Modulating Inflammaging via Microbiome-Regulated Signaling in Hepatocytes and Kupffer Cells
Description: Aging is recognized not as a passive degenerative process, but as a progressive and actively regulated state characterized by chronic, low-grade inflammation—a phenomenon termed “inflammaging.” This persistent sterile inflammation plays a pivotal role in the pathogenesis of a broad array of age-associated complications and diseases, including malignancies, cardiovascular and neurodegenerative diseases, autoimmune disorders, and increased susceptibility to infections. Inflammaging is not caused by pathogen infection or tissue injury, but rather by a combination of endogenous factors such as the accumulation of senescent cells that secrete pro-inflammatory cytokines (SASP), dysregulated immune cell networks, metabolic stress, mitochondrial dysfunction, and impaired clearance of apoptotic debris. Collectively, these perturbations lead to a progressive remodeling of both systemic and tissue-resident immune landscapes.Among emerging modulators of inflammaging, the gut microbiota has gained prominence as a central regulator of age-related immune decline, particularly through its ability to reshape host metabolite profiles. A key microbiota-derived metabolite class involved in immunoregulation is secondary bile acid derivatives, which produced from bile acid following chemical transformation operated by specific gut microbial taxa . In addition to the traditional view for the role of bile acids in dietary fat emulsification, emerging findings have highlighted that secondary bile acid derivatives can act as multifunctional signaling molecules that engage host receptors such as, Takeda G protein-coupled receptor 5 (TGR5), farnesoid X receptor (FXR), and nuclear receptor subfamily 4 group A member 1 (NR4A1), to regulate immune function, metabolism, and inflammation. A particularly relevant pathway involves the conversion of primary bile acids into 3-oxoLCA and isoalloLCA by commensal microbes including Clostridium and Eggerthella. Amon the potential sensors for secondary bile acid derivatives, including 3-oxoLCA and isoalloLCA, TGR5 receptor (encoded by GPBAR1) is widely expressed in hepatic immune and parenchymal cells, including Kupffer cells and hepatocytes. Of note, activation of TGR5 triggers intracellular signaling cascades that inhibit NF-?B activity and the NLRP3 inflammasome in macrophages, both of which are key drivers of inflammaging. Moreover, TGR5 signaling enhances mitochondrial oxidative phosphorylation and reduces glycolytic flux in macrophages, promoting a shift toward an anti-inflammatory phenotype. Furthermore, in hepatocytes, TGR5 has been suggested to modulate gluconeogenesis and cytokine production. Altogether, these findings highlight that TGR5-mediated bile acid sensing positions the liver as a central hub to bridge gut microbiome-mediated regulation and systemic immune and metabolism homeostasis. Moreover, these effects collectively may suppress the chronic inflammation characteristic of aging.Building on these insights, our interdisciplinary project aims to delineate how bile acid signaling in liver-resident cells modulates systemic inflammaging and T cell dysfunction—two hallmarks of immunosenescence. We will focus on both hepatocytes and Kupffer cells, which together orchestrate hepatic responses to microbial metabolites and systemic immune and metabolic cues. Our central hypothesis is that bile acid–mediated sognaling can reprogram hepatic immunity to suppress inflammatory cytokine output and rewire metabolic features in the whole body, thereby delaying or reversing age-associated immune decline. In parallel, we will investigate how sex-based differences in bile acid synthesis, microbiota composition, and receptor expression influence the progression of inflammaging. Females and males differ significantly in both bile acid profiles and immune aging trajectories, yet the molecular basis of these differences remains poorly defined. Addressing this gap will allow us to identify sex-specific therapeutic targets and contribute to more personalized approaches in treating age-related inflammatory conditions. Finally, we plan to incorporate a synthetic biology strategy to engineer probiotic strains capable of producing secondary bile acid derivatives. These genetically customized bacteria will be designed to colonize the gut and locally generate defined signaling metabolites, offering a powerful, non-invasive route to immunomodulation. Moreover, we aim to develop a CAR-T cell design that selectively eliminate senescent hepatocytes caused by microbiome imbalance for ameliorating inflammaging. By integrating microbial engineering, liver immunometabolism, aging biology and a synthetic CAR T-cell design, this collaboration between the University of Lausanne and Keio University will generate foundational insights and translational tools for counteracting inflammaging and rejuvenating immune function in aging populations.Specific aims are:Aim 1: Characterize how secondary bile acid derivatives ameliorate inflammaging and T cell and hepatocyte senescence.Aim 2: Engineer probiotic strains capable of modulating host bile acid metabolism to alleviate inflammaging phenotypes.Aim 3: Examine whether senescent cell-specific CAR T-cells can ameliorate inflammaging by removing senescent hepatocytes and synergize with engineered probiotics.
Amount: CHF 625,000
Funding type: research
Funder scheme: Bilateral programmes
Start date: 2026-01-01
End date: 2029-12-31
Investigator: Ho, Ping-Chih
Institution: University of Lausanne – LA
Funded outputs count: 0
Funder award ID: 238769
OpenAlex ID: G7061700707