Leveraging inter-individual transcriptional correlation structure to infer discrete signaling mechanisms across metabolic tissues.

Inter-organ communication is a vital process to maintain physiologic homeostasis, and its dysregulation contributes to many human diseases. Given that circulating bioactive factors are stable in serum, occur naturally, and are easily assayed from blood, they present obvious focal molecules for therapeutic intervention and biomarker development. Recently, studies have shown that secreted proteins mediating inter-tissue signaling could be identified by 'brute force' surveys of all genes within RNA-sequencing measures across tissues within a population. Expanding on this intuition, we reasoned that parallel strategies could be used to understand how individual genes mediate signaling across metabolic tissues through correlative analyses of gene variation between individuals. Thus, comparison of quantitative levels of gene expression relationships between organs in a population could aid in understanding cross-organ signaling. Here, we surveyed gene-gene correlation structure across 18 metabolic tissues in 310 human individuals and 7 tissues in 103 diverse strains of mice fed a normal chow or high-fat/high-sucrose (HFHS) diet. Variation of genes such as FGF21, ADIPOQ, GCG, and IL6 showed enrichments which recapitulate experimental observations. Further, similar analyses were applied to explore both within-tissue signaling mechanisms (liver PCSK9) and genes encoding enzymes producing metabolites (adipose PNPLA2), where inter-individual correlation structure aligned with known roles for these critical metabolic pathways. Examination of sex hormone receptor correlations in mice highlighted the difference of tissue-specific variation in relationships with metabolic traits. We refer to this resource as gene-derived correlations across tissues (GD-CAT) where all tools and data are built into a web portal enabling users to perform these analyses without a single line of code (gdcat.org). This resource enables querying of any gene in any tissue to find correlated patterns of genes, cell types, pathways, and network architectures across metabolic organs.

Microbiome modulation, microbiome protein metabolism index, and growth performance of broilers supplemented with a precision biotic.

The objectives of the present studies were to evaluate: 1) the in vivo impact of the supplementation with a precision biotic (PB) on the growth performance and microbiome modulation of broiler chickens; 2) the role of PB on the modulation of functional pathways of the microbiome collected from animals with low and high body weight gain, and 3) to develop a Microbiome Protein Metabolism Index (MPMI) derived from gut metagenomic data to link microbial protein metabolism with performance. The in vivo work consisted of 2 experiments with 2 treatments: Control vs. PB at 1.1 kg/MT of PB with 21 or 14 replicates of 40 birds per replicate, in experiments 1 and 2, respectively. Growth performance was evaluated in both experiments, and from experiment 1, cecal samples from one bird/replicate was collected on d 21 and 42 (n = 21/treatment) to evaluate the microbiome through whole genome sequencing. In the ex vivo assay, 6 cecal samples were collected from low body weight (BW) birds (at 10% below average), and 6 samples from high BW birds (at least 10% above average). The samples were incubated in the presence or absence of PB. After incubation, DNA was isolated to develop a functional genomic assay and the supernatant was separated to measure short-chain fatty acid (SCFA) production. The MPMI is the sum of beneficial genes in the pathways related to protein metabolism. In the in vivo grow out experiments, it was observed that the supplementation improved the BW gain by 3% in both studies, and the corrected feed conversion ratio (cFCR) by 3.7 and 3.4% in studies 1 and 2, respectively (P < 0.05). The functional microbiome analysis revealed that the PB shifted the microbiome pathways toward a beneficial increase in protein utilization, as shown by higher MPMI. In the ex vivo experiment, the PB increased the abundance of genes related to the beneficial metabolism of protein (quantitative MPMI), and the concentration of SCFA, regardless of the underline BW of the birds. Taken together, the microbiome metabolic shift observed in the in vivo study and higher MPMI, plus the observations from the ex vivo assay with higher SFCA production, may explain the improvement in growth performance obtained with the supplementation of PB.

Evaluation of a Novel Precision Biotic on Enterohepatic Health Markers and Growth Performance of Broiler Chickens under Enteric Challenge.

This study evaluated the supplementation of a precision biotic (PB) on the enterohepatic health markers and growth performance of broiler chickens undergoing an enteric challenge. In the first study, three treatments were used: Unchallenged Control (UC); Challenged Control (CC; dietary challenge and 10× dose of coccidia vaccine); and a challenged group supplemented with PB (1.3 kg/ton). In the second study, three treatments were used: control diet, diet supplemented with Avilamycin (10 ppm), and a diet supplemented with PB (0.9 kg/ton). All the birds were exposed to natural challenge composed by dietary formulation and reused litter from a coccidiosis positive flock. In Trial 1, PB decreased ileal histological damage, increased villi length, and the expression of SLC5A8 in ileal tissue versus CC; it reduced ileal expression of IL-1ß compared to both UC and CC treatments. PB increased the expression of cell cycling gene markers CCNA2 and CDK2 in the ileum compared to CC. In Trial 2, PB improved the growth performance, intestinal lesion scores and intestinal morphology of broiler chickens. These results indicate that birds supplemented with PB are more resilient to enteric challenges, probably by its action in modulating microbiome metabolic pathways related to nitrogen metabolism and protein utilization.