Biology subjects

Guthrie, G.

Publications and source records attributed to Guthrie, G..

4 recordsLinked to original sources

bioRxiv2026

Evaluation of a Novel Recombinant Human Protein Formula Compared to Donor Human Milk and Standard Formula in Neonatal Piglets

BackgroundDespite the advancements in infant nutrition, a gap still exists in the nutritional composition bioactive ingredients between infant formula and human milk. We developed a next-generation, proof-of-concept infant formula that contains recombinant human milk proteins. ObjectiveTo determine the impact of a novel infant formula (H1) on organ growth and development, and intestinal function compared to donor human milk (DHM) and standard infant formula (S) in a term piglet model. MethodsTerm piglets delivered via cesarean section were fed either a donor human milk (DHM) control, the investigational formula (H1), or infant formula (S) for 10 days. On d 10, a blood sample and tissues were collected. ResultsThere was no difference (P > 0.05) in piglet growth, although H1 piglets had a smaller relative stomach and liver than DHM and S piglets. H1 piglets had higher (P < 0.05) interleukins in the distal ileum, but no other systemic cytokines were elevated compared to the DHM and S piglets. H1 piglet small intestinal histology was similar (P > 0.05) to that of DHM and S piglets. Additionally, H1 piglets had either the same (P > 0.05) or higher (P < 0.05) amino acids in circulation compared to DHM and S piglets. Recombinant human proteins had either similar (P > 0.05) or lower (P < 0.05) activity compared to the native human proteins when assessing the individual ingredients in the H1 formula. ConclusionH1 formula was noninferior to DHM and S based on growth, small intestinal histology and plasma amino acid endpoints when fed to neonatal piglets. These findings warrant further studies to use the neonatal piglet as a model to evaluate more in-depth outcomes of health and safety for new infant formulas. Lay SummaryA novel piglet study shows a hypoallergenic, next-generation infant formula containing recombinant human milk proteins rivals donor human milk and standard formula for growth, gut health, and nutrient status.

physiology↗

bioRxiv2026

ERRγ deletion in podocytes accelerates aging related kidney disease

We have recently demonstrated that treatment of aged mice with a pan-ERR agonist reverses age-related increase in urinary albumin, decrease in podocyte density, impaired mitochondrial function, and inflammation. The contribution of individual isoforms of ERRs however has not been determined. Since the aging kidney showed a possible compensatory increased expression of ERR{gamma} in the podocytes, in the face of decreased ERR expression, in the present study we aimed to determine the role of ERR{gamma} in aging podocyte. To this end, we cross bred ERR{gamma} floxed mice with podocin-Cre mice to achieve a podocyte-specific ERR{gamma} deletion. While these mice at 3 months of age showed no effect on albuminuria compared to the wild type, when the mice were aged to 21 months of age, there was a significant increase in albuminuria and decrease in podocyte density. Furthermore, we found that the podocyte deletion of ERR{gamma} primarily targeted the expression of mitochondrial biogenesis regulator PGC-1, and mitochondrial fatty acid oxidation enzymes CPT1a and MCAD in the kidney. Electron Microscopy (EM) revealed thickened glomerular basement membrane and diffuse podocyte foot process effacement, as well as severe mitochondrial damage including cristae abnormalities, fragmentation, and changes indicative of altered fusion and fission dynamics. Fluorescence Lifetime Imaging Microscopy (FLIM) to determine NADH and FAD lifetimes indicate a metabolic shift from mitochondrial oxidative phosphorylation towards glycolysis, and decrease in mitochondrial redox capacity. Considering a significantly decreased expression of ERR in aging podocytes plus its traditional role in mitochondrial function, these studies using podocyte ERR{gamma} deletion suggested an overlapping mechanism for ERR/ERR{gamma} to act as modulators of age-related mitochondrial dysfunction and age-related kidney disease.

pharmacology and toxicology↗

bioRxiv2025

Pre- and postnatal 1,4-phenylene di-isothiocyanate treatment does not induce bile duct injury in neonatal pigs

BackgroundBiliary atresia (BA) is the leading cause of pediatric liver transplants, however; the cause of biliary atresia (BA) is unknown. Furthermore, the most common treatment for this disease is with a surgical procedure, which has a greater than 50% failure rate after 5 years. Due to a lack of proper animal models to study the pathology of the disease, little progress has been made in the field. ObjectiveThe objective of this study was to test whether pre and postnatal 1,4-phenylene di-isothiocyanate (DITC) would induce bile duct injury and cholestasis in neonatal pigs. MethodsPregnant sows received DITC once at gestation week 5 (100 mg/kg; n=2), or 3 times at gestation weeks 5, 6, and 7 (100 mg/kg each; n=2), or twice per week at gestation weeks 5-16 (15 mg/kg each; n=2). Cesarian-delivered piglets of the sows were randomly assigned to receive approximately 200 mg/kg DITC on days two, four, and six of life or to remain untreated. Piglets were fed enterally and collected blood samples were monitored for markers of liver injury for 14 days. At the end of 14 days, tissues were weighed and collected for immunohistochemistry and histopathology scoring. ResultsPiglets from sows that received DITC for 11 weeks had lower (P < 0.05) final body weight and daily gain compared to other treatments. Piglets from sows that received DITC for 11 weeks had a transient increase in gamma-glutamyl transferase. Liver histological scoring and analysis also did not show signs of BA. Piglets that received DITC from 11-week DITC-treated sows had elevated hepatic bile acids (P < 0.05), but there was no difference in serum bile acids (P > 0.05). ConclusionsThe administration of DITC to pregnant sows and neonatal piglets did not result in the development of bile duct or hepatic injury.

pathology↗

bioRxiv2024

Selective Agonism of Liver and Gut FXR Prevents Cholestasis and Intestinal Atrophy in Parenterally Fed Neonatal Pigs

BACKGROUND & AIMSWe aimed to investigate the relative efficacy of feeding different bile acids in preventing PNALD in neonatal pigs. METHODSNewborn pigs given total parenteral nutrition (TPN) combined with minimal enteral feeding of chenodeoxycholic acid (CDCA), or increasing doses of obeticholic acid (OCA) for 19 days. RESULTSEnteral OCA (5 and 15 mg/kg), but not CDCA (30 mg/kg) reduced blood cholestasis markers compared to TPN controls and increased bile acids in the gallbladder and intestine. Major bile acids in the liver and distal intestine were CDCA, HCA, HDCA and OCA, and their relative proportions were increased by the type of bile acid (CDCA or OCA) given enterally. High doses of OCA increased the total NR1H4-agonistic bile acid profile in the liver and intestine above 50% total bile acids. Both CDCA and OCA treatments suppressed hepatic cyp7a1 expression, but only OCA increased hepatobiliary transporters, ABCB11, ABCC$ and ABCB1. Plasma phytosterol levels were reduced and biliary levels were increased by CDCA and OCA and hepatic sterol transporters, abcg5/8, expression were increased by OCA. Both CDCA and OCA increased plasma FGF19 and OCA increased intestinal FGF19, FABP6, and SLC51A. Both CDCA and OCA increased intestinal mucosal growth, whereas CDCA increased the plasma GLP-2, GLP-1 and GIP. CONCLUSIONSEnteral OCA prevented cholestasis and phytosterolemia by increased hepatic bile acid and sterol transport via induction of hepatobiliary transporter FXR target genes and not by suppression of bile acid synthesis genes. We also showed an intestinal trophic action of OCA that demonstrates a dual clinical benefit of FXR agonism in the prevention of PNALD in piglets.

physiology↗