Biology subjects

Amend, L.

Publications and source records attributed to Amend, L..

6 recordsLinked to original sources

bioRxiv2025

Ablation of polysaccharide breakdown in Bacteroides thetaiotaomicron prevents cross-feeding and growth of Salmonella Typhimurium in the mouse gut

Pathogens invading the intestine compete for nutrients with the resident microbiota. However, there is evidence that commensal members of the gut also provide nutritional resources to enteropathogens and thus promote their outgrowth. In this study, we investigated metabolic cross-feeding mechanisms between the abundant gut commensal Bacteroides thetaiotaomicron and the model enteropathogen Salmonella enterica serovar Typhimurium. We discovered that the processing of various dietary and host-derived glycans by B. thetaiotaomicron liberated building blocks available to Salmonella and identified a range of cross-fed metabolites. Interfering with polysaccharide degradation in B. thetaiotaomicron by genetic manipulation of specific polysaccharide utilization loci (PUL) inhibited pathogenic cross-feeding, both in vitro and in a gnotobiotic mouse model. Our findings highlight the complex metabolic commensal-pathogen interaction in the intestine and propose the disruption of polysaccharide breakdown as a potential microbiota-centric strategy to intervene in intestinal infections.

microbiology↗

bioRxiv2025

Mucosal innate immune activation as the trigger to Prevotella species-induced arthritis in genetically resistant mice

An altered gut microbiota, particularly the expansion of Prevotellaceae members, is increasingly implicated in the pathogenesis of rheumatoid arthritis (RA), yet the mechanisms hind this phenomenon remain unclear. Here, we demonstrate that Palleniella intestinalis, a member of the Prevotellaceae family, induces a 100% arthritis incidence in genetically resistant C57BL/6 mice. Inoculation with P. intestinalis modifies gut microbiota ecology, increases intestinal permeability, and selectively activates colonic CD11bCD11c myeloid cells, facilitating Th17 differentiation and driving joint inflammation. In vitro, outer membrane vesicles (OMV) from P. intestinalis and Segatella copri (formerly known as Prevotella copri) prime bone marrow-derived dendritic cells (BMDCs) to drive Th17 differentiation in an IL-6-dependent manner. Similar changes with increase in innate immune cell activation and IL-6 levels were shown in gut biopsies from new-onset RA patients. The transfer of Prevotellaceae-derived OMVs or Prevotellaeae-primed BMDCs replicates the hightened arthritis incidence in resistant mice, highlighting the critical role of intestinal immune activation in RA. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=130 SRC="FIGDIR/small/643707v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@1ce227corg.highwire.dtl.DTLVardef@3a2d0eorg.highwire.dtl.DTLVardef@16404b6org.highwire.dtl.DTLVardef@1717dc1_HPS_FORMAT_FIGEXP M_FIG C_FIG O_LIColonization with Paleniella intestinalis bypasses genetic resistance, consistently inducing arthritis incidence in non-susceptible C57BL/6 mice C_LIO_LIP. intestinalis activates colonic CD11b+CD11c+ myeloid cells, driving systemic Th17 cell differentiation C_LIO_LIIn vitro, outer membrane vesicles from P. intestinalis or RA-derived S. copri RPC01 primed DCs that drive Th17 differentiation in an IL-6-dependent manner C_LIO_LITransfer of P. intestinalis-primed DCs or its outer membrane vesicles alone increases arthritis incidence in non-susceptible C57BL/6 mice C_LI

immunology↗

bioRxiv2024

Comparative analysis of the treatment-naive microbiome across rheumatic diseases to predict MTX treatment response

The human gut microbiota is recognized as a modulator of inflammatory diseases and has been linked to interindividual differences in therapy responsiveness. However, the robustness of disease-specific microbiome signatures across closely related diseases is rarely compared. Here, we compared treatment-naive microbiota composition and functional potential across rheumatic diseases, including rheumatoid arthritis (RA) and spondyloarthritis subforms, to identify disease-specific biomarkers. While we failed to define robust disease-specific microbiota signatures, we identified microbial signatures linked to methotrexate (MTX) responsiveness for the two rheumatic diseases RA and psoriatic arthritis (PsA), for which MTX is the first-line treatment. Notably, the signatures were distinct, i.e., we could define a signature based on the relative abundance of microbial species for RA, yet the signature for PsA was based on the relative abundance of microbial pathways. Together this supports the previously recognized value of microbiota to predict treatment responses to MTX in RA and identifies distinct signatures predicting MTX responsiveness for PsA.

microbiology↗

bioRxiv2024

Gut-specific H3R signaling orchestrates microglia-dependent resolution of peripheral inflammation

Chronic inflammatory diseases, like rheumatoid arthritis (RA) have been described to cause central nervous system (CNS) activation. Less is known about environmental factors that enable the CNS to suppress peripheral inflammation in RA. Here, we identified gut microbiota-derived histamine as such factor. We show that low levels of histamine activate the enteric nervous system, increase inhibitory neurotransmitter concentrations in the spinal cord and restore homeostatic microglia, thereby reducing inflammation in the joints. Selective histamine 3 receptor (H3R) signaling in the intestine is critical for this effect, as systemic and intrathecal application did not show effects. Microglia depletion or pharmacological silencing of local nerve fibers impaired oral H3R agonist-induced pro-resolving effects on arthritis. Moreover, therapeutic supplementation of the SCFA propionate identified one way to expand local intestinal histamine concentrations in mice and humans. Thus, we define a gut-CNS-joint axis pathway where microbiota-derived histamine initiates the resolution of arthritis via the CNS. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=109 HEIGHT=200 SRC="FIGDIR/small/603031v1_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@c217b8org.highwire.dtl.DTLVardef@a340ceorg.highwire.dtl.DTLVardef@1f3c1d8org.highwire.dtl.DTLVardef@3b6fc9_HPS_FORMAT_FIGEXP M_FIG C_FIG O_LIGut microbiota-derived histamine activates enteric neurons via H3R C_LIO_LILocal intestinal H3R activation induces shift to homeostatic microglia in the spinal cord C_LIO_LICNS controlled decrease in endothelial leakiness resolves synovial inflammation C_LI

immunology↗

bioRxiv2024

The RNA landscape of the human commensal Segatella copri reveals a small RNA essential for gut colonization

The bacterium Segatella copri is a prevalent member of the human gut microbiota associated with both health and disease states, but intrinsic factors that determine its ability to effectively colonize the gut are not understood. By extensive transcriptome mapping of S. copri and examining human-derived samples, we discover a previously unknown small RNA named here Segatella RNA colonization factor (SrcF). We show that SrcF is essential for S. copri gut colonization in a gnotobiotic mouse model. SrcF regulates genes involved in nutrient acquisition, and its own expression is controlled by complex carbohydrates, particularly fructans. Furthermore, SrcF expression is strongly influenced by human microbiome composition and by the breakdown of fructans by cohabitating commensals, suggesting that the breakdown of complex carbohydrates mediates inter-species signaling among commensals beyond its established function in generating energy. Together, this study highlights the contribution of a small RNA as a key regulator in gut colonization.

microbiology↗

bioRxiv2021

Versatile genetic toolbox for Prevotella copri enables studying polysaccharide utilization systems

Prevotella copri is a prevalent inhabitant of the human gut and has been associated with plant-rich diet consumption and diverse health states. The underlying genetic basis of these associations remains enigmatic due to the lack of genetic tools. Here, we developed a novel versatile genetic toolbox for rapid and efficient genetic insertion and allelic exchange applicable to P. copri strains from multiple clades. Enabled by the genetic platform, we systematically investigated the specificity of polysaccharide utilization loci (PULs), and identified four highly conserved PULs for utilizing arabinan, pectic galactan, arabinoxylan and inulin, respectively. Further genetic and functional analysis of arabinan utilization systems illustrate that P. copri has evolved two distinct types of arabinan-processing PULs (PULAra) and that the type-II PULAra is significantly enriched in individuals consuming a vegan diet compared to other diets. In summary, this genetic toolbox will enable functional genetic studies for P. copri in the future.

microbiology↗