Exploiting trans-domain syntrophy for the reduction of obesity using biotherapeutic Christensenella

Obesity is a leading factor in global mortality and contributes to a widening problem in overall health through associated manifestations such as metabolic syndrome and cardiovascular disease. Specifically in Oklahoma, disparaging numbers were released for 2024 which suggests Oklahoma ranks 49th in overall obesity metrics. The gut microbiome has been linked to host health, with various taxa implicated in disease development. Over the last decade, Next Generation Sequencing (NGS) has revealed significant differences in the microbial composition of healthy patients and those with obesity and related cardiometabolic syndromes. In more recent years, a targeted approach has focused on identifying the culprits and benefactors, including Christensenellaceae, a bacterial family enriched in lean individuals. Research shows that murine fecal transplants with supplementation of Christensenella sp. promote weight loss despite mice maintaining a high fat diet. Meta-analyses of human microbiome studies position Christensenella as the major hub within a co-occurrence network of taxa, including Methanobrevibacter smithii, the most dominant archaea in the human gut. However, much remains unexplored with regard to syntrophic interactions between archaea and bacteria, despite acknowledgement on the importance of mutualism and cooperation in complex communities. Both taxa are implicated in early life colonization, with Christensenella enriched in vaginally delivered infants and Methanobrevibacter present in breastmilk. It stands to reason that these two taxa are connected to each other and to host metabolic fitness. To test the hypothesis that Christensenella and Methanobrevibacter cooperate to affect host physiology related to energy harvest, we will identify mechanisms by which Christensenella mitigates obesity progression. In addition to confirming the role of appetite and satiety hormones, GLP-1 and PYY, we will perform transcriptomic studies to reveal the syntrophic story between Christensenella and Methanobrevibacter via differential gene expression. This will enable identification of genes associated with the syntrophy of these two keystone microbes. In Aim 2, we will determine if trans-domain interactions pay a role in Christensenella-stimulated obesity reduction in vivo using a ‘westernized diet’ porcine model. Aim 3 involves recovering novel strains of Christensenella and Methanobrevibacter from mammalian sources using a culturomics approach. The studies presented here will reveal for the first time the degree to which transdomain syntrophy influences obesity progression and will establish mechanisms through which Christensenella impacts host health in order to provide avenues for therapeutic intervention to reduce the obesity burden. Project Number: 5P20GM152333-03 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: Crystal Johnson | Institution: OKLAHOMA STATE UNIVERSITY STILLWATER, STILLWATER, OK | Award Amount: $226,357 | Activity Code: P20 | Study Section: ZGM1-RCB-4(C1) View on NIH RePORTER: https://reporter.nih.gov/project-details/11460478