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A mosaic of cross-phylum chemical interactions occurs between all metazoans and their microbiomes. A number of molecular families that are known to be produced by the microbiome have a marked effect on the balance between health and disease 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 – 9 . Considering the diversity of the human microbiome (which numbers over 40,000 operational taxonomic units 10 ), the effect of the microbiome on the chemistry of an entire animal remains underexplored. Here we use mass spectrometry informatics and data visualization approaches 11 , 12 – 13 to provide an assessment of the effects of the microbiome on the chemistry of an entire mammal by comparing metabolomics data from germ-free and specific-pathogen-free mice. We found that the microbiota affects the chemistry of all organs. This included the amino acid conjugations of host bile acids that were used to produce phenylalanocholic acid, tyrosocholic acid and leucocholic acid, which have not previously been characterized despite extensive research on bile-acid chemistry 14 . These bile-acid conjugates were also found in humans, and were enriched in patients with inflammatory bowel disease or cystic fibrosis. These compounds agonized the farnesoid X receptor in vitro, and mice gavaged with the compounds showed reduced expression of bile-acid synthesis genes in vivo. Further studies are required to confirm whether these compounds have a physiological role in the host, and whether they contribute to gut diseases that are associated with microbiome dysbiosis. Metabolomics data from germ-free and specific-pathogen-free mice reveal effects of the microbiome on host chemistry, identifying conjugations of bile acids that are also enriched in patients with inflammatory bowel disease or cystic fibrosis.

Postnatal growth restriction (PGR) can increase the risk of cardiovascular disease (CVD) potentially due to impairments in oxidative phosphorylation (OxPhos) within cardiomyocyte mitochondria. The purpose of this investigation was to determine if PGR impairs cardiac metabolism, specifically OxPhos. FVB (Friend Virus B‐type) mice were fed a normal‐protein (NP: 20% protein), or low‐protein (LP: 8% protein) isocaloric diet 2 weeks before mating. LP dams produce ∼20% less milk, and pups nursed by LP dams experience reduced growth into adulthood as compared to pups nursed by NP dams. At birth (PN1), pups born to dams fed the NP diet were transferred to LP dams (PGR group) or a different NP dam (control group: CON). At weaning (PN21), all mice were fed the NP diet. At PN22 and PN80, mitochondria were isolated for respirometry (oxygen consumption rate, JO2 ${J_{{{\\mathrm{O}}_{\\mathrm{2}}}$ ) and fluorimetry (reactive oxygen species emission, JH2O2 ${J_{{{\\mathrm{H}}_{\\mathrm{2}}}{{\\mathrm{O}}_{\\mathrm{2}}}$ ) analysis measured as baseline respiration (LEAK) and with saturating ADP (OxPhos). Western blotting at PN22 and PN80 determined protein abundance of uncoupling protein 3, peroxiredoxin‐6, voltage‐dependent anion channel and adenine nucleotide translocator 1 to provide further insight into mitochondrial function. ANOVAs with the main effects of diet, sex and age with α‐level of 0.05 was set a priori. Overall, PGR (7.8 ± 1.1) had significant (P = 0.01) reductions in respiratory control in complex I when compared to CON (8.9 ± 1.0). In general, our results show that PGR led to higher electron leakage in the form of free radical production and reactive oxygen species emission. No significant diet effects were found in protein abundance. The observed reduced respiratory control and increased ROS emission in PGR mice may increase risk for CVD in mice. What is the central question of this study? Postnatal growth restriction (PGR) in early life is associated with cardiovascular disease: what are the mechanisms with regard to oxidative phosphorylation (OxPhos)? What is the main finding and its importance? PGR during development reduces cardiac metabolism through impairments in OxPhos. Our results show the PGR heart has higher electron leakage in the form of free radical production and reactive oxygen species emission. These findings are associated with an increased risk for cardiovascular disease in adulthood. Simply put, a brief period of growth restriction in early life has long‐lasting effects on cardiac metabolism in adulthood.

Early life growth-restriction is a significant global issue, with over 161 million children experiencing growth-restriction under the age of 5 years. Undernutrition induced growth restriction during postnatal life (PNGR) is characterized by permanent stunting of growth and is associated with increased risk of developing cardiometabolic disease in adulthood. Additionally, PNGR significantly reduces exercise capacity in adulthood, further increasing the risk for chronic disease development. Exercise is beneficial in preventing and treating cardiometabolic disease, however, evidence characterizing the metabolic effects of exercise in the PNGR population is limited. Furthermore, it has become increasingly evident from recent literature that metabolism is impacted not only by host biochemical pathways but also that from the gut microbiome. Human metabolism should be studied from a holistic approach including impacts from microbial residents of the gut, human tissues, and the interplay between both entities. There is also evidence that the gut microbiome plays a role in exercise adaptations, both of which are altered as a response to PNGR as previously shown in mice. Recent studies have investigated the effects of high-intensity interval training (HIIT) in comparison to more commonly tested moderate-intensity continuous exercise protocols which resulted in more pronounced health benefits and in a shorter timeframe, especially in individuals with chronic disease. Until now, however, HIIT has yet to be tested in the PNGR population, as well as its effects on the microbiome and metabolome. The three objectives of this dissertation were to 1) determine the effect of a HIIT intervention on maximal exercise capacity (Wmax) in adult PNGR mice as compared to controls (CON), 2) to determine the effects of HIIT on the microbial compositions in PNGR and CON, and 3) to determine the effects of HIIT on the gut and serum metabolome in PNGR and CON. For the first objective, exercise capacity (Wmax) was assessed via maximal treadmill tests performed at baseline, after one week of training, and post-intervention. Wmax data analyzed via repeated measures ANOVA between baseline and post-intervention revealed improvements in all treatment groups. HIIT resulted in showed greater positive improvements in CON compared to PNGR and in males as compared to their respective female counterparts. HIIT was successful in improving Wmax in PNGR, which has yet to be shown in previous studies utilizing this mouse model. Future work is encouraged to further examine physiological aspects allowing adaptation to HIIT in areas such as skeletal muscle or cardiovascular differentiation with training in PNGR compared to CON.To accomplish the second objective, fecal samples were used to profile the gut microbiome. It was hypothesized that HIIT in CON and PNGR would increase microbial diversity as well as enrichment of unique taxa compared to their SED counterparts. Majority of the microbial differences, aside from a few genre and species differences, were not significant between treatment groups. Two microbes Christenellacae g.s. and Clostridiacae g.s. were altered in response to HIIT, although their specific roles in exercise capacity or adaptation are currently not clear.To accomplish the third objective, fecal and serum samples collected post-intervention were processed for untargeted metabolomics. The effects of HIIT on host metabolism was evidently differential in PNGR compared to CON, with alternate patterns of heme, glutathione and acylcarnitine abundances post-intervention. Despite exposure to 4-weeks of HIIT, PNGR retained downregulated essential amino acids, acylcarnitines, glutathione and heme, all of which are potentially important components in the process of exercise adaptations. To summarize, PNGR leads to reduced exercise capacity which improves with HIIT, although the metabolome remains significantly altered compared to CON. By accomplishing the objectives of this dissertation, a more comprehensive profile of the metabolic baseline as well as responses to HIIT were characterized. It is encouraged that future studies further examine and compare the cardiovascular, skeletal muscle and mitochondrial activities in response to HIIT to determine where the alterations in metabolome derive from in PNGR.

INTRODUCTION. Growth restriction induced by undernutrition in early life increases the risk of developing chronic diseases in adulthood. We hypothesized growth restriction would alter the gut microbiome and metabolome across the lifespan, impairing vital growth signaling processes necessary for proper development, with a primary focus on muscular and hepatic Insulin-like Growth Factor (IGF-1) expression. METHODS. A cross-fostering, protein-restricted nutritive model (8% protein) was used to induce undernutrition during gestation (GUN) or lactation (PUN). At 21 days of age (PN21), all mice were weaned to a control diet (CON; 20% protein), isolating undernutrition to specific windows of early life. Fecal samples were collected weekly PN18-PN80 to determine longitudinal programming effects of growth restriction on the gut microbiome (CON N = 5, GUN N = 6, PUN N = 6) and metabolome. Fecal sample DNA was extracted for amplification of the bacterial 16S rRNA genes using PCR, and then the amplicons were sequenced with the Illumina pipeline and analyzed using the Qiita bioinformatics software. Cecum samples were also collected at PN21 (CON N = 4, GUN N = 6, PUN N = 5) and PN80 (CON N = 5, GUN N = 6, PUN N = 6) for microbiome analysis. Liver samples were collected at PN21(CON N = 12, GUN N = 6, PUN N = 7) and PN80 (CON N = 13, GUN N = 9, PUN N = 11) and analyzed along with the cecum for metabolomics via tandem mass spectrometry (LC-MS/MS) and analyzed with the Global Natural Products Social Molecular Networking (GNPS) bioinformatics software. IGF-1 expression in the liver and gastrocnemius (CON N = 15, GUN N = 12, PUN N = 13) was analyzed via a Total Protein NIR western blot to establish a connection between the gut microbiome, tissue metabolome and organ growth. RESULTS. The Beta-Diversity of the fecal microbiome was significantly separated by treatment group using Weighted UniFrac measures (PERMANOVA p = 0.0001). Differences in the microbiome were not evident through analysis at the Phylum level (Firmicutes/Bacteroidetes ratio) but were instead driven by longitudinal alterations in the abundance of specific genera and species in PUN. Linear mixed model (LMM) analysis revealed PUN having significantly higher abundance of specific bacteria compared to GUN and CON across the lifespan including: Bacteroides uniformis, B. acidifaciens, B. ovatus, Bifidobacterium sp. and Clostridium sacchrogumia. Rikenellaceae was the only microbe that was significantly lower in abundance in the PUN group over time compared to GUN and CON. Additionally, the PUN metabolome was significantly altered compared to GUN and CON, primarily characterized by reduced: essential amino acids (EAAs: methionine, phenylalanine and tyrosine), riboflavin (B2), primary bile acids, and decreased Dehydroepiandrosterone (DHEA); and increased acylcarnitines and fecal peptides. NIR Western blot analysis revealed significantly lower IGF-1 expression in the liver at PN21 in GUN (p = 0.0012) and PUN (p < 0.001) as well as overall lower expression in the muscle in PUN (p = 0.037) and GUN (p = 0.007) compared to CON. CONCLUSION. The gut microbiome and metabolome are altered by early life growth restriction at PN21 and through adulthood. Elevated sugar-fermenting bacteria in the PUN group represent gut microbiome immaturity and delayed development. Temporary metabolic alterations of early life growth restriction are seen in decreased primary bile acids and increased synthesis of liver acylcarnitines, both of which are indicative as adaptations of the pups being calorie-restricted as a result of the low-protein fed dam. More permanent outcomes of growth restriction were evident by increased peptide excretion over the lifespan, significantly decreased methionine and riboflavin–which prevented protein synthesis to occur during early life development, and overall decreased muscle IGF-1 expression and DHEA levels in the PUN mice. Many of the metabolic pathways permanently altered by growth restriction are seen in the liver, making this organ an important site for future research on the development of treatment modalities that can limit growth restriction induced chronic disease.

Educators and researchers recognize that each individual prefers their own different learning styles. Learning styles are defined as a set of factors that aid individuals in learning. Knowing one's learning styles can help develop study strategies to compensate for weaknesses and capitalize on strengths. Providing students, especially students in the beginning of their collegiate career, tools to aid in their learning experience can assist in setting them up for success. This study investigates the unique nature of anatomy courses by examining the preferred learning styles of undergraduate anatomy students, as well as their lecture delivery method of choice throughout the course. Students enrolled in Anatomy 2300 Human Anatomy, a large enrollment undergraduate anatomy course offered through the Division of Anatomy at The Ohio State University – Columbus Campus, were given the opportunity to complete the Index of Learning Styles (ILS) questionnaire developed by Drs. Richard Felder and Barbara Solomon, along with a short demographics survey. Afterwards, each participant was provided with their personalized learning styles scores on each of the four dimensions of learning styles (i.e. active/reflective, sensing/intuitive, visual/verbal, and sequential/global; as indicated by the ILS questionnaire), as well as information about study strategies for each of the four dimensions. Additional data collected included lecture delivery method of choice, demographic information, highest ACT composite scores, and anatomy written examination scores. Data analyses indicated that the students enrolled in Anatomy 2300 Human Anatomy were generally active, sensing, visual, and sequential learners, although a learning styles profile was constructed for the students in each of the declared majors/programs enrolled in the course which showed minor variation in the active/reflective dimension. In terms of gender differences for learning styles, statistical analyses indicated that females preferred an active learning style more so over males, who preferred a reflective learning style, while there was no statistical difference when comparing the genders in the other learning style dimensions. The results of the study also indicated that academic achievement, when controlling for academic ability, was only statically predicted by the active/reflective dimension in the head and neck curricular unit. Results of the different lecture delivery method choices indicated that for all three units, the most commonly chosen lecture delivery method was the online only method, followed by face-to-face only, and, lastly the mixture of both online and face-to-face. It was also found that only the sensing/intuitive dimension was statistically significant in predicting the lecture delivery method. The results also indicated individuals who utilized the face-to-face only lecture delivery method had higher examination scores over those who chose either of the other methods. There was no difference between the genders and their lecture delivery method of choice, although results indicated that there was a difference between the Pre-Nursing and Pre-Medicine majors, as well as between the Pre-Nursing and Pre-Health Science majors in their choice of lecture delivery method. Implications for anatomy instructors, undergraduate students, and future research are discussed.