outcomes. By studying classical type 2 T helper cells (TH2) in lean and obese male mouse models for atopic dermatitis, investigators found that the biologic therapies protected lean mice but exacerbated disease in obese mice. RNA sequencing and genome analyses revealed decreased activity of nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) in TH2 cells in obese mice when compared to lean mice, indicating that PPARγ is required to prevent aberrant non-TH2 inflammation. Understanding the effects of obesity on immunological disease could inform a potential precision medicine approach to target obesity-induced immune dysregulation. Supported by ORIP (S10OD023689), NIAID, NCI, NIDDK, and NIGMS.
Natural Killer Cells Activated Through NKG2D Mediate Lung Ischemia-Reperfusion Injury
Calabrese et al., Journal of Clinical Investigation. 2021.
https://www.jci.org/articles/view/137047
Pulmonary ischemia-reperfusion injury (IRI) causes early mortality and has no effective therapies. While natural killer (NK) cells are innate lymphocytes capable of recognizing injured cells, their roles in acute lung injury are incompletely understood. Here, investigators demonstrated that NK cells were increased in frequency and cytotoxicity in 2 different IRI mouse models. They showed that NK cells trafficked to the lung tissue from peripheral reservoirs and were more mature within lung tissue. Acute lung ischemia-reperfusion injury was blunted in a NK cell–deficient mouse strain but restored with adoptive transfer of NK cells. In human lung tissue, NK cells were increased at sites of ischemia-reperfusion injury and activated NK cells were increased in prospectively-collected human bronchoalveolar lavage in subjects with severe IRI. These data support a causal role for recipient peripheral NK cells in pulmonary IRI via NK cell NKG2D receptor ligation. Therapies targeting NK cells may hold promise in acute lung injury. Supported by ORIP (S10OD026940), NHLBI, and NIDDK.
Lipocalin-2 Is an Anorexigenic Signal in Primates
Petropoulou et al., eLife. 2020.
https://doi.org/10.7554/eLife.58949
The hormone lipocalin-2 (LCN2) suppresses food intake in mice. Researchers demonstrated that LCN2 increases after a meal and reduces hunger in people with normal weight or overweight, but not in obese individuals. The researchers also showed that LCN2 crosses the blood-brain barrier and binds to the hypothalamus in vervet monkeys. LCN2 was found to bind to the hypothalamus in human, baboon, and rhesus macaque brain sections. When injected into vervets, LCN2 suppressed food intake and lowered body weight without toxic effects in short-term experiments. These findings lay the groundwork to investigate whether LCN2 might be a useful treatment for obesity. Supported by ORIP (P40OD010965), NCATS, NIDDK, NIA, and NHLBI.
Fructose Stimulated De Novo Lipogenesis Is Promoted by Inflammation
Jelena et al., Nature Metabolism. 2020.
https://pubmed.ncbi.nlm.nih.gov/32839596
Non-alcoholic fatty liver disease (NAFD) affects 30% of adult Americans. While NAFD starts as simple steatosis with little liver damage, its severe manifestation as non-alcoholic steatohepatitis (NASH) is a leading cause of liver failure, cirrhosis, and cancer. Fructose consumption is proposed to increase the risk of hepatosteatosis and NASH. Excessive intake of fructose causes barrier deterioration and low-grade endotoxemia. Using a mouse model, the study examined the mechanism of how fructose triggers these alterations and their roles in hepatosteatosis and NASH pathogenesis. The results demonstrated that microbiota-derived Toll-like receptor (TLR) agonists promote hepatosteatosis without affecting fructose-1-phosphate (F1P) and cytosolic acetyl-CoA. Activation of mucosal-regenerative gp130 signaling, administration of the YAP-induced matricellular protein CCN1 or expression of the antimicrobial peptide Reg3b (beta) counteract fructose-induced barrier deterioration, which depends on endoplasmic-reticulum stress and subsequent endotoxemia. Endotoxin engages TLR4 to trigger TNF production by liver macrophages, thereby inducing lipogenic enzymes that convert F1P and acetyl-CoA to fatty acid in both mouse and human hepatocytes. The finding may be of relevance to several common liver diseases and metabolic disorders. Supported by ORIP (S10OD020025), NCI, NIEHS, NIDDK, NIAID, and NIAAA.