Ruth Schade

All Publications

• Manipulation of feeding patterns in high fat diet fed rats improves microbiota composition dynamics, inflammation and gut-brain signaling. Physiology & behavior Klingbeil, E. A., Schade, R., Lee, S. H., Kirkland, R., de La Serre, C. B. 2024; 285: 114643

  Abstract

  Chronic consumption of high fat (HF) diets has been shown to increase meal size and meal frequency in rodents, resulting in overeating. Reducing meal frequency and establishing periods of fasting, independently of caloric intake, may improve obesity-associated metabolic disorders. Additionally, diet-driven changes in microbiota composition have been shown to play a critical role in the development and maintenance of metabolic disorders. In this study, we used a pair-feeding paradigm to reduce meal frequency and snacking episodes while maintaining overall intake and body weight in HF fed rats. We hypothesized that manipulation of feeding patterns would improve microbiota composition and metabolic outcomes. Male Wistar rats were placed in three groups consuming either a HF, low fat diet (LF, matched for sugar), or pair-fed HF diet for 7 weeks (n = 11-12/group). Pair-fed animals received the same amount of food consumed by the HF fed group once daily before dark onset (HF-PF). Rats underwent oral glucose tolerance and gut peptide cholecystokinin sensitivity tests. Bacterial DNA was extracted from the feces collected during both dark and light cycles and sequenced via Illumina MiSeq sequencing of the 16S V4 region. Our pair-feeding paradigm reduced meal numbers, especially small meals in the inactive phase, without changing total caloric intake. This shift in feeding patterns reduced relative abundances of obesity-associated bacteria and maintained circadian fluctuations in microbial abundances. These changes were associated with improved gastrointestinal (GI) function, reduced inflammation, and improved glucose tolerance and gut to brain signaling. We concluded from these data that targeting snacking may help improve metabolic outcomes, independently of energy content of the diet and hyperphagia.

  View details for DOI 10.1016/j.physbeh.2024.114643

  View details for PubMedID 39059597

• Transcriptional profiling links unique human macrophage phenotypes to the growth of intracellular Salmonella enterica serovar Typhi. Scientific reports Schade, R., Butler, D. S., McKenna, J. A., Di Luccia, B., Shokoohi, V., Hamblin, M., Pham, T. H., Monack, D. M. 2024; 14 (1): 12811

  Abstract

  Macrophages provide a crucial environment for Salmonella enterica serovar Typhi (S. Typhi) to multiply during typhoid fever, yet our understanding of how human macrophages and S. Typhi interact remains limited. In this study, we delve into the dynamics of S. Typhi replication within human macrophages and the resulting heterogeneous transcriptomic responses of macrophages during infection. Our study reveals key factors that influence macrophage diversity, uncovering distinct immune and metabolic pathways associated with different stages of S. Typhi intracellular replication in macrophages. Of note, we found that macrophages harboring replicating S. Typhi are skewed towards an M1 pro-inflammatory state, whereas macrophages containing non-replicating S. Typhi exhibit neither a distinct M1 pro-inflammatory nor M2 anti-inflammatory state. Additionally, macrophages with replicating S. Typhi were characterized by the increased expression of genes associated with STAT3 phosphorylation and the activation of the STAT3 transcription factor. Our results shed light on transcriptomic pathways involved in the susceptibility of human macrophages to intracellular S. Typhi replication, thereby providing crucial insight into host phenotypes that restrict and support S. Typhi infection.

  View details for DOI 10.1038/s41598-024-63588-6

  View details for PubMedID 38834738

  View details for PubMedCentralID 6376096

• The gut-brain axis mediates bacterial driven modulation of reward signaling. Molecular metabolism Kim, J. S., Williams, K. C., Kirkland, R. A., Schade, R., Freeman, K. G., Cawthon, C. R., Rautmann, A. W., Smith, J. M., Edwards, G. L., Glenn, T. C., Holmes, P. V., de Lartigue, G., de La Serre, C. B. 2023; 75: 101764

  Abstract

  Our goal is to investigate if microbiota composition modulates reward signaling and assess the role of the vagus in mediating microbiota to brain communication.Male germ-free Fisher rats were colonized with gastrointestinal contents from chow (low fat (LF) ConvLF) or HF (ConvHF) fed rats.Following colonization, ConvHF rats consumed significantly more food than ConvLF animals. ConvHF rats displayed lower feeding-induced extracellular DOPAC levels (a metabolite of dopamine) in the Nucleus Accumbens (NAc) as well as reduced motivation for HF foods compared to ConvLF rats. Dopamine receptor 2 (DDR2) expression levels in the NAc were also significantly lower in ConvHF animals. Similar deficits were observed in conventionally raised HF fed rats, showing that diet-driven alteration in reward can be initiated via microbiota. Selective gut to brain deafferentation restored DOPAC levels, DRD2 expression, and motivational drive in ConvHF rats.We concluded from these data that a HF-type microbiota is sufficient to alter appetitive feeding behavior and that bacteria to reward communication is mediated by the vagus nerve.

  View details for DOI 10.1016/j.molmet.2023.101764

  View details for PubMedID 37380023

  View details for PubMedCentralID PMC10372379

• Salmonella enterica serovar Typhi uses two type 3 secretion systems to replicate in human macrophages and colonize humanized mice. mBio Hamblin, M., Schade, R., Narasimhan, R., Monack, D. M. 2023: e0113723

  Abstract

  Salmonella enterica serovar Typhi (S. Typhi) is a human-restricted pathogen that replicates in macrophages. In this study, we investigated the roles of the S. Typhi type 3 secretion systems (T3SSs) encoded on Salmonella pathogenicity islands (SPI)-1 (T3SS-1) and SPI-2 (T3SS-2) during human macrophage infection. We found that mutants of S. Typhi deficient for both T3SSs were defective for intramacrophage replication as measured by flow cytometry, viable bacterial counts, and live time-lapse microscopy. T3SS-secreted proteins PipB2 and SifA contributed to S. Typhi replication and were translocated into the cytosol of human macrophages through both T3SS-1 and T3SS-2, demonstrating functional redundancy for these secretion systems. Importantly, an S. Typhi mutant strain that is deficient for both T3SS-1 and T3SS-2 was severely attenuated in the ability to colonize systemic tissues in a humanized mouse model of typhoid fever. Overall, this study establishes a critical role for S. Typhi T3SSs during its replication within human macrophages and during systemic infection of humanized mice. IMPORTANCE Salmonella enterica serovar Typhi is a human-restricted pathogen that causes typhoid fever. Understanding the key virulence mechanisms that facilitate S. Typhi replication in human phagocytes will enable rational vaccine and antibiotic development to limit the spread of this pathogen. While S. Typhimurium replication in murine models has been studied extensively, there is limited information available about S. Typhi replication in human macrophages, some of which directly conflict with findings from S. Typhimurium murine models. This study establishes that both of S. Typhi's two type 3 secretion systems (T3SS-1 and T3SS-2) contribute to intramacrophage replication and virulence.

  View details for DOI 10.1128/mbio.01137-23

  View details for PubMedID 37341487

• Rat offspring's microbiota composition is predominantly shaped by the postnatal maternal diet rather than prenatal diet. Physiology & behavior Schade, R., Song, L., Cordner, Z. A., Ding, H., Peterson, D. A., Moran, T. H., Tamashiro, K. L., Serre, C. l. 2022; 258: 113987

  Abstract

  This study assessed the impact of maternal diet during pregnancy versus lactation on offspring gut microbiota. Sprague-Dawley dams were fed high fat (HF) or Chow diets during pregnancy, and their male offspring were raised by a different dam consuming the same or opposite diet (Chow-Chow, Chow-HF, HF-Chow, and HF-HF). Microbiota analysis showed that maternal lactation diet, rather than pregnancy diet, determined offspring microbiota profiles at weaning. Increased abundances of Turicibacter, Staphylococcus , and Ruminococcus were characteristic of chow lactation groups. Lactococcus , Streptococcus , and Parabacteroides were characteristic of HF lactation groups and positively correlated with offspring body weight.

  View details for DOI 10.1016/j.physbeh.2022.113987

  View details for PubMedID 36198343

• Gut microbial taxa elevated by dietary sugar disrupt memory function. Translational psychiatry Noble, E. E., Olson, C. A., Davis, E., Tsan, L., Chen, Y. W., Schade, R., Liu, C., Suarez, A., Jones, R. B., de La Serre, C., Yang, X., Hsiao, E. Y., Kanoski, S. E. 2021; 11 (1): 194

  Abstract

  Emerging evidence highlights a critical relationship between gut microbiota and neurocognitive development. Excessive consumption of sugar and other unhealthy dietary factors during early life developmental periods yields changes in the gut microbiome as well as neurocognitive impairments. However, it is unclear whether these two outcomes are functionally connected. Here we explore whether excessive early life consumption of added sugars negatively impacts memory function via the gut microbiome. Rats were given free access to a sugar-sweetened beverage (SSB) during the adolescent stage of development. Memory function and anxiety-like behavior were assessed during adulthood and gut bacterial and brain transcriptome analyses were conducted. Taxa-specific microbial enrichment experiments examined the functional relationship between sugar-induced microbiome changes and neurocognitive and brain transcriptome outcomes. Chronic early life sugar consumption impaired adult hippocampal-dependent memory function without affecting body weight or anxiety-like behavior. Adolescent SSB consumption during adolescence also altered the gut microbiome, including elevated abundance of two species in the genus Parabacteroides (P. distasonis and P. johnsonii) that were negatively correlated with hippocampal function. Transferred enrichment of these specific bacterial taxa in adolescent rats impaired hippocampal-dependent memory during adulthood. Hippocampus transcriptome analyses revealed that early life sugar consumption altered gene expression in intracellular kinase and synaptic neurotransmitter signaling pathways, whereas Parabacteroides microbial enrichment altered gene expression in pathways associated with metabolic function, neurodegenerative disease, and dopaminergic signaling. Collectively these results identify a role for microbiota "dysbiosis" in mediating the detrimental effects of early life unhealthy dietary factors on hippocampal-dependent memory function.

  View details for DOI 10.1038/s41398-021-01309-7

  View details for PubMedID 33790226

  View details for PubMedCentralID PMC8012713