Browsing by Author "Schmidt, Nathan W."
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Item Creation of a non-Western humanized gnotobiotic mouse model through the transplantation of rural African fecal microbiota(American Society for Microbiology, 2023) Van Den Ham, Kristin M.; Little, Morgan R.; Bednarski, Olivia J.; Fusco, Elizabeth M.; Mandal, Rabindra K.; Mitra, Riten; Li, Shanping; Doumbo, Safiatou; Doumtabe, Didier; Kayentao, Kassoum; Ongoiba, Aissata; Traore, Boubacar; Crompton, Peter D.; Schmidt, Nathan W.; Pediatrics, School of MedicineThere is increasing evidence that microbes residing within the intestines (gut microbiota) play important roles in the well-being of humans. Yet, there are considerable challenges in determining the specific role of gut microbiota in human diseases owing to the complexity of diverse internal and environmental factors that can contribute to diseases. Mice devoid of all microorganisms (germ-free mice) can be colonized with human stool samples to examine the specific contribution of the gut microbiota to a disease. These approaches have been primarily focused on stool samples obtained from individuals in Western countries. Thus, there is limited understanding as to whether the same methods used to colonize germ-free mice with stool from Western individuals would apply to the colonization of germ-free mice with stool from non-Western individuals. Here, we report the results from colonizing germ-free mice with stool samples of Malian children.Item Dynamic modulation of spleen germinal center reactions by gut bacteria during Plasmodium infection(Cell Press, 2021-05-11) Mandal, Rabindra K.; Denny, Joshua E.; Namazzi, Ruth; Opoka, Robert O.; Datta, Dibyadyuti; John, Chandy C.; Schmidt, Nathan W.; Pediatrics, School of MedicineGut microbiota educate the local and distal immune system in early life to imprint long-term immunological outcomes while maintaining the capacity to dynamically modulate the local mucosal immune system throughout life. It is unknown whether gut microbiota provide signals that dynamically regulate distal immune responses following an extra-gastrointestinal infection. We show here that gut bacteria composition correlated with the severity of malaria in children. Using the murine model of malaria, we demonstrate that parasite burden and spleen germinal center reactions are malleable to dynamic cues provided by gut bacteria. Whereas antibiotic-induced changes in gut bacteria have been associated with immunopathology or impairment of immunity, the data demonstrate that antibiotic-induced changes in gut bacteria can enhance immunity to Plasmodium. This effect is not universal but depends on baseline gut bacteria composition. These data demonstrate the dynamic communications that exist among gut bacteria, the gut-distal immune system, and control of Plasmodium infection.Item Dysbiotic lung microbial communities of neonates from allergic mothers confer neonate responsiveness to suboptimal allergen(Frontiers Media, 2023-03-10) Bloodworth, Jeffery C.; Hoji, Aki; Wolff, Garen; Mandal, Rabindra K.; Schmidt, Nathan W.; Deshane, Jessy S.; Morrow, Casey D.; Kloepfer, Kirsten M.; Cook-Mills, Joan M.; Pediatrics, School of MedicineIn humans and animals, offspring of allergic mothers have increased responsiveness to allergens. This is blocked in mice by maternal supplementation with α-tocopherol (αT). Also, adults and children with allergic asthma have airway microbiome dysbiosis with increased Proteobacteria and may have decreased Bacteroidota. It is not known whether αT alters neonate development of lung microbiome dysbiosis or whether neonate lung dysbiosis modifies development of allergy. To address this, the bronchoalveolar lavage was analyzed by 16S rRNA gene analysis (bacterial microbiome) from pups of allergic and non-allergic mothers with a basal diet or αT-supplemented diet. Before and after allergen challenge, pups of allergic mothers had dysbiosis in lung microbial composition with increased Proteobacteria and decreased Bacteroidota and this was blocked by αT supplementation. We determined whether intratracheal transfer of pup lung dysbiotic microbial communities modifies the development of allergy in recipient pups early in life. Interestingly, transfer of dysbiotic lung microbial communities from neonates of allergic mothers to neonates of non-allergic mothers was sufficient to confer responsiveness to allergen in the recipient pups. In contrast, neonates of allergic mothers were not protected from development of allergy by transfer of donor lung microbial communities from either neonates of non-allergic mothers or neonates of αT-supplemented allergic mothers. These data suggest that the dysbiotic lung microbiota is dominant and sufficient for enhanced neonate responsiveness to allergen. Importantly, infants within the INHANCE cohort with an anti-inflammatory profile of tocopherol isoforms had an altered microbiome composition compared to infants with a pro-inflammatory profile of tocopherol isoforms. These data may inform design of future studies for approaches in the prevention or intervention in asthma and allergic disease early in life.Item Gut Bacteroides act in a microbial consortium to cause susceptibility to severe malaria(Springer, 2023-10-13) Mandal, Rabindra K.; Mandal, Anita; Denny, Joshua E.; Namazii, Ruth; John, Chandy C.; Schmidt, Nathan W.; Pediatrics, School of MedicineMalaria is caused by Plasmodium species and remains a significant cause of morbidity and mortality globally. Gut bacteria can influence the severity of malaria, but the contribution of specific bacteria to the risk of severe malaria is unknown. Here, multiomics approaches demonstrate that specific species of Bacteroides are causally linked to the risk of severe malaria. Plasmodium yoelii hyperparasitemia-resistant mice gavaged with murine-isolated Bacteroides fragilis develop P. yoelii hyperparasitemia. Moreover, Bacteroides are significantly more abundant in Ugandan children with severe malarial anemia than with asymptomatic P. falciparum infection. Human isolates of Bacteroides caccae, Bacteroides uniformis, and Bacteroides ovatus were able to cause susceptibility to severe malaria in mice. While monocolonization of germ-free mice with Bacteroides alone is insufficient to cause susceptibility to hyperparasitemia, meta-analysis across multiple studies support a main role for Bacteroides in susceptibility to severe malaria. Approaches that target gut Bacteroides present an opportunity to prevent severe malaria and associated deaths.Item Gut Bacteroides act in a microbial consortium to cause susceptibility to severe malaria(Springer Nature, 2023-10-13) Mandal, Rabindra K.; Mandal, Anita; Denny, Joshua E.; Namazii, Ruth; John, Chandy C.; Schmidt, Nathan W.; Pediatrics, School of MedicineMalaria is caused by Plasmodium species and remains a significant cause of morbidity and mortality globally. Gut bacteria can influence the severity of malaria, but the contribution of specific bacteria to the risk of severe malaria is unknown. Here, multiomics approaches demonstrate that specific species of Bacteroides are causally linked to the risk of severe malaria. Plasmodium yoelii hyperparasitemia-resistant mice gavaged with murine-isolated Bacteroides fragilis develop P. yoelii hyperparasitemia. Moreover, Bacteroides are significantly more abundant in Ugandan children with severe malarial anemia than with asymptomatic P. falciparum infection. Human isolates of Bacteroides caccae, Bacteroides uniformis, and Bacteroides ovatus were able to cause susceptibility to severe malaria in mice. While monocolonization of germ-free mice with Bacteroides alone is insufficient to cause susceptibility to hyperparasitemia, meta-analysis across multiple studies support a main role for Bacteroides in susceptibility to severe malaria. Approaches that target gut Bacteroides present an opportunity to prevent severe malaria and associated deaths.Item Gut Microbial Changes Associated With Obesity in Youth With Type 1 Diabetes(Oxford University Press, 2025) Ismail, Heba M.; Perera, Dimuthu; Mandal, Rabindra; DiMeglio, Linda A.; Evans-Molina, Carmella; Hannon, Tamara; Petrosino, Joseph; Javornik Cregeen, Sara; Schmidt, Nathan W.; Pediatrics, School of MedicineContext: Obesity is prevalent in type 1 diabetes (T1D) and is problematic with higher risk for diabetes complications. It is unknown to what extent gut microbiome changes are associated with obesity and T1D. Objective: This work aimed to describe the gut microbiome and microbial metabolite changes associated with obesity in T1D. We hypothesized statistically significant gut microbial and metabolite differences in lean T1D youth (body mass index [BMI]: 5%-<85%) vs those with obesity (BMI: ≥95%). Methods: We analyzed stool samples for gut microbial (using metagenomic shotgun sequencing) and short-chain fatty acid (SCFA) differences in lean (n = 27) and obese (n = 21) T1D youth in a pilot study. The mean ± SD age was 15.3 ± 2.2 years, glycated hemoglobin A1c 7.8 ± 1.3%, diabetes duration 5.1 ± 4.4 years, 42.0% female, and 94.0% were White. Results: Bacterial community composition showed between sample diversity differences (β-diversity) by BMI group (P = .013). There was a higher ratio of Prevotella to Bacteroides in the obese group (P = .0058). There was a differential distribution of significantly abundant taxa in either the lean or obese groups, including increased relative abundance of Prevotella copri, among other taxa in the obese group. Functional profiling showed an upregulation of branched-chain amino acid (BCAA) biosynthesis in the obese group and upregulation of BCAA degradation, tyrosine metabolism, and secondary bile acid biosynthesis in the lean group. Stool SCFAs were higher in the obese vs the lean group (P < .05 for all). Conclusion: Our findings identify a gut microbiome and microbial metabolite signature associated with obesity in T1D. These findings could help identify gut microbiome-targeted therapies to manage obesity in T1D.Item The gut microbiome, immunity, and Plasmodium severity(Elsevier, 2020-12) Waide, Morgan L.; Schmidt, Nathan W.; Pediatrics, School of MedicineMalaria continues to pose a severe threat to over half of the world's population each year. With no long-term, effective vaccine available and a growing resistance to antimalarials, there is a need for innovative methods of Plasmodium treatment. Recent evidence has pointed to a role of the composition of the gut microbiota in the severity of Plasmodium infection in both animal models and human studies. Further evidence has shown that the gut microbiota influences the adaptive immune response of the host, the arm of the immune system necessary for Plasmodium clearance, sustained Plasmodium immunity, and vaccine efficacy. Together, this illustrates the future potential of gut microbiota modulation as a novel method of preventing severe malaria.Item Gut Microbiota Composition Modulates the Magnitude and Quality of Germinal Centers during Plasmodium Infections(Cell Press, 2020-12-15) Waide, Morgan L.; Polidoro, Rafael; Powell, Whitney L.; Denny, Joshua E.; Kos, Justin; Tieri, David A.; Watson, Corey T.; Schmidt, Nathan W.; Pediatrics, School of MedicineGut microbiota composition is associated with human and rodent Plasmodium infections, yet the mechanism by which gut microbiota affects the severity of malaria remains unknown. Humoral immunity is critical in mediating the clearance of Plasmodium blood stage infections, prompting the hypothesis that mice with gut microbiota-dependent decreases in parasite burden exhibit better germinal center (GC) responses. In support of this hypothesis, mice with a low parasite burden exhibit increases in GC B cell numbers and parasite-specific antibody titers, as well as better maintenance of GC structures and a more targeted, qualitatively different antibody response. This enhanced humoral immunity affects memory, as mice with a low parasite burden exhibit robust protection against challenge with a heterologous, lethal Plasmodium species. These results demonstrate that gut microbiota composition influences the biology of spleen GCs as well as the titer and repertoire of parasite-specific antibodies, identifying potential approaches to develop optimal treatments for malaria.Item Hypertension Increases Susceptibility to Experimental Malaria in Mice(Oxford University Press, 2024-02-28) Kandalgaonkar, Mrunmayee R.; Yeoh, Beng San; Joe, Bina; Schmidt, Nathan W.; Vijay-Kumar, Matam; Saha, Piu; Pediatrics, School of MedicineGlobal prevalence of hypertension is on the rise, burdening healthcare, especially in developing countries where infectious diseases, such as malaria, are also rampant. Whether hypertension could predispose or increase susceptibility to malaria, however, has not been extensively explored. Previously, we reported that hypertension is associated with abnormal red blood cell (RBC) physiology and anemia. Since RBC are target host cells for malarial parasite, Plasmodium, we hypothesized that hypertensive patients with abnormal RBC physiology are at greater risk or susceptibility to Plasmodium infection. To test this hypothesis, normotensive (BPN/3J) and hypertensive (BPH/2J) mice were characterized for their RBC physiology and subsequently infected with Plasmodium yoelii (P. yoelii), a murine-specific non-lethal strain. When compared to BPN mice, BPH mice displayed microcytic anemia with RBC highly resistant to osmotic hemolysis. Further, BPH RBC exhibited greater membrane rigidity and an altered lipid composition, as evidenced by higher levels of phospholipids and saturated fatty acid, such as stearate (C18:0), along with lower levels of polyunsaturated fatty acid like arachidonate (C20:4). Moreover, BPH mice had significantly greater circulating Ter119+ CD71+ reticulocytes, or immature RBC, prone to P. yoelii infection. Upon infection with P. yoelii, BPH mice experienced significant body weight loss accompanied by sustained parasitemia, indices of anemia, and substantial increase in systemic pro-inflammatory mediators, compared to BPN mice, indicating that BPH mice were incompetent to clear P. yoelii infection. Collectively, these data demonstrate that aberrant RBC physiology observed in hypertensive BPH mice contributes to an increased susceptibility to P. yoelii infection and malaria-associated pathology.Item Innate immune activation restricts priming and protective efficacy of the radiation-attenuated PfSPZ malaria vaccine(American Society for Clinical Investigation, 2024-04-30) Senkpeil, Leetah; Bhardwaj, Jyoti; Little, Morgan R.; Holla, Prasida; Upadhye, Aditi; Fusco, Elizabeth M.; Swanson, Phillip A., II; Wiegand, Ryan E.; Macklin, Michael D.; Bi, Kevin; Flynn, Barbara J.; Yamamoto, Ayako; Gaskin, Erik L.; Sather, D. Noah; Oblak, Adrian L.; Simpson, Edward; Gao, Hongyu; Haining, W. Nicholas; Yates, Kathleen B.; Liu, Xiaowen; Murshedkar, Tooba; Richie, Thomas L.; Sim, B. Kim Lee; Otieno, Kephas; Kariuki, Simon; Xuei, Xiaoling; Liu, Yunlong; Polidoro, Rafael B.; Hoffman, Stephen L.; Oneko, Martina; Steinhardt, Laura C.; Schmidt, Nathan W.; Seder, Robert A.; Tran, Tuan M.; Medicine, School of MedicineA systems analysis was conducted to determine the potential molecular mechanisms underlying differential immunogenicity and protective efficacy results of a clinical trial of the radiation-attenuated whole-sporozoite PfSPZ vaccine in African infants. Innate immune activation and myeloid signatures at prevaccination baseline correlated with protection from P. falciparum parasitemia in placebo controls. These same signatures were associated with susceptibility to parasitemia among infants who received the highest and most protective PfSPZ vaccine dose. Machine learning identified spliceosome, proteosome, and resting DC signatures as prevaccination features predictive of protection after highest-dose PfSPZ vaccination, whereas baseline circumsporozoite protein-specific (CSP-specific) IgG predicted nonprotection. Prevaccination innate inflammatory and myeloid signatures were associated with higher sporozoite-specific IgG Ab response but undetectable PfSPZ-specific CD8+ T cell responses after vaccination. Consistent with these human data, innate stimulation in vivo conferred protection against infection by sporozoite injection in malaria-naive mice while diminishing the CD8+ T cell response to radiation-attenuated sporozoites. These data suggest a dichotomous role of innate stimulation for malaria protection and induction of protective immunity by whole-sporozoite malaria vaccines. The uncoupling of vaccine-induced protective immunity achieved by Abs from more protective CD8+ T cell responses suggests that PfSPZ vaccine efficacy in malaria-endemic settings may be constrained by opposing antigen presentation pathways.