Biology subjects

Kaser, A.

Publications and source records attributed to Kaser, A..

4 recordsLinked to original sources

bioRxiv2025

An inherited mtDNA mutation remodels inflammatory cytokine responses in macrophages and in vivo

Impaired mitochondrial bioenergetics in macrophages can drive hyperinflammatory cytokine responses1-6, but whether this may also be caused by inherited mtDNA mutations is unknown. Here, we address this question using a multi-omic approach that integrates super-resolution imaging and metabolic analyses to profile macrophages from a mouse model of mitochondrial disease arising from a heteroplasmic mutation (m.5019A>G) in the mitochondrial tRNA for alanine7. These m.5019A>G macrophages exhibit defects in respiratory chain complexes and oxidative phosphorylation (OxPhos) due to decreased intra-mitochondrial translation. To adapt to this metabolic stress, mitochondrial fusion, reductive glutamine metabolism, and aerobic glycolysis are all increased. Upon inflammatory activation, type I interferon (IFN-I) release is enhanced, while the production of pro-inflammatory cytokines and oxylipins are restrained in m.5019A>G macrophages. Finally, an in vivo endotoxemia model using m.5019A>G mice reveal elevated IFN-I levels and sickness behaviour. In conclusion, our study identifies an unexpected imbalance in innate immune signalling in response to a pathogenic mtDNA mutation, with important implications for the progression of pathology in patients with mtDNA diseases8.

immunology↗

bioRxiv2023

Intestinal epithelial Atg16l1 influences pregnancy-induced fecal microbiota shifts in mice

Throughout gestation, the female body undergoes a series of transformations, including profound alterations in intestinal microbial communities. Changes gradually increase towards the end of pregnancy and comprise reduced -diversity of microbial communities and an increased propensity for energy harvest. Despite the importance of the intestinal microbiota for the pathophysiology of inflammatory bowel diseases, very little is known about the relationship between these microbiota shifts and pregnancy-associated complications of the disease. Here, we explored the longitudinal dynamics of gut microbiota composition and functional potential during pregnancy and after lactation in Atg16l1{Delta}IECmice carrying an intestinal epithelial deletion of the Croh[n]s disease risk gene Atg16l1. Using 16S rRNA amplicon and shotgun metagenomic sequencing, we demonstrated divergent temporal shifts in microbial composition between Atg16l1 wildtype and Atg16l1{Delta}IECpregnant mice in trimester 3, which was validated in an independent experiment. Observed differences included microbial genera implicated in IBD such as Lachnospiraceae, Roseburia, Ruminococcus, and Turicibacter. Changes partially recovered after lactation. In addition, functional inference of metagenomic data suggest a reduced potential to biosynthesize mucosal protective polyamines and reduced capacity to metabolize acidic polysaccharides (ketogluconate metabolism). On the host side, we found that the immunological response of Atg16l1{Delta}IEC mice is characterized by higher colonic mRNA levels of TNFA, and CXCL1 in trimester 3 and a lower weight of offspring at birth. Understanding pregnancy-dependent microbiome changes in the context of IBD may constitute the first step in the identification of fecal microbial biomarkers and microbiota-directed therapies that could help improving precision care for managing pregnancies in IBD patients.

microbiology↗

bioRxiv2022

Adaptation to ER-stress via serine glycine metabolism licences STING signalling and CMV control in intestinal epithelial cells

Inflammatory bowel diseases (IBD) are characterized by chronic relapsing inflammation of the gastrointestinal tract. While the molecular causality between endoplasmic reticulum (ER) stress and intestinal inflammation is widely accepted, the metabolic consequences of chronic ER-stress on the pathophysiology of IBD remain unclear. By using in vitro, ex vivo, in vivo mouse models and patient datasets, we identified a distinct polarisation of the mitochondrial one-carbon (1C) metabolism and a fine-tuning of the amino acid uptake in intestinal epithelial cells tailored to support GSH and NADPH metabolism upon chronic ER-stress. This metabolic phenotype strongly correlates with IBD severity and therapy-response. Mechanistically, we uncover that both chronic ER-stress and serine limitation disrupt cGAS/STING-signalling, impairing the epithelial response against viral and bacterial infection, fuelling experimental enteritis. Consequently, antioxidant treatment restores STING function and virus control. Collectively, our data highlight the importance of the plasticity of serine metabolism to allow proper cGAS/STING-signalling and innate immune responses upon chronic inflammation in the gut.

cell biology↗

bioRxiv2021

Two microbiota subtypes identified in Irritable Bowel Syndrome with distinct responses to the low-FODMAP diet

ObjectiveReducing FODMAPs can be clinically beneficial in IBS but the mechanism is poorly understood. We aimed to detect microbial signatures that might predict response to the low FODMAP diet and assess whether microbiota compositional and functional shifts could provide insights into its mode of action. DesignWe used metagenomics to determine high-resolution taxonomic and functional profiles of the stool microbiota from IBS cases and household controls (n=56 pairs) on their usual diet. Clinical response and microbiota changes were studied in 41 pairs after 4 weeks on a low FODMAP diet. ResultsUnsupervised analysis of baseline IBS cases pre-diet identified two distinct microbiota profiles, which we refer to as IBSP (pathogenic-like) and IBSH (health-like) subtypes. IBSP microbiomes were enriched in Firmicutes and genes for amino acid and carbohydrate metabolism, but depleted in Bacteroidetes species. IBSH microbiomes were similar to controls. On the low FODMAP diet IBSH and control microbiota were unaffected, but the IBSP signature shifted towards a health-associated microbiome with an increase in Bacteroidetes (p=0.009), a decrease in Firmicutes species (p=0.004) and normalization of primary metabolic genes. The clinical response to the low FODMAP diet was greater in IBSP subjects compared to IBSH (p = 0.02). Conclusion50% of IBS cases manifested a pathogenic gut microbial signature. This shifted towards the healthy profile on the low FODMAP diet; and IBSP cases showed an enhanced clinical responsiveness to the dietary therapy. The effectiveness of FODMAP exclusion in IBSP may result from the alterations in gut microbiota and metabolites produced. Microbiota signatures could be useful as biomarkers to guide IBS treatment; and investigating IBSP species and metabolic pathways might yield insights regarding IBS pathogenic mechanisms. O_TEXTBOXSignificance of this studyO_ST_ABSWhat is already known on this subject?C_ST_ABSO_LIIBS subjects often respond to a low FODMAP diet. C_LIO_LIThe gut microbiota has been implicated in IBS. C_LIO_LIThe microbiota in IBS subjects may change with diet. C_LI What are the new findings?O_LIWe were able to stratify patients with IBS according to their gut microbiota species and metabolic gene signatures. C_LIO_LIWe identified a distinct gut microbiota subtype with an enhanced clinical response to a low FODMAP diet compared to other IBS subjects. C_LI How might it impact on clinical practice in the foreseeable future?O_LIThe potential development of a microbiota signature as a biomarker to manage IBS cases with a low FODMAP diet recommendation. C_LIO_LIIf the bacteria represented in the IBSP subtype are shown to play a pathogenic role in IBS, perhaps through the metabolic activity this provides a target for new therapies and an intermediate phenotype by which to assess them. C_LI C_TEXTBOX

microbiology↗