Oral conditions are relatively common in patients with inflammatory bowel disease (IBD). However, the contribution of oral maladies to gut inflammation remains unexplored. Here, we investigated the impact of periodontitis on disease phenotypes of IBD patients. In all, 60 IBD patients (42 with ulcerative colitis [UC] and 18 with Crohn’s disease [CD]) and 45 non-IBD healthy controls (HCs) were recruited for this clinical investigation. The effects of incipient periodontitis on the oral and gut microbiome, IBD characteristics were examined. In addition, patients were prospectively monitored up to 12 months after enrollment. We found that in both UC and CD patients, the gut microbiome was significantly more similar to the oral microbiome than in HCs, suggesting that ectopic gut colonization by oral bacteria is increased in IBD patients. Incipient periodontitis did not further enhance gut colonization by oral bacteria. The presence of incipient periodontitis did not significantly affect the clinical outcomes of UC and CD patients. However, the short Crohn’s disease activity index increased in CD patients with incipient periodontitis but declined or unchanged during the study period in patients without periodontitis. Thus, early periodontitis may associate with worse clinically symptoms in some patients with CD.
Jin Imai, Hitoshi Ichikawa, Sho Kitamoto, Jonathan L. Golob, Motoki Kaneko, Junko Nagata, Miho Takahashi, Merritt G. Gillilland, Rika Tanaka, Hiroko Nagao-Kitamoto, Atsushi Hayashi, Kohei Sugihara, Shrinivas Bishu, Shingo Tsuda, Hiroyuki Ito, Seiichiro Kojima, Kazunari Karakida, Masashi Matsushima, Takayoshi Suzuki, Katsuto Hozumi, Norihito Watanabe, William V. Giannobile, Takayuki Shirai, Hidekazu Suzuki, Nobuhiko Kamada
Cerebral malaria (CM) affects children and adults, but brain swelling is more severe in children. To investigate features associated with brain swelling in malaria, we performed blood profiling and brain MRI in a cohort of pediatric and adult patients with CM in Rourkela, India, and compared them with an African pediatric CM cohort in Malawi. We determined that higher plasma Plasmodium falciparum histidine rich protein 2 (PfHRP2) levels and elevated var transcripts that encode for binding to endothelial protein C receptor (EPCR) were linked to CM at both sites. Machine learning models trained on the African pediatric cohort could classify brain swelling in Indian children CM cases but had weaker performance for adult classification, due to overall lower parasite var transcript levels in this age group and more severe thrombocytopenia in Rourkela adults. Subgrouping of patients with CM revealed higher parasite biomass linked to severe thrombocytopenia and higher Group A–EPCR var transcripts in mild thrombocytopenia. Overall, these findings provide evidence that higher parasite biomass and a subset of Group A–EPCR binding variants are common features in children and adult CM cases, despite age differences in brain swelling.
Praveen K. Sahu, Fergal J. Duffy, Selasi Dankwa, Maria Vishnyakova, Megharay Majhi, Lukas Pirpamer, Vladimir Vigdorovich, Jabamani Bage, Sameer Maharana, Wilson Mandala, Stephen J. Rogerson, Karl B. Seydel, Terrie E. Taylor, Kami Kim, D. Noah Sather, Akshaya Mohanty, Rashmi R. Mohanty, Anita Mohanty, Rajyabardhan Pattnaik, John D. Aitchison, Angelika Hoffman, Sanjib Mohanty, Joseph D. Smith, Maria Bernabeu, Samuel C. Wassmer
BACKGROUND. Catheterization facilitates continuous bacteriuria, for which the clinical significance remains unclear. This study aimed to determine the clinical presentation, epidemiology, and dynamics of bacteriuria in a cohort of long-term catheterized nursing home residents. METHODS. Prospective urine culture, urinalysis, chart review, and assessment of signs and symptoms of infection were performed weekly for 19 study participants over 7 months. All bacteria ≥103 cfu/ml were cultured, isolated, identified, and tested for susceptibility to select antimicrobials. RESULTS. 226 of the 234 urines were polymicrobial (97%), with an average of 4.7 isolates per weekly specimen. 228 urines (97%) exhibited ≥106 CFU/ml, 220 (94%) exhibited abnormal urinalysis, 126 (54%) were associated with at least one possible sign or symptom of infection, 82 (35%) would potentially meet a standardized definition of CAUTI, but only 3 had a caregiver diagnosis of CAUTI. 286 (30%) of bacterial isolates were resistant to a tested antimicrobial agent, and bacteriuria composition was remarkably stable despite a combined total of 54 catheter changes and 23 weeks of antimicrobial use. CONCLUSIONS. Bacteriuria composition was largely polymicrobial, including persistent colonization by organisms previously considered to be urine culture contaminants. Neither antimicrobial use nor catheter changes sterilized the urine, at most resulting in transient reductions in bacterial burden followed by new acquisition of resistant isolates. Thus, this patient population exhibits a high prevalence of bacteriuria coupled with potential indicators of infection, necessitating further exploration to identify sensitive markers of true infection. FUNDING. This work was supported by the NIH (R00 DK105205, R01 DK123158, UL1 TR001412)
Chelsie E. Armbruster, Aimee L. Brauer, Monica S. Humby, Jiahui Shao, Saptarshi Chakraborty
The syndrome of spontaneous preterm birth (sPTB) presents a challenge to mechanistic understanding, effective risk stratification, and management. Individual associations between sPTB, ethnicity, vaginal microbiota, metabolome and innate immune response are known, but not fully understood and knowledge has yet to impact clinical practice. Here we use multi-data type integration and composite statistical models to gain insight into sPTB risk by exploring the cervicovaginal environment of an ethnically heterogenous pregnant population (n=346 women; n=60 sPTB <37 weeks’ gestation, including n=27 sPTB <34 weeks). Analysis of cervicovaginal samples (10-15+6 weeks) identified novel interactions between risk of sPTB and microbiota, metabolite, and maternal host defense molecules. Statistical modelling identified a composite of metabolites (leucine, tyrosine, aspartate, lactate, betaine, acetate and Ca2+) associated with risk of sPTB <37 weeks (Area Under the Curve - AUC 0.752). A combination of glucose, aspartate, Ca2+ and Lactobacillus crispatus and L. acidophilus relative abundance, identified risk of early sPTB <34 weeks, (AUC 0.758); improved by ethnicity stratification (AUC 0.835). Increased relative abundance of L. acidophilus appeared protective against sPTB <34 weeks. By using cervicovaginal fluid samples, we demonstrate the potential of multi-datatype integration for developing composite models towards understanding the contribution of the vaginal environment to risk of sPTB.
Flavia Flaviani, Natasha L. Hezelgrave, Tokuwa Kanno, Erica M. Prosdocimi, Evonne Chin-Smith, Alexandra E. Ridout, Djuna K. von Maydell, Vikash Mistry, William G. Wade, Andrew H. Shennan, Konstantina Dimitrakopoulou, Paul T. Seed, Andrew James Mason, Rachel M. Tribe
Background: The fungal cell-wall constituent 1,3-beta-D-glucan (BDG) is a pathogen-associated molecular pattern that can stimulate innate immunity. We hypothesized that BDG from colonizing fungi in critically-ill patients may translocate into the systemic circulation and be associated with host inflammation and outcomes. Methods: We enrolled 453 mechanically-ventilated patients with acute respiratory failure (ARF) without invasive fungal infection and measured BDG, innate immunity and epithelial permeability biomarkers in serially collected plasma samples. Results: Compared to healthy controls, ARF patients had significantly higher BDG levels (median [interquartile-range] 26 [15-49]pg/ml, p<0.001), whereas ARF patients with high BDG levels (≥40pg/ml, 31%) had higher odds for assignment to the prognostically adverse hyperinflammatory subphenotype (odds ratio [confidence interval] 2.88 [1.83-4.54], p<0.001). Baseline BDG levels were predictive of fewer ventilator-free days and worse 30-day survival (adjusted p<0.05). Integrative analyses of fungal colonization and epithelial barrier disruption suggested that BDG may translocate from either the lung or gut compartment. We validated the associations between plasma BDG and host inflammatory responses in 97 hospitalized patients with COVID-19. Conclusions: BDG measurements offered prognostic information in critically-ill patients without fungal infections. Further research in the mechanisms of translocation and innate immunity recognition and stimulation may offer new therapeutic opportunities in critical illness.
Georgios D. Kitsios, Daniel Kotok, Haopu Yang, Malcolm A. Finkelman, Yonglong Zhang, Noel Britton, Xiaoyun Li, Marina S. Levochkina, Amy K. Wagner, Caitlin Schaefer, John J. Villandre, Rui Guo, John W. Evankovich, William Bain, Faraaz Shah, Yingze Zhang, Barbara A. Methé, Panayiotis V. Benos, Bryan J. McVerry, Alison Morris
TNFRSF13B encodes the "transmembrane-activator and CAML-interactor" (TACI) receptor, which drives plasma cell differentiation. Although TNFRSF13B supports host defense, dominant-negative TNFRSF13B alleles are common in humans and other species and only rarely associate with disease. We reasoned the high frequency of disruptive TNFRSF13B alleles reflects balancing selection, the loss of function conferring advantage in some settings. Testing that concept, we asked whether and how a common human dominant negative variant, TNFRSF13B A181E, imparts resistance to enteric pathogens. Mice engineered to express mono-allelic or bi-allelic A144E variants of tnrsf13B, corresponding to A181E exhibited striking resistance to pathogenicity and transmission of C. rodentium, a murine pathogen that models enterohemorrhagic E. coli, and resistance was principally owed to deficiency of natural IgA in the intestine. In wild type mice with gut IgA and in mutant mice fed IgA, binding of Ig induces expression of LEE encoded virulence genes, which confer pathogenicity and transmission. C. rodentium and probably some other enteric organisms thus appropriated binding of otherwise protective antibodies to signal induction of the virulence program and the high prevalence of TNFRSF13B dominant negative variants thus reflects balancing selection.
Jeffrey L. Platt, Mayara Garcia de Mattos Barbosa, Daniel Huynh, Adam R. Lefferts, Juhi Katta, Cyra Kharas, Peter L. Freddolino, Christine Marie Bassis, Christiane E. Wobus, Raif Geha, Richard J. Bram, Gabriel Nunez, Nobuhiko Kamada, Marilia Cascalho
Chagas disease is caused by infection with the protozoan parasite Trypanosoma cruzi (T. cruzi), an intracellular pathogen that causes significant morbidity and death among millions in the Americas from Canada to Argentina. Current therapy involves oral administration of the nitroimidazole benznidazole (BNZ), which has serious side effects that often necessitate cessation of treatment. To both avoid off-target side effects and reduce the necessary dosage of BNZ, we packaged the drug within poly(ethylene glycol)-block-poly(propylene sulfide) polymersomes (BNZ-PSs). We show that these vesicular nanocarriers enhanced intracellular delivery to phagocytic cells and tested this formulation in a mouse model of T. cruzi infection. BNZ-PS is not only nontoxic but also significantly more potent than free BNZ, effectively reducing parasitemia, intracellular infection, and tissue parasitosis at a 466-fold lower dose of BNZ. We conclude that BNZ-PS was superior to BNZ for treatment of T. cruzi infection in mice and that further modifications of this nanocarrier formulation could lead to a wide range of custom controlled delivery applications for improved treatment of Chagas disease in humans.
Xiaomo Li, Sijia Yi, Débora B. Scariot, Santiago J. Martinez, Ben A. Falk, Cheryl L. Olson, Patricia S. Romano, Evan A. Scott, David M. Engman
Gut microbe–derived metabolites influence human physiology and disease. However, establishing mechanistic links between gut microbial metabolites and disease pathogenesis in animal models remains challenging. The major route of absorption for microbe-derived small molecules is venous drainage via the portal vein to the liver. In the event of presystemic hepatic metabolism, the route of metabolite administration becomes critical. To our knowledge, we describe here a novel portal vein cannulation technique using a s.c. implanted osmotic pump to achieve continuous portal vein infusion in mice. We first administered the microbial metabolite trimethylamine (TMA) over 4 weeks, during which increased peripheral plasma levels of TMA and its host liver-derived cometabolite, trimethylamine-N-oxide, were observed when compared with a vehicle control. Next, 4-hydroxyphenylacetic acid (4-HPAA), a microbial metabolite that undergoes extensive presystemic hepatic metabolism, was administered intraportally to examine effects on hepatic gene expression. As expected, hepatic levels of 4-HPAA were elevated when compared with the control group while peripheral plasma 4-HPAA levels remained the same. Moreover, significant changes in the hepatic transcriptome were revealed by an unbiased RNA-Seq approach. Collectively, to our knowledge this work describes a novel method for administering gut microbe–derived metabolites via the portal vein, mimicking their physiologic delivery in vivo.
Danny Orabi, Lucas J. Osborn, Kevin Fung, William Massey, Anthony J. Horak III, Federico Aucejo, Ibrahim Choucair, Beckey DeLucia, Zeneng Wang, Jan Claesen, J. Mark Brown
The drive to withstand environmental stresses and defend against invasion is a universal trait extant in all forms of life. While numerous canonical signaling cascades have been characterized in detail, it remains unclear how these pathways interface to generate coordinated responses to diverse stimuli. To dissect these connections, we follow heparanase (HPSE), a protein best known for its endoglycosidic activity at the extracellular matrix but recently recognized to drive various forms of late stage disease through unknown mechanisms. Using herpes simplex virus-1 (HSV-1) infection as a model cellular perturbation, we demonstrate that HPSE acts beyond its established enzymatic role to restrict multiple forms of cell-intrinsic defense and facilitate host cell reprogramming by the invading pathogen. We reveal that cells devoid of HPSE are innately resistant to infection and counteract viral takeover through multiple amplified defense mechanisms. With a unique grasp of the fundamental processes of transcriptional regulation and cell death, HPSE represents a potent cellular intersection with broad therapeutic potential.
Alex Agelidis, Benjamin A. Turturice, Rahul K. Suryawanshi, Tejabhiram Yadavalli, Dinesh Jaishankar, Joshua Ames, James Hopkins, Lulia Koujah, Chandrashekhar D. Patil, Satvik R. Hadigal, Evan J. Kyzar, Anaamika Campeau, Jacob M. Wozniak, David J. Gonzalez, Israel Vlodavsky, Jin-ping Li, David L. Perkins, Patricia W. Finn, Deepak Shukla
BACKGROUND Identifying factors conferring responses to therapy in cancer is critical to select the best treatment for patients. For immune checkpoint inhibition (ICI) therapy, mounting evidence suggests that the gut microbiome can determine patient treatment outcomes. However, the extent to which gut microbial features are applicable across different patient cohorts has not been extensively explored.METHODS We performed a meta-analysis of 4 published shotgun metagenomic studies (Ntot = 130 patients) investigating differential microbiome composition and imputed metabolic function between responders and nonresponders to ICI.RESULTS Our analysis identified both known microbial features enriched in responders, such as Faecalibacterium as the prevailing taxa, as well as additional features, including overrepresentation of Barnesiella intestinihominis and the components of vitamin B metabolism. A classifier designed to predict responders based on these features identified responders in an independent cohort of 27 patients with the area under the receiver operating characteristic curve of 0.625 (95% CI: 0.348–0.899) and was predictive of prognosis (HR = 0.35, P = 0.081).CONCLUSION These results suggest the existence of a fecal microbiome signature inherent across responders that may be exploited for diagnostic or therapeutic purposes.FUNDING This work was funded by the Knut and Alice Wallenberg Foundation, BioGaia AB, and Cancerfonden.
Angelo Limeta, Boyang Ji, Max Levin, Francesco Gatto, Jens Nielsen
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