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Modeling undernutrition with enteropathy in mice.

ABSTRACT: Undernutrition is a global health issue leading to 1 out 5 all deaths in children under 5 years. Undernutrition is often associated with environmental enteric dysfunction (EED), a syndrome associated with increased intestinal permeability and gut inflammation. We aimed to develop a novel murine model of undernutrition with these EED features. Post-weaning mice were fed with low-protein diet (LP) alone or combined with a gastrointestinal insult trigger (indomethacin or liposaccharides). Growth, intestinal permeability and inflammation were assessed. LP diet induced stunting and wasting in post-weaning mice but did not impact gut barrier. We therefore combined LP diet with a single administration of indomethacin or liposaccharides (LPS). Indomethacin increased fecal calprotectin production while LPS did not. To amplify indomethacin effects, we investigated its repeated administration in addition to LP diet and mice exhibited stunting and wasting with intestinal hyperpermeability and gut inflammation. The combination of 3-weeks LP diet with repeated oral indomethacin administration induced wasting, stunting and gut barrier dysfunction as observed in undernourished children with EED. As noninvasive methods for investigating gut function in undernourished children are scarce, the present pre-clinical model provides an affordable tool to attempt to elucidate pathophysiological processes involved in EED and to identify novel therapeutic strategies.

SUBMITTER: Salameh E

PROVIDER: S-EPMC7518247 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Modeling undernutrition with enteropathy in mice.

Salameh Emmeline E Jarbeau Marine M Morel Fanny B FB Zeilani Mamane M Aziz Moutaz M Déchelotte Pierre P Marion-Letellier Rachel R

Scientific reports 20200924 1

Undernutrition is a global health issue leading to 1 out 5 all deaths in children under 5 years. Undernutrition is often associated with environmental enteric dysfunction (EED), a syndrome associated with increased intestinal permeability and gut inflammation. We aimed to develop a novel murine model of undernutrition with these EED features. Post-weaning mice were fed with low-protein diet (LP) alone or combined with a gastrointestinal insult trigger (indomethacin or liposaccharides). Growth, i ...[more]

PMID: 32973261

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Project description:BACKGROUND:Adult undernutrition (BMI <18.5 kg/m2) is responsible for immune deficits, increased risk of disease burden, and higher rates of mortality. The prevalence of adult undernutrition in Bangladesh is substantial, but there have been few studies on the etiology of this condition for the inhabitants of urban slums. OBJECTIVE:The aim of this study was to identify the factors associated with undernutrition among slum-dwelling adults in Bangladesh. METHODS:A case-control study was conducted in the Bauniabadh area of Dhaka, Bangladesh. 270 adult participants (135 cases with a BMI <18.5 and 135 controls with a BMI between 18.5 and 24.9) aged 18-45 y were enrolled between October 2018 and January 2019. Sociodemographic variables, dietary diversity, micronutrient deficiencies, psychological symptoms, infection, and biomarkers of gut health were assessed to identify the factors associated with undernutrition using multivariable logistic regression analysis. RESULTS:A higher number of siblings [adjusted odds ratio (aOR): 1.39; 95% CI: 1.11, 1.77], increased self-reporting questionnaire-20 score (an instrument to screen mental health disorders and detect psychological symptoms) (aOR: 1.12; 95% CI: 1.04, 1.23), elevated fecal concentration of α-1 antitrypsin (aOR: 4.82; 95% CI: 1.01, 25.29), and anemia (aOR: 3.63; 95% CI: 1.62, 8.58) were positively associated with undernutrition in adults. Age (aOR: 0.90; 95% CI: 0.84, 0.96), dietary diversity score (aOR: 0.75; 95% CI: 0.56, 0.99), C-reactive protein (aOR: 0.82; 95% CI: 0.73, 0.92), Helicobacter pylori infection (aOR: 0.11; 95% CI: 0.05, 0.23), and always washing hands before eating or preparing foods (aOR: 0.33; 95% CI: 0.12, 0.87) were associated with reduced odds of undernutrition among the study population. CONCLUSIONS:Our results indicate that undernutrition in slum-dwelling adults in Bangladesh is associated with numerous physiological and sociodemographic factors, including evidence of gastrointestinal inflammation and altered intestinal permeability.

Project description:ObjectiveLow birth weight (LBW) is associated with increased risk of obesity, diabetes, and cardiovascular disease during adult life. Moreover, this programmed disease risk can progress to subsequent generations. We previously described a mouse model of LBW, produced by maternal caloric undernutrition (UN) during late gestation. LBW offspring (F(1)-UN generation) develop progressive obesity and impaired glucose tolerance (IGT) with aging. We aimed to determine whether such metabolic phenotypes can be transmitted to subsequent generations in an experimental model, even in the absence of altered nutrition during the second pregnancy.Research design and methodsWe intercrossed female and male F(1) adult control (C) and UN mice and characterized metabolic phenotypes in F(2) offspring.ResultsWe demonstrate that 1) reduced birth weight progresses to F(2) offspring through the paternal line (Cfemale -Cmale = 1.64 g; Cfemale -UNmale = 1.57 g, P < 0.05; UNfemale -Cmale = 1.64 g; UNfemale -UNmale = 1.60 g, P < 0.05), 2) obesity progresses through the maternal line (percent body fat: Cfemale -Cmale = 22.4%; Cfemale -UNmale = 22.9%; UNfemale -Cmale = 25.9%, P < 0.05; UNfemale -UNmale = 27.5%, P < 0.05), and 3) IGT progresses through both parental lineages (glucose tolerance test area under curve Cfemale -Cmale = 100; Cfemale -UNmale = 122, P < 0.05; UNfemale -Cmale = 131, P < 0.05; UNfemale -UNmale = 151, P < 0.05). Mechanistically, IGT in both F(1) and F(2) generations is linked to impaired beta-cell function, explained, in part, by dysregulation of Sur1 expression.ConclusionsMaternal undernutrition during pregnancy (F(0)) programs reduced birth weight, IGT, and obesity in both first- and second-generation offspring. Sex-specific transmission of phenotypes implicates complex mechanisms including alterations in the maternal metabolic environment (transmaternal inheritance of obesity), gene expression mediated by developmental and epigenetic pathways (transpaternal inheritance of LBW), or both (IGT).

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Modeling undernutrition with enteropathy in mice.

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Modeling undernutrition with enteropathy in mice.

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