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Impact of Maternal Malnutrition on Gut Barrier Defense: Implications for Pregnancy Health and Fetal Development

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Impact of Maternal Malnutrition on Gut Barrier Defense: Implications for Pregnancy Health and Fetal Development

Sebastian A Srugo et al. Nutrients.

Abstract

Small intestinal Paneth cells, enteric glial cells (EGC), and goblet cells maintain gut mucosal integrity, homeostasis, and influence host physiology locally and through the gut-brain axis. Little is known about their roles during pregnancy, or how maternal malnutrition impacts these cells and their development. Pregnant mice were fed a control diet (CON), undernourished by 30% vs. control (UN), or fed a high fat diet (HF). At day 18.5 (term = 19), gut integrity and function were assessed by immunohistochemistry and qPCR. UN mothers displayed reduced mRNA expression of Paneth cell antimicrobial peptides (AMP; Lyz2, Reg3g) and an accumulation of villi goblet cells, while HF had reduced Reg3g and mucin (Muc2) mRNA and increased lysozyme protein. UN fetuses had increased mRNA expression of gut transcription factor Sox9, associated with reduced expression of maturation markers (Cdx2, Muc2), and increased expression of tight junctions (TJ; Cldn-7). HF fetuses had increased mRNA expression of EGC markers (S100b, Bfabp, Plp1), AMP (Lyz1, Defa1, Reg3g), and TJ (Cldn-3, Cldn-7), and reduced expression of an AMP-activator (Tlr4). Maternal malnutrition altered expression of genes that maintain maternal gut homeostasis, and altered fetal gut permeability, function, and development. This may have long-term implications for host-microbe interactions, immunity, and offspring gut-brain axis function.

Keywords: development; gut barrier; malnutrition; pregnancy.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Maternal malnutrition was associated with altered gene expression of antimicrobial peptides and mucin. Maternal UN was associated with decreased mRNA expression of antimicrobial peptide genes Lyz2 (p = 0.02) and Reg3g (p = 0.003) vs. CON, while HF diet was associated with decreased Reg3g (p = 0.003) and mucin (Muc2; p = 0.001) mRNA expression vs. CON (n = 6–8/group). Groups with different letters are significantly different (p < 0.05). UN, undernourished; HF, high fat; CON, control.
Figure 2
Figure 2
Maternal malnutrition may influence small intestinal goblet cell number. (A) Staining of goblet cells by alcian blue in small intestine (20× magnification). Arrows indicate goblet cells. Mean number of goblet cells across 8 villi (B) or crypts (C). Mean percentage of goblet cells (proportion of total number of epithelial cells) in villi (D) or crypts (E). There were a greater number of goblet cells in UN villi vs. CON (p = 0.008; n = 6–8/group). Groups with different letters are significantly different (p < 0.05). UN, undernourished; HF, high fat; CON, control.
Figure 3
Figure 3
Maternal HF diet was associated with less low-intensity lysozyme staining in intestinal crypts. (A) Representative images of lysozyme protein immunoreactivity (ir) staining show localization to the crypts of the maternal small intestine (SI) at d18.5, with negative control inset (40× magnification). Arrows indicate lysozyme proteins within Paneth cells. (BE) Lyz staining was quantified into low, moderate, high, and strong intensities, representing increasing levels of protein expression (n = 6–8/group). Semi-quantitative analysis revealed less low-intensity Lyz staining in SI from HF mothers (p = 0.03) vs. CON, and an overall difference in moderate-intensity Lyz staining (p = 0.04), but no difference between groups with post hoc testing. Groups with different letters are significantly different (p < 0.05). UN, undernourished; HF, high fat; CON, control.
Figure 4
Figure 4
UN fetuses displayed activation of a gut transcription factor that represses gut barrier development and mucus production. Maternal UN was associated with increased fetal gut mRNA expression of Sox9 (p = 0.02) vs. CON, and decreased Muc2 (p = 0.002) and Cdx2 (p = 0.003) vs. CON (n = 8–15/group). Groups with different letters are significantly different (p < 0.05). UN, undernourished; HF, high fat; CON, control.
Figure 5
Figure 5
HF fetuses showed activation of enteric glial cell markers in the gut. Maternal HF diet was associated with increased fetal gut mRNA expression of enteric glial cells (EGC) markers S100b (p < 0.001) and Bfabp (p = 0.003) vs. CON, and Plp1 (p = 0.04) vs. UN (n = 7–15/group). Groups with different letters are significantly different (p < 0.05). UN, undernourished; HF, high fat; CON, control.
Figure 6
Figure 6
HF fetuses showed an upregulation of gut barrier function genes and downregulation of a microbe-sensing receptor. Maternal HF diet was associated with increased mRNA expression of antimicrobial peptide (AMP) genes Lyz1 (p = 0.007), Reg3g (p = 0.01), and Defa1 (p = 0.001) in the fetal gut vs. CON, though mRNA expression of the purported AMP-activating receptor Tlr4 was decreased in these fetuses (p = 0.02) vs. CON (n = 9–15/group). Groups with different letters are significantly different (p < 0.05). UN, undernourished; HF, high fat; CON, control.
Figure 7
Figure 7
Maternal malnutrition altered fetal gut tight junction gene expression. Maternal UN was associated with increased mRNA expression of Cldn-7 (p < 0.001) in fetal gut vs. CON, while fetuses from HF mothers increased Cldn-3 (p = 0.008) and Cldn-7 (p < 0.001) mRNA expression vs. CON (n = 9–15/group). Groups with different letters are significantly different (p < 0.05). UN, undernourished; HF, high fat; CON, control.
Figure 8
Figure 8
Maternal UN affected fetal gut barrier maturity in both sexes and mucus layer maturity in male fetuses only. Maternal UN was associated with increased gut transcription factor Sox9 (p = 0.004) vs. CON and decreased Cdx2 (p = 0.02) vs. HF in female fetal guts, and reduced Cdx2 (p = 0.02) and Muc2 (p < 0.001) vs. CON in male fetal guts (n = 3–8/group). Groups with different letters are significantly different (p < 0.05). UN, undernourished; HF, high fat; CON, control.
Figure 9
Figure 9
Maternal HF diet was associated with increased mRNA expression of enteric glial cell markers in male fetuses. In male fetal guts, maternal HF diet was associated with increased Bfabp (p < 0.001), S100b (p < 0.001), and Plp1 (p = 0.001), while maternal UN was associated with increased Bfabp (p < 0.001). Maternal malnutrition (UN and HF) did not affect enteric glial cell development in female fetal guts (n = 3–8/group). Groups with different letters are significantly different (p < 0.05). UN, undernourished; HF, high fat; CON, control.
Figure 10
Figure 10
Maternal HF diet was associated with increased expression of antimicrobial peptides and decreased expression of microbe-sensing receptor in male fetuses. In male fetal guts, maternal HF diet was associated with increased Lyz1 (p < 0.001) and Lyz2 (p < 0.001), and decreased Tlr4 (p = 0.03) mRNA expression levels. Maternal malnutrition (UN and HF) did not affect Defa1 or Reg3g expression levels in male fetuses or antimicrobial peptide levels in female fetal guts (n = 3–8/group). Groups with different letters are significantly different (p < 0.05). UN, undernourished; HF, high fat; CON, control.
Figure 11
Figure 11
Maternal malnutrition was associated with an increase in gut tight junction gene expression in both fetal sexes. In male fetal guts, maternal HF diet was associated with increased Cldn-3 (p = 0.02) and Cldn-7 (p = 0.004), while maternal UN was associated with increased Cldn-7 (p = 0.004); in female fetal guts, maternal UN was associated with increased Cldn-3 (p = 0.03) mRNA expression (n = 3–8/group). Groups with different letters are significantly different (p < 0.05). UN, undernourished; HF, high fat; CON, control.

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References

    1. Vaishnava S., Behrendt C.L., Ismail A.S., Eckmann L., Hooper L.V. Paneth cells directly sense gut commensals and maintain homeostasis at the intestinal host-microbial interface. Proc. Natl. Acad. Sci. USA. 2008;105:20858–20863. doi: 10.1073/pnas.0808723105. - DOI - PMC - PubMed
    1. Kinross J.M., Darzi A.W., Nicholson J.K. Gut microbiome-host interactions in health and disease. Genome Med. 2011;3:14. doi: 10.1186/gm228. - DOI - PMC - PubMed
    1. Greenwood-Van Meerveld B., Johnson A.C., Grundy D. Handbook of Experimental Pharmacology. Volume 239. Springer; Cham, Switzerland: 2017. Gastrointestinal physiology and function; pp. 1–16. - PubMed
    1. LeBlanc J.G., Milani C., de Giori G.S., Sesma F., van Sinderen D., Ventura M. Bacteria as vitamin suppliers to their host: A gut microbiota perspective. Curr. Opin. Biotechnol. 2013;24:160–168. doi: 10.1016/j.copbio.2012.08.005. - DOI - PubMed
    1. Nicholson J.K., Holmes E., Kinross J., Burcelin R., Gibson G., Jia W., Pettersson S. Host-gut microbiota metabolic interactions. Science. 2012;336:1262–1267. doi: 10.1126/science.1223813. - DOI - PubMed

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