Karin Kleigrewe

We introduce a novel machine learning framework for predicting resting metabolic rate (RMR), emphasizing the superior performance of Lasso regression. Our analysis incorporates both standard clinical variables and previously underexplored factors such as gut microbiota, fecal short-chain fatty acids (SCFAs), and mean outdoor temperature.

Changes in the intestinal microbiome and microbiota-derived metabolites predict clinical outcomes after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Here, we report that desaminotyrosine (DAT), a product of bacterial flavonoid metabolism, correlates with improved overall survival and reduced relapse rates in patients receiving allo-HSCT. In preclinical mouse models, treatment with synthetic DAT prevents graft-versus-host disease by protecting the intestinal barrier and promoting intestinal regeneration and contributes to graft-vs.-leukemia responses. DAT´s beneficial effects on intestinal regeneration remain effective despite broad-spectrum antibiotics-induced dysbiosis, also when administered by fecal microbiota transfer with flavonoid-degrading F. plautii. Mechanistically, DAT promotes mTORC1-dependent activation and proliferation of intestinal stem cells, with concomitant engagement of the innate immune receptor STING required to mitigate metabolic stress and maintain an undifferentiated stem cell state independently of type-I interferon responses. Additionally, DAT can skew T cells towards an effector phenotype to modulate graft-versus-leukemia responses. Our data uncover DAT’s dual, tissue- and immune-modulating properties and underscore its potential in precision microbiome-based therapies to improve tissue regeneration and minimize immune-mediated side effects.

Monitoring urine composition is a valuable method for identifying metabolic disorders and diseases noninvasively. This study analyzed urination events, urine amounts, and urine composition in dairy calves during their first week of life, comparing calves fed dam's milk to calves fed milk replacer. Calves (n = 18) were housed individually in calf hutches and fed twice daily in unlimited amounts their dams' milk for the first 6 feedings, then switched to milk replacer or continued receiving dam's milk. Urine events were recorded by weight difference every 10 s and urine samples were collected quantitatively between feedings and analyzed for various parameters. Calves began urinating on average 10.5 h after birth. Time significantly influenced urine amounts and urination events, increasing from birth to d 7. Treatment did not affect urine excretion or urination events, but sex did, with females excreting less urine due to less feed consumption. Urine constituents were most concentrated immediately after birth, decreasing with increasing feed consumption. Proteinuria was identified in all calves immediately after birth, lasting 58.5 h. High urinary concentrations of purine derivatives indicated high nucleic acid turnover. Significant differences between treatments were absent for most parameters in urine except DM, crude ash, electrical conductivity, salinity, density, and xanthine concentration in milk replacer-fed calves. These findings highlight the dynamic nature of calves' urine composition postnatally and its sensitivity to dietary variations. Understanding these changes is crucial for optimizing feeding strategies to ensure the health and growth of neonatal calves.

Background/Objectives: The gut-microbiota-dependent metabolite trimethylamine-N-oxide (TMAO) has been linked to cardiovascular disease (CVD) risk, while dietary fiber is associated with reduced CVD risk and improved gut health. Considering these associations, we conducted a randomized, double-blind, pilot study to investigate the influence of fiber supplementation on intestinal TMAO formation after beef consumption. Subjects/Methods: 13 volunteers underwent a two-week dietary fiber and placebo intervention. We assessed the effect of fiber supplementation on the gut microbiota and gene abundance of the enzyme cutC, a key enzyme for microbial TMA formation, a precursor for TMAO. We measured the TMAO response following beef consumption after the two-week intervention. We also examined the role of hepatic enzyme FMO3 on TMAO plasma levels. Results: Although overall TMAO production did not change between the dietary fiber and placebo group (p-value = 0.26, 95% CI), subgroup analysis revealed that fiber supplementation attenuated TMAO formation following beef intake in participants with lower habitual meat consumption ( p-value = 0.029, 95% CI). Furthermore, fiber intervention significantly downregulated microbial cutC gene abundance (p = 0.034, 95% CI), suggesting a mechanism by which fiber might reduce plasma TMAO levels. While dietary fiber intervention did not alter TMAO production across all participants, it showed a potential effect in individuals with lower habitual meat intake. The observed downregulation of cutC gene abundance suggests a mechanism for the beneficial impact of fiber on TMAO formation. Conclusion: These findings support the role of a high-fiber, low-meat diet as a promising strategy to mitigate TMAO-related CVD risk.

Early life stress (ELS) can negatively impact health, increasing the risk of stress-related disorders, such as post-traumatic stress disorder (PTSD). Importantly, PTSD disproportionately affects women, emphasizing the critical need to explore how sex differences influence the genetic and metabolic neurobiological pathways underlying trauma-related behaviors. This study uses the limited bedding and nesting (LBN) paradigm to model ELS and investigate its sex-specific effects on fear memory formation. Employing innovative unsupervised behavioral classification, the current study reveals distinct behavioral patterns associated with fear acquisition and retrieval in male and female mice following ELS. Females exposed to LBN display heightened active fear responses, contrasting with males. Furthermore, the study examined the crucial link between behavioral regulation and cellular metabolism in key brain regions involved in fear and stress processing. Sex-specific and stress-dependent alterations were observed in purine, pyrimidine, and glutamate metabolism within the basolateral amygdala, the dorsal hippocampus, and the ventral hippocampus. These findings provide crucial insights into the complex interplay between metabolic pathways, the neurobiological underpinnings of fear memory, and stress responses. Importantly, they emphasize the significance of considering sex-specific metabolic alterations when investigating stress-related disorders, opening potential avenues for the development of targeted interventions.

A multimetabo-lipid-prote-omics workflow was developed to characterize the molecular interplay within proximal (PC) and distal (DC) colonic epithelium of healthy mice. This multiomics data set lays the foundation to better understand the two tissue types and can be used to study, for example, colon-related diseases like colorectal cancer or inflammatory bowel disease. First, the methyl tert-butyl ether extraction method was optimized, so that from a single tissue biopsy >350 reference-matched metabolites, >1850 reference-matched lipids, and >4500 proteins were detected by using targeted and untargeted metabolomics, untargeted lipidomics, and proteomics. Next, each omics-data set was analyzed individually and then merged with the additional omics disciplines to generate a deep understanding of the underlying complex regulatory network within the colon. Our data demonstrates, for example, differences in mucin formation, detected on substrate level as well as on enzyme level, and altered lipid metabolism by the detection of phospholipases hydrolyzing sphingomyelins to ceramides. In conclusion, the combination of the three mass spectrometry-based omics techniques can better entangle the functional and regional differences between PC and DC tissue compared to each single omics technique.

Many neutralophilic bacterial species try to evade acid stress with an escape strategy, which is reflected in the increased expression of genes coding for flagellar components. Extremely acid-tolerant bacteria, such as Escherichia coli , survive the strong acid stress, e.g., in the stomach of vertebrates. Recently, we were able to show that the induction of motility genes in E. coli is strictly dependent on the degree of acid stress, i.e., they are induced under mild acid stress but not under severe acid stress. However, it was not known to what extent fine-tuned expression of motility genes is related to fitness and the ability to survive periods of acid shock. In this study, we demonstrate that the expression of FlhDC, the master regulator of flagellation, is inversely correlated with the acid shock survival of E. coli . We encountered this phenomenon when analyzing mutants from the Keio collection, in which the expression of flhDC was altered by an insertion sequence element. These results suggest a fitness trade-off between acid tolerance and motility. IMPORTANCE: Escherichia coli is extremely acid-resistant, which is crucial for survival in the gastrointestinal tract of vertebrates. Recently, we systematically studied the response of E. coli to mild and severe acidic conditions using Ribo-Seq and RNA-Seq. We found that motility genes are induced at pH 5.8 but not at pH 4.4, indicating stress-dependent synthesis of flagellar components. In this study, we demonstrate that motility-activating mutations upstream of flhDC , encoding the master regulator of flagella genes, reduce the ability of E. coli to survive periods of acid shock. Furthermore, we show an inverse correlation between motility and acid survival using a chromosomal isopropyl β-D-thio-galactopyranoside (IPTG)-inducible flhDC promoter and by sampling differentially motile subpopulations from swim agar plates. These results reveal a previously undiscovered trade-off between motility and acid tolerance and suggest a differentiation of E. coli into motile and acid-tolerant subpopulations, driven by the integration of insertion sequence elements.