Advances in Antimicrobial Peptide Discovery via Machine Learning and Delivery via Nanotechnology

Antimicrobial peptides (AMPs) have been investigated for their potential use as an alternative to antibiotics due to the increased demand for new antimicrobial agents. AMPs, widely found in nature and obtained from microorganisms, have a broad range of antimicrobial protection, allowing them to be applied in the treatment of infections caused by various pathogenic microorganisms. Since these peptides are primarily cationic, they prefer anionic bacterial membranes due to electrostatic interactions. However, the applications of AMPs are currently limited owing to their hemolytic activity, poor bioavailability, degradation from proteolytic enzymes, and high-cost production. To overcome these limitations, nanotechnology has been used to improve AMP bioavailability, permeation across barriers, and/or protection against degradation. In addition, machine learning has been investigated due to its time-saving and cost-effective algorithms to predict AMPs. There are numerous databases available to train machine learning models. In this review, we focus on nanotechnology approaches for AMP delivery and advances in AMP design via machine learning. The AMP sources, classification, structures, antimicrobial mechanisms, their role in diseases, peptide engineering technologies, currently available databases, and machine learning techniques used to predict AMPs with minimal toxicity are discussed in detail

Tejaas: reverse regression increases power for detecting trans-eQTLs

Trans-acting expression quantitative trait loci (trans-eQTLs) account for ≥70% expression heritability and could therefore facilitate uncovering mechanisms underlying the origination of complex diseases. Identifying trans-eQTLs is challenging because of small effect sizes, tissue specificity, and a severe multiple-testing burden. Tejaas predicts trans-eQTLs by performing L2-regularized “reverse” multiple regression of each SNP on all genes, aggregating evidence from many small trans-effects while being unaffected by the strong expression correlations. Combined with a novel unsupervised k-nearest neighbor method to remove confounders, Tejaas predicts 18851 unique trans-eQTLs across 49 tissues from GTEx. They are enriched in open chromatin, enhancers, and other regulatory regions. Many overlap with disease-associated SNPs, pointing to tissue-specific transcriptional regulation mechanisms.Fil: Banerjee, Saikat. Max Planck Institute For Biophysical Chemistry; AlemaniaFil: Simonetti, Franco Lucio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina. Max Planck Institute For Biophysical Chemistry; AlemaniaFil: Detrois, Kira E.. Max Planck Institute For Biophysical Chemistry; Alemania. Universität Göttingen; AlemaniaFil: Kaphle, Anubhav. Universität Göttingen; Alemania. Max Planck Institute For Biophysical Chemistry; AlemaniaFil: Mitra, Raktim. Indian Institute of Technology; IndiaFil: Nagial, Rahul. Indian Institute of Technology; IndiaFil: Söding, Johannes. Max Planck Institute For Biophysical Chemistry; Alemania. University of Göttingen; Alemani

Clostridium Hiranonis, a Bile Acid 7α-Dehydroxylating Bacterium in Dogs

Bile acids (BAs) are bioactive molecules that are crucial for the absorption of fat-soluble nutrients and regulation of host metabolism, including glucose, lipid, and energy homeostasis. BAs are synthesized in the liver and are further metabolized by microbiota in the gut. Previous studies have shown that an alteration of gastrointestinal microbiota, referred to as dysbiosis, can alter the bile acid profiles. This aim of this project was to identify and characterize Clostridium hiranonis, a bile acid 7α-dehydroxylating bacterium from canine feces, and to study the association between C. hiranonis and secondary bile acids (SBAs). Firstly, this study evaluated the fecal microbiome of dogs with exocrine pancreatic insufficiency (EPI) based on 16S rRNA sequencing. The fecal microbiota of dogs with EPI was different when compared to healthy control dogs. In dogs with EPI, the bacterial families, Lachnospiraceae and Ruminococcaceae were decreased, while Lactobacillus, Bifidobacterium, and Enterococcus were increased in dogs with EPI. At the species level, Blautia producta, Clostridium hiranonis, Faecalibacterium prausnitzii, Ruminoccocus gnavus, and Collinsella stercoris were decreased in dogs with EPI. Secondly, this study isolated, identified, and characterized C. hiranonis from canine feces. The canine isolates were similar to the reference strain C. hiranonis DSM 13275 based on morphological, biochemical, and fatty acid profiles. Based on whole genome sequencing results, these isolates possess genes for the enzymes choloylglycine hydrolase, and bile acid 7α- dehydratase, which are essential for deconjugation and bile acid 7α-dehydroxylation of primary bile acids. Finally, this study examined the correlation between C. hiranonis and SBAs in canine fecal samples. Results show that C. hiranonis and SBA concentrations are significantly correlated in canine feces. The ROC analysis showed that the fecal abundance of C. hiranonis can be used to discern between normal and low fecal SBAs with a sensitivity of 88% and specificity of 90% in dogs. In conclusion, this is the first study to isolate and characterize C. hiranonis from canine feces and to find a significant correlation between SBA concentrations and abundance of C. hiranonis in canine feces

CROSSTALK BETWEEN GASTROINTESTINAL EPITHELIAL CELLS AND RESIDENT MICROBIOTA PROMOTES IMMUNE HOMEOSTASIS

The gastrointestinal tract houses one of the most dense and diverse communities of bacteria on the planet. The mutualistic relationship between the host and commensal microbe permits the microbe an ideal environment to grow and provides the host with increased caloric intake, maturation of the adaptive immune system, and resistance against invading pathogens. To maintain a system in which both parties benefit, the epithelium has evolved numerous strategies to ensure epithelial cells respond to microbes appropriately and that potentially hazardous commensals remain distanced from the soma proper. Breakdown of these propitiating mechanisms elicits unchecked inflammation and can lead to pathology and reduction of host fitness. We show that oral and intestinal epithelial cells respond to the circulating hormone adiponectin in the presence of bacterial constituents, and that adiponectin has the potential to downregulate NF-κB signaling. We also show many commensal bacteria have no effect on TNF or IL-8 proinflammatory gene expression in intestinal cells. Commensals within the family Enterobacteriaceae can increase TNF and IL-8 expression, but also expression of the NF-κB regulator A20 and MAPK phosphatase MKP-1. Importantly, Enterobacteriaceae also increased expression of the IgA transporter pIgR. In the mouse model, we show pIgR expression along the intestinal epithelium is necessary for SIgA accumulation in the outer mucus layer where commensal bacteria reside. Loss of the mucus layer, but not pIgR is sufficient to allow direct bacterial-epithelial cell contact and induce spontaneous inflammation along the colon. Secretory IgA is supplied maternally through breast milk early in life to compensate for the neonate’s inability to produce sufficient endogenous amounts. By utilizing a breeding scheme in which mouse dams were unable to provide their offspring with SIgA, we show the necessity of maternally-supplied SIgA to control bacterial invasion to mesenteric lymph nodes before weaning. In addition, 8-10 week old adult offspring not receiving SIgA as neonates showed both a unique intestinal microbiota and different patterns of intestinal epithelial cell gene expression with and without chemically-induced acute colitis. In summary, we reveal new mechanisms the mammalian host utilizes in order to maintain peace between the commensal microbe and host immune system