Biology subjects

Schwalbe, M.

Publications and source records attributed to Schwalbe, M..

9 recordsLinked to original sources

bioRxiv2026

Feeding-mode-defined microbial communities modulate prebiotic responses and alters colonic motility in early life

Prebiotic supplementation a well-established impact on early-life gut microbiota, yet how substrate type and baseline community structure interact to shape microbial and metabolic responses remains incompletely understood. Using donor-derived infant faecal fermentations, a defined synthetic microbial community (SynCom), and multi-layered metabolomics, we demonstrate that prebiotic responses are strongly dependent on feeding-mode and mediated by species-specific metabolic interactions. While both human milk oligosaccharides (HMOs) and galacto-oligosaccharides (GOS) robustly promoted bifidobacterial expansion, modulation of Bacteroides/Phocaeicola species varied according to feeding background and substrate identity with 2'-fucosyllactose (2'FL) selectively alleviating growth inhibition in breast milk-derived communities. Mechanistic dissection using SynCom revealed extensive cross-feeding networks and substrate-dependent interaction rewiring, identifying Phocaeicola vulgatus as a context-dependent ecological hub that disproportionately shaped succinate and propionate production and altered Escherichia coli metabolic activity without affecting its abundance. Competitive outcomes were determined not only by environmental acidification, but also by the chemical identity of fermentation products, with lactate exerting species-specific inhibitory effects independent of bulk pH changes. Using an in-house ex vivo IntestiFlow gut organ platform, we further show that metabolites produced by the defined community induced a strong but reversible suppression of colonic peristaltic activity, an effect not recapitulated by SCFAs alone. Biogenic amine metabolites, including phenethylamine, partially reproduced key aspects of this response, suggesting a role for specific microbial fermentation products in modulating intestinal motility. Together, these findings demonstrate that early-life prebiotic responses extend beyond uniform bifidogenic expansion and instead emerge from interaction-driven metabolic specialization within feeding-mode-specific community contexts, with direct functional consequences for infant intestinal physiology.

microbiology↗

bioRxiv2025

Patched regulates cell cycle and tissue architecture in C. elegans gonad

Hedgehog (Hh) signaling is essential for embryonic development and tissue homeostasis in several organisms. However, Caenorhabditis elegans lacks canonical Hh signaling due to the absence of key components, such as smoothened (SMO) and Hh ligands. Despite this, C. elegans retains Patched homologs, ptc-1 and ptc-3, which have specialized independent functions. Although ptc-1 is predominantly expressed in the gonads and ptc-3 in somatic tissues, we demonstrate that both genes are required to maintain germ cell populations and proper actin cytoskeletal architecture in the progenitor zone of the germline. Disruption of actin-encoding genes impairs germ cell cycle progression and reduces germ cell numbers, indicating that cytoskeletal integrity is critical for maintaining the germline. Furthermore, defects observed upon loss of Patched function are linked to disruptions in cholesterol metabolism. We show that the phenotypes observed in the gonads due to the loss of Patched function can be rescued by modulating dietary cholesterol. Together, our findings reveal a role for Patched receptors in regulating germline architecture and germ cell development through cholesterol-sensitive functions, offering insights into how metabolic cues influence the organization of complex tissues.

cell biology↗

bioRxiv2025

Serotonin modulation of metabolism and stress response in Pseudomonas fluorescens

BackgroundPseudomonas fluorescens is a gram-negative bacterium with a remarkable metabolic and physiological versatility that enables it to adapt and colonize diverse ecological niches, including the human small intestine. While serotonin is primarily found in high concentrations in gut tissue, its levels in the lumen can be elevated in conditions such as celiac disease, where P. fluorescens is also found in increased abundance. The potential effects of serotonin on P. fluorescens in such contexts remain unclear. ResultsWe demonstrate that P. fluorescens metabolizes serotonin primarily into 5-hydroxyindole-3-acetic acid (5-HIAA) and, to a lesser extent, into 5-hydroxytryptophol and N-acetylserotonin. Gene expression analysis revealed significant changes in oxidative stress-related pathways over time, and proteomic analysis confirmed the shifts seen particularly in amino acid catabolic pathways. Serotonin metabolism also enhanced bacterial resistance to oxidative stress, suggesting a protective role. ConclusionsThe findings reveal a novel mechanism by which serotonin modulates the metabolism and stress responses of P. fluorescens. This study provides insight into how P. fluorescens adapts to serotonin-rich environments, such as in celiac disease, and may inform future research on microbial interactions with host-derived metabolites in disease contexts.

microbiology↗

bioRxiv2024

Gut microbiota-mediated conversion of mangiferin to norathyriol alters short chain fatty acid and urate metabolism

Mangiferin (MAN), a natural C-glycosylxanthone, is recognized for its health-promoting effects in traditional medicinal preparations. However, its poor bioavailability and limited intestinal permeability restrict its direct biological activity in vivo. Previous studies have suggested a potential bacterial breakdown of MAN into norathyriol (NOR), an aglycone with significantly higher bioavailability and absorption. Yet, the prevalence of MAN-metabolizing microbes, the presence of MAN or NOR within the gut microbial community, and their effects on the composition and metabolic activity of the gut microbiome remain unclear. In this study, fecal samples from healthy adult volunteers treated with MAN revealed its conversion to NOR, with interindividual variation attributed to the uncultured bacterial strain CAKRHR01 sp934339005. While MAN had minimal impact on microbial composition and metabolic activity, NOR treatment significantly increased pH, reduced overall bacterial cell counts, and selectively suppressed short-chain fatty acid-producing bacteria, including Faecalibacterium prausnitzii as well as urate consumers, such as Enterocloster bolteae. These findings underscore the potential of NOR to modulate gut microbial activity and highlight the importance of understanding microbiome-mediated metabolism when assessing the health implications of phytochemicals.

microbiology↗

bioRxiv2023

Probiotics supplementation to adult human small intestinal stoma microbiota causes dynamic increase in the community resistance to perturbations and nutrient utilization

The gut microbiota plays a pivotal role in health and disease. The use of probiotics as microbiota-targeted therapies is a promising strategy to improve host health. However, dynamic molecular mechanisms are often not elucidated, especially when targeting the small intestinal microbiota. Here, we show that supplementation of a probiotic formula (Ecologic(R)825) to the adult human small intestinal ileostoma microbiota counteracts the growth of Enterococcaceae and Enterobacteriaceae and reduces ethanol production, leading to major changes in nutrient utilization and resistance to perturbations. The observed alterations coincided with an initial increase in lactate production and decrease in pH by the probiotics, followed by a sharp increase in the levels of butyrate and propionate. Additionally, increased production of multiple N-acyl amino acids was detected in the stoma samples supplemented with the probiotic formula. Overall, this study shows how network theory can be used to improve the current or identify novel microbiota-targeted therapies. The outcome may help further understand the reported effects of these probiotic formula on the host.

microbiology↗

bioRxiv2022

Gut microbiota transplantation drives the adoptive transfer of colonic genotype-phenotype characteristics between mice lacking catestatin and their wild type counterparts

The gut microbiota is in continuous interaction with the intestinal mucosa via metabolic, neuro- immunological, and neuroendocrine pathways. Disruption in levels of antimicrobial peptides produced by the enteroendocrine cells, such as catestatin, has been associated with changes in the gut microbiota and imbalance in intestinal homeostasis. However, whether the changes in the gut microbiota have a causational role in intestinal dyshomeostasis has remained elusive. To this end, we performed reciprocal fecal microbial transplantation in wild-type mice and mice with a knockout in the catestatin coding region of the chromogranin-A gene (CST-KO mice). Combined microbiota phylogenetic profiling, RNA sequencing, and transmission electron microscopy were employed. Fecal microbiota transplantation from mice deficient in catestatin (CST-KO) to microbiota-depleted wild-type mice induced transcriptional and physiological features characteristic of a distorted colon in the recipient animals, including impairment in tight junctions, as well as an increased collagen area fraction indicating colonic fibrosis. In contrast, fecal microbiota transplantation from wild-type mice to microbiota-depleted CST-KO mice reduced collagen fibrotic area, restored disrupted tight junction morphology, and altered fatty acid metabolism in recipient CST-KO mice. This study provides a comprehensive overview of the murine metabolic- and immune-related cellular pathways and processes that are co-mediated by the fecal microbiota transplantation and supports a prominent role for the gut microbiota in the colonic distortion associated with the lack of catestatin in mice. Overall, the data show that the gut microbiota may play a causal role in the development of features of intestinal inflammation and metabolic disorders, known to be associated with altered levels of catestatin and may, thus, provide a tractable target in the treatment and prevention of these disorders.

microbiology↗

bioRxiv2021

Catestatin selects for the colonization of antimicrobial-resistant gut bacterial communities

The gut microbiota is in continuous interaction with the innermost layer of the gut, namely the epithelium. One of the various functions of the gut epithelium, is to keep the microbes at bay to avoid overstimulation of the underlying mucosa immune cells. To do so, the gut epithelia secrete a variety of antimicrobial peptides, such as chromogranin A (CgA) peptide catestatin (CST: hCgA352-372). As a defense mechanism, gut microbes have evolved antimicrobial resistance mechanisms to counteract the killing effect of the secreted peptides. To this end, we treated wild-type mice and CST knockout (CST-KO) mice (where only the 63 nucleotides encoding CST have been deleted) with CST for 15 consecutive days. CST treatment was associated with a shift in the diversity and composition of the microbiota in the CST-KO mice. This effect was less prominent in WT mice. Levels of the microbiota-produced short-chain fatty acids, in particular, butyrate and acetate were significantly increased in CST-treated CST-KO mice but not the WT group. Both CST-treated CST-KO and WT mice showed a significant increase in microbiota-harboring phosphoethanolamine transferase-encoding genes, which facilitate their antimicrobial resistance. Finally, we show that CST was degraded by Escherichia coli via an omptin-protease and that the abundance of this gene was significantly higher in metagenomic datasets collected from patients with Crohns disease but not with ulcerative colitis. Overall, this study illustrates how the endogenous antimicrobial peptide, CST, shapes the microbiota composition in the gut and primes further research to uncover the role of bacterial resistance to CST in disease states such as inflammatory bowel disease.

microbiology↗

bioRxiv2020

Patient-Derived Mutant Forms of NFE2L2/NRF2 Drive Aggressive Murine Hepatoblastomas

Background and AimsHepatoblastoma (HB), the most common pediatric liver cancer, often bears {beta}-catenin mutations and deregulates the Hippo tumor suppressor pathway. Murine HBs can be generated by co-expressing {beta}-catenin mutants and the constitutively active Hippo effector YAPS127A. Some HBs and other cancers also express mutants of NFE2L2/NRF2 (NFE2L2), a transcription factor that tempers oxidative and electrophilic stress. In doing so, NFE2L2 either suppresses or facilitates tumorigenesis. MethodsWe evaluated NFE2L2s role in HB pathogenesis by co-expressing all combinations of mutant {beta}-catenin, YAPS127A and the patient-derived NFE2L2 mutants L30P and R34P in murine livers. We evaluated growth, biochemical and metabolic profiles and transcriptomes of the ensuing tumors. ResultsIn association with {beta}-catenin+YAPS127A, L30P and R34P markedly accelerated HB growth and generated widespread cyst formation and necrosis, which are otherwise uncommon features. Surprisingly, any two members of the mutant {beta}-catenin-YAPS127A-L30P/R34P triad were tumorigenic, thus directly establishing NFE2L2s oncogenicity. Each tumor group displayed distinct features but shared 22 similarly deregulated transcripts, 10 of which perfectly correlated with survival in human HBs and 17 of which correlated with survival in multiple adult cancers. One highly up-regulated transcript encoded serpin E1, a serine protease inhibitor that regulates fibrinolysis, growth and extracellular matrix. The combination of mutant {beta}-catenin, YAPS127A and Serpin E1, while not accelerating cystogenic tumor growth, did promote the wide-spread necrosis associated with mutant {beta}-catenin-YAPS127A-L30P/R34P tumors. ConclusionsOur findings establish the direct oncogenicity of NFE2L2 mutants and key transcripts, including serpin E1, that drive specific HB features.

cancer biology↗

bioRxiv2020

Acquired deficiency of the peroxisomal enzyme enoyl-CoA hydratase/3-hydroxyacyl CoA dehydrogenase is a metabolic vulnerability in hepatoblastoma

Metabolic reprogramming provides transformed cells with proliferative and/or survival advantages. However, capitalizing on this therapeutically has been only moderately successful due to the relatively small magnitude of these differences and because cancers may re-program their metabolism to evade metabolic pathway inhibition. Mice lacking the peroxisomal bi-functional enzyme enoyl-CoA hydratase/3-hydroxyacyl CoA dehydrogenase (Ehhadh) and supplemented with the 12-carbon fatty acid lauric acid (C12) accumulate dodecanedioic acid (DDDA), a toxic C12 metabolite that causes hepatocyte necrosis and acute liver failure. In a murine model of pediatric hepatoblastoma (HB), down-regulation of Ehhadh also occurs in combination with a more general suppression of mitochondrial {beta}- and peroxisomal {omega}-fatty acid oxidation (FAO) pathways. HB-bearing mice provided with C12 and/or DDDA-supplemented diets survived significantly longer than those on standard diets. The tumors also developed massive necrosis in response to short-term DDDA supplementation. Reduced Ehhadh was noted in murine hepatocellular carcinomas (HCCs) and in substantial subsets of human cancers, including HCCs. Acquired DDDA resistance was not associated with Ehhadh re-expression but was associated with 129 transcript differences ~90% of which were down-regulated in DDDA-resistant tumors and ~two-thirds of which correlated with survival in several human cancers. These transcripts often encoded components of the extracellular matrix suggesting that DDDA resistance arises from its reduced intracellular transport. Our results demonstrate the feasibility of a metabolic intervention that is non-toxic, inexpensive and likely compatible with traditional therapies. C12 and/or DDDA-containing diets could potentially be used to supplement other treatments or as alternative therapeutic choices.

cancer biology↗