Early‐life malnutrition causes gastrointestinal dysmotility that is sexually dimorphic

Abstract

Background: Slow gastrointestinal (GI) transit occurs in moderate-to-severe malnutrition. Mechanisms underlying malnutrition-associated dysmotility remain unknown, partially due to lack of animal models. This study sought to characterize GI dysmotility in mouse models of malnutrition. Methods: Neonatal mice were malnourished by timed maternal separation. Alternatively, low-protein, low-fat diet was administered to dams, with malnourished neonates tested at two weeks or weaned to the same chow and tested as young adults. We determined total GI transit time by carmine red gavage, colonic motility by rectal bead latency, and both gastric emptying and small bowel motility with fluorescein isothiocyanate-conjugated dextran. We assessed histology with light microscopy, ex vivo contractility and permeability with force-transduction and Ussing chamber studies, and gut microbiota composition by 16S rDNA sequencing. Key Results: Both models of neonatal malnutrition and young adult malnourished males but not females exhibited moderate growth faltering, stunting, and grossly abnormal stomachs. Progression of fluorescent dye was impaired in both neonatal models of malnutrition, whereas gastric emptying was delayed only in maternally separated pups and malnourished young adult females. Malnourished young adult males but not females had atrophic GI mucosa, exaggerated intestinal contractile responses, and increased gut barrier permeability. These sex-specific abnormalities were associated with altered gut microbial communities. Conclusions & Inferences: Multiple models of early-life malnutrition exhibit delayed upper GI transit. Malnutrition affects young adult males more profoundly than females. These models will facilitate future studies to identify mechanisms underlying malnutrition-induced pathophysiology and sex-specific regulatory effects.

Coagulopathy in Malnourished Mice Is Sexually Dimorphic and Regulated by Nutrient‐Sensing Nuclear Receptors

“…The altered fecal quantities of secondary bile acids, including deoxycholic acid, ursodeoxycholic acid, and lithocholic acid in the LPLFD male mice also might be due to changes in the gut microbiome, which we recently described in this model. ( 17 )…”

“…The altered fecal quantities of secondary bile acids, including deoxycholic acid, ursodeoxycholic acid, and lithocholic acid in the LPLFD male mice also might be due to changes in the gut microbiome, which we recently described in this model. (17) Chenodeoxycholic acid is the most potent natural FXR agonist, while lithocholic acid and deoxycholic acid also can activate FXR. (18) All three of these FXR agonists were decreased in stool from the LPLFD male mice (Fig.…”

Pathologic Inflammation in Malnutrition Is Driven by Proinflammatory Intestinal Microbiota, Large Intestine Barrier Dysfunction, and Translocation of Bacterial Lipopolysaccharide

“…Oral gavage of mice with low and medium molecular weight fluorescent dextran did not show increased paracellular translocation in MN mice at a time when the dextran would have likely transited to the ileum. However, the report of reduced intestinal mobility in MN mice (28) suggests these data need to be interpreted cautiously. On the other hand, intracolonic delivery of low molecular weight fluorescent dextran revealed increased paracellular translocation in the colon in MN mice.…”

“…Studies in mouse models of undernutrition (protein deficiency) have also focused on the small intestine where a range of severity in histopathological changes, increased intestinal permeability, and altered expression of tight junction proteins and claudins have been shown to be dependent on the level of protein restriction (17). A single study reported increased permeability in duodenum and proximal colon (but not distal colon) in MN male but not female mice (28). None of these studies investigated the impact of undernutrition on the large intestine.…”

“…Fluorescent dextran was quantified in plasma or liver tissue by fluorometry. Ex vivo: Intestinal permeability was quantified in a P2300 Ussing chamber system (Physiologic Instruments, San Diego, CA) as described previously (28). Briefly, full-thickness sections of cecum and colon were harvested and flushed with KBR buffer (in mM: 115 NaCl, 1.2 CaCl 2 , 25 NaHCO 3 , 2.4 K 2 HPO 4 , 0.4 KH 2 PO 4 , 1.2 MgCl 2 , 10 glucose).…”