Biology subjects

Thymann, T.

Publications and source records attributed to Thymann, T..

4 recordsLinked to original sources

bioRxiv2024

Chemostat culturing reduces fecal eukaryotic virus load and delays diarrhea after virome transplantation

Fecal virome transfer (FVT) shows promise in reducing necrotizing enterocolitis (NEC), likely due to donor bacteriophages preventing the gut dysbiosis preceding disease. However, concurrent transfer of eukaryotic viruses may carry a risk of infection for the recipient. To increase safety, we investigated chemostat propagation as a method to eliminate eukaryotic viruses from donor feces while maintaining a diverse and reproducible bacteriophage community. Donor feces was collected from healthy suckling piglets and inoculated into a fermenter containing growth media supplemented with lactose and milk oligosaccharides (MOs). During continuous medium exchange (20% volume/h), dilution significantly reduced eukaryotic viruses. Viral richness was concurrently reduced although still preserving a stable community of 200-250 bacteriophages. Inclusion of MOs in the medium ensured higher bacterial richness and a bacterial community closer resembling donor feces. Fecal Lactobacillaceae bacteria were lost during cultivation but partially replaced by members of the Bacteroidota phylum in MO-supplemented cultures, accompanied by phages predicted to have Parabacteroides as host. After cultivation, virus-like particles (VLPs) were isolated, and their ability to reduce NEC incidence tested in vivo. Preterm piglets were delivered by cesarean section and received either the lactose- or MO-propagated viromes by oral route (n = 14-15/group). These were compared with groups receiving the same dose of donor fecal virome (1010 VLPs/kg) or vehicle control. The piglets were subsequently fed infant formula for 96 hours followed by euthanasia and tissue sampling. Both chemostat-propagated viromes effectively mitigated diarrhea compared to the donor virome. The donor virome partially engrafted in recipients and led to higher levels of Lactobacillaceae bacteria and Lactobacillaceae targeting phages. However, these signatures were lost in recipients of chemostat-propagated viromes, and only minor microbiome effects and no NEC prevention were observed. To conclude, we provide in vivo proof-of-concept for chemostat propagation of fecal viruses as a means to deplete eukaryotic viruses and in turn reduce side effects in newborn virome recipients. However, chemostat culture conditions need further optimization to preserve the donor phageome.

microbiology↗

bioRxiv2024

Reduced glucose supply during neonatal infection attenuates neurological and renal pathology via modulation of innate and Th1 immunity

BackgroundPremature infants are highly susceptible to infections that can lead to sepsis with life-threatening organ dysfunctions. The clinical practice of high parenteral glucose supply in preterm infants can exacerbate infection outcomes through excessive glycolysis-induced inflammatory response. This in turn can affect the health of vital preterm organs, including the brain and kidneys. We hypothesized that reducing glucose supply in infected preterm newborns may help protect against pathology in these two key organs. MethodsCaesarean-delivered preterm pigs were nourished with high or low parenteral glucose levels, infected with Staphylococcus epidermidis or saline, and cared for until 22h. Blood, brain, and kidney samples were collected at the end of the study for analyses. ResultsInfection led to multiple pathological changes, increased inflammation and tissue injury and dysfunction in both brain and kidneys of preterm piglets. Reduced glucose supply in infected animals alleviated neurological degradation, hyperemia and enhanced M2 microglial phenotype in the brain. This intervention also reduced plasma creatinine, renal edema, tubular vacuolization and dilatation. Multiple genes related to innate and Th1 immunity in both organs were highly correlated and dampened by reduced glucose supply, but there were clear signs that renal inflammation was closely connected to systemic inflammation while neuroinflammation was likely driven by immune response to the bacteria translocated into the brain. ConclusionReduced glucose supply can protect brain and kidney health in infected preterm neonates.

immunology↗

bioRxiv2023

Insulin-like Growth Factor-1 Supplementation Promotes Kidney Development and Alleviate Renal Inflammation in Preterm Pigs

BackgroundPreterm birth and its associated complications cause disruption of normal prenatal renal development, leading to postnatal kidney injury and failure. Preterm infants are deficient in insulin-like growth factor 1 (IGF-1), a critical growth factor that stimulates tissue perfusion and development. Using necrotizing enterocolitis-sensitive preterm pigs as a model for preterm infants, we investigated whether IGF-1 supplementation during early life could improve kidney development and health. MethodsCaesarean-delivered preterm pigs were allocated into two groups, either consistently receiving vehicle or IGF-1 immediately after birth for 5, 9 or 19 days. Postnatal age-matched term pigs were selected and served as term control on postnatal day (PND) 5, 9, and 19. Blood, urine and kidney tissue were collected for biochemical, histological and gene expression analyses. ResultsPreterm pigs showed impaired kidney development and increased kidney insults, as indicated by reduced average glomerular area, increased abnormal glomeruli percentage and increased markers of renal injury and inflammation compared to term pigs. IGF-1 supplementation significantly reduced the abnormal glomeruli percentage, renal injury and inflammation related markers, and up-regulated certain maturation-related genes on PND5. ConclusionIGF-1 supplementation supports kidney maturation and restoration of kidney insults after preterm birth in the early life of newborns. ImpactO_LIPreterm birth disrupts kidney development in preterm pigs. C_LIO_LIPreterm birth leads to kidney injury and inflammation in preterm pigs. C_LIO_LIIGF-1 supplementation might promote kidney maturation and alleviate preterm birth associated kidney injury and inflammation in preterm pigs. C_LI

physiology↗

bioRxiv2020

Fecal filtrate transfer protects against necrotizing enterocolitis in preterm pigs

Background and aimsNecrotizing enterocolitis (NEC) is an acute and life-threatening gastrointestinal disorder afflicting preterm infants, which is currently unpreventable. Fecal microbiota transplantation (FMT) is a promising preventative therapy, but potential side effects raise concern. Removal of bacteria from donor fecal water may reduce side effects while maintaining wanted effects. We aimed to assess preclinical efficacy and safety of bacteria-free fecal filtrate transfer (FFT). MethodsUsing fecal material from healthy suckling piglets, we administered rectal FMT or cognate FFT by either rectal or oro-gastric administration to formula-fed preterm, cesarean piglets, and compared gut pathology and related safety parameters with saline controls. We then analyzed mucosa and luminal bacterial and viral composition using 16S rRNA gene amplicon and metavirome sequencing, respectively. Finally, we used isolated ileal mucosa, coupled with RNA-Seq, to gauge the host response to the different treatments. ResultsOro-gastric FFT eliminated NEC, which was confirmed by microscopy, whereas FMT did not perform better than control. Moreover, FFT but not FMT reduced intestinal permeability, whereas FMT animals had reduced body weight increase and intestinal growth. Oro-gastric FFT increased viral diversity and reduced Proteobacteria abundance in ileal mucosa relative to control. Global gene expression of host mucosa responded to FMT but not FFT with increased and decreased bacterial and viral defense mechanisms, respectively. ConclusionsAs preterm infants are extremely vulnerable, rational therapies need incontestable safety profiles. Here we show in a clinically relevant animal model that FFT, as opposed to FMT, efficiently prevents NEC without any recognizable side effects. If translatable to preterm infants, this could lead to a change of practice and in turn a reduction in NEC burden.

microbiology↗