Biology subjects

van Loo, G.

Publications and source records attributed to van Loo, G..

7 recordsLinked to original sources

bioRxiv2026

Indigenous Yanomami gut microbiota protects against diet-induced metabolic dysfunction

Industrialization profoundly alters the human gut microbiota, reducing microbial diversity and eliminating taxa prevalent in non-industrialized populations. These microbiota alterations accompanying industrialization might contribute to the increasing prevalence of obesity and other chronic inflammatory diseases, yet direct experimental evidence remains lacking. We compared the gut microbiota of Indigenous Brazilian Yanomami and urban Belgian donors and transplanted these into germ-free (GF) mice subjected to high-fat diet (HFD). The Yanomami microbiota exhibited greater richness and distinct composition enriched for VANISH (Volatile and/or Associated Negatively with Industrialized Societies of Humans) taxa. Transplantation of Yanomami microbiota significantly attenuated HFD-induced metabolic dysfunction, reducing weight gain, diabetes incidence, and promoting adipose and hepatic Th2 immunity. Yanomami-derived microbial communities displayed enhanced ecological stability and enrichment for short-chain fatty acid-associated taxa and metabolic functions post-HFD. Our findings demonstrate that the microbiota from low-urbanization populations confer protection against diet-induced metabolic disease, highlighting ecological resilience and specific microbial functions as potential targets for microbiota-inspired therapeutics.

microbiology↗

bioRxiv2025

Canonical Wnt induction by OTULIN prevents keratinocyte death and skin inflammation

Loss-of-function mutations in the human OTULIN gene, encoding a deubiquitinase with exclusive specificity for linear ubiquitin chains, cause a severe multi-organ autoinflammatory condition involving the skin1,2. Mice lacking OTULIN selectively in keratinocytes develop inflamed skin lesions that progress into squamous tumours, a phenotype driven by excessive TNF-induced cell death3,4. Previous studies suggested a role for OTULIN in mediating Wnt signalling during development5, but the physiological relevance of this association is unknown. Here, we show that OTULIN promotes Wnt signalling in keratinocytes by regulating the linear ubiquitination status of {beta}-catenin. Stabilisation of {beta}-catenin in OTULIN-deficient keratinocytes prevents progressive skin inflammation in prophylactic and therapeutic settings by blocking keratinocyte death. We demonstrate that linearly ubiquitinated {beta}-catenin accumulates in OTULIN-deficient keratinocytes, promoting its ubiquitination with K48 chains and subsequent proteasomal degradation. Reduced Wnt signalling in OTULIN-deficient keratinocytes leads to degradation of TCF3, an essential survival factor for keratinocytes6. Collectively, our data identify OTULINs linear deubiquitination activity as a key regulator of epithelial cell viability, not only by preventing cell death downstream of TNF, but also by promoting canonical Wnt signalling.

cell biology↗

bioRxiv2024

M1-linked Ubiquitination by LUBAC Regulates AMPK Activity and the Response to Energetic Stress

Methionine-1 (M1)-linked ubiquitin chains, assembled by the ubiquitin ligase LUBAC and cleaved by the deubiquitinase OTULIN, are critical regulators of inflammation and immune homeostasis. Genetic loss of either LUBAC or OTULIN causes autoinflammatory syndromes, which are associated with defects in glycogen and lipid metabolism. However, how LUBAC and OTULIN regulate metabolic signalling remains unknown. Here, we demonstrate that LUBAC promotes, while OTULIN restricts, activation of the key metabolic regulator AMP-activated protein kinase (AMPK) in cells, mice, and human samples. LUBAC and OTULIN interact with AMPK, control its M1-ubiquitination, and regulate its activation in response to glucose starvation and allosteric activation. During starvation, LUBAC deficiency impairs autophagy induction and hinders the shift from oxidative phosphorylation to glycolysis. Strikingly, LUBAC-deficient Drosophila have a strongly reduced survival rate after starvation. Our work identifies LUBAC and OTULIN as physiological regulators of AMPK, providing the first mechanism by which M1-linked ubiquitin chains regulate metabolic signalling.

cell biology↗

bioRxiv2023

Myeloid A20 is critical for type-2 immune mediated helminth resistance

Protective immunity against intestinal helminths requires induction of robust Type-2 immunity orchestrated by various cellular and soluble effectors which promote goblet cell hyperplasia, mucus production, epithelial proliferation and smooth muscle contractions to expel worms and reestablish immune homeostasis. Conversely, defects in type-2 immunity result in ineffective helminth clearance, persistent infection and chronic inflammation. We identify A20 as an essential myeloid factor for the induction of type-2 immune responses against the intestinal parasite Trichuris muris. Myeloid cell-specific loss of A20 in mice (A20myel-KO) results in chronic Trichuris muris infection and intestinal inflammation. Myeloid A20 deficient mice are not able to induce anti-helmith type-2 immune responses while instead mount detrimental Th1/Th17 polarized immune responses. Antibody-mediated neutralization of the type-1 cytokines IFN{gamma}, IL18 and IL12 prevents Th1/Th17 polarization and reestablishes Type-2 mediated protective immunity against Trichuris muris in A20myel-KO mice. In contrast, the strong Th1/Th17 biased immunity in A20myel-KO mice offers protection against Salmonella infection. We hereby identify A20 as an essential myeloid factor to initiate approriate adaptive immunity in response to infection, and to induce a balanced type-2 immune response against the intestinal parasite Trichuris muris. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/556360v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@632052org.highwire.dtl.DTLVardef@1def1f2org.highwire.dtl.DTLVardef@1de8459org.highwire.dtl.DTLVardef@1c316ff_HPS_FORMAT_FIGEXP M_FIG C_FIG Graphical abstractThe clearance of gastrointestinal helmiths depends on type-2 immunity. Helminths interact with and damage intestinal tissue, which leads to the release of intracellular DAMPs and cytokines such as TSLP and IL33, and IL25 produced by epithelial cells. These factors may activate myeloid cells and ILCs, which further activate T and B cells to mount effective Th2 responses and the secretion of IL4, IL5 and IL13 cytokines, as well as helminth-specific IgG1 immunoglobulins, leading to effective expulsion of the helminths. Deletion of A20 in the myeloid cells leads to enhanced secretion of type-1 cytokines, including IL12, IL18 and IFN{gamma}, which impede type-2 immune-mediated helminth clearance and promotes chronic intestinal inflammation.

immunology↗

bioRxiv2023

Colibactin-induced genotoxicity and colorectal cancer exacerbation critically depends on adhesin-mediated epithelial binding

Various bacteria are suggested to contribute to colorectal cancer (CRC) development, including pks+ E. coli which produce the genotoxin colibactin that induces characteristic mutational signatures in host epithelial cells. It remains unclear how the highly unstable colibactin molecule is able to access host epithelial cells and its DNA to cause harm. Using the microbiota-dependent ZEB2-transgenic mouse model of invasive CRC, we found that pks+ E. coli drives CRC exacerbation and tissue invasion in a colibactin-dependent manner. Using isogenic mutant strains, we further demonstrate that CRC exacerbation critically depends on expression of the E. coli type-1 pilus adhesin FimH and the F9-pilus adhesin FmlH. Blocking bacterial adhesion using a pharmacological FimH inhibitor attenuates colibactin-mediated genotoxicity and CRC exacerbation. Together, we show that the oncogenic potential of pks+ E. coli critically depends on bacterial adhesion to host epithelial cells and is critically mediated by specific bacterial adhesins. Adhesin-mediated epithelial binding subsequently allows production of the genotoxin colibactin in close proximity to host epithelial cells, which promotes DNA damage and drives CRC development. These findings present promising therapeutic avenues for the development of anti-adhesive therapies aiming at mitigating colibactin-induced DNA damage and inhibiting the initiation and progression of CRC, particularly in individuals at risk for developing CRC.

cancer biology↗

bioRxiv2023

Sterile triggers drive joint inflammation in TNF and IL-1beta dependent mouse arthritis models

Arthritis is the most common extra-intestinal complication in inflammatory bowel disease (IBD). Conversely, arthritis patients are at risk for developing IBD and often display subclinical gut inflammation. These observations suggest a shared disease etiology, commonly termed the gut-joint-axis. The clinical association between gut and joint inflammation is further supported by the success of common therapeutic strategies and microbiota dysbiosis in both conditions. Most data however support a correlative relationship between gut & joint inflammation, while causative evidence is lacking. Using two independent transgenic mouse arthritis models, either TNF or IL1{beta} dependent, we demonstrate that arthritis develops independently of the microbiota and intestinal inflammation, since both lines develop full-blown articular inflammation under germ-free conditions. In contrast, TNF-driven gut inflammation is fully rescued in germ-free conditions indicating that the microbiota is driving TNF-induced gut inflammation. Together, our study demonstrates that, although common inflammatory pathways may drive both gut and joint inflammation, the molecular triggers initiating such pathways are distinct in these tissues.

immunology↗

bioRxiv2019

OTULIN prevents liver inflammation and hepatocellular carcinoma by inhibiting FADD- and RIPK1 kinase-mediated hepatocyte apoptosis

Inflammatory signaling pathways are tightly regulated to avoid chronic inflammation and the development of inflammatory pathologies. OTULIN is a deubiquitinating enzyme that specifically cleaves linear ubiquitin chains generated by the linear ubiquitin chain assembly complex (LUBAC), and OTULIN deficiency causes OTULIN-related autoinflammatory syndrome (ORAS) in humans. OTULIN was shown to negatively control NF-{kappa}B signaling in response to various stimuli, but also to protect cells from tumor necrosis factor (TNF)-induced apoptosis. To investigate the importance of OTULIN in liver homeostasis and pathology, we developed a novel mouse line specifically lacking OTULIN in liver parenchymal cells. These mice spontaneously develop a severe liver disease, characterized by liver inflammation, hepatocyte apoptosis and compensatory hepatocyte proliferation, leading to steatohepatitis, fibrosis and hepatocellular carcinoma (HCC). Genetic ablation of Fas-associated death domain (FADD) completely rescues the severe liver pathology, and knock-in expression of kinase inactive receptor-interacting protein kinase 1 (RIPK1) significantly protects from developing liver disease, demonstrating that death receptor-mediated apoptosis of OTULIN-deficient hepatocytes triggers disease pathogenesis in this model. Finally, we demonstrate that type I interferons contribute to disease pathogenesis in hepatocyte-specific OTULIN deficient mice. Together, our study reveals the critical importance of OTULIN in protecting hepatocytes from death, and thereby avoid development of chronic liver inflammation and HCC in mice.

cancer biology↗