Carnitine Deficiency in OCTN2−/− Newborn Mice Leads to a Severe Gut and Immune Phenotype with Widespread Atrophy, Apoptosis and a Pro-Inflammatory Response

Sonne, Srinivas; Shekhawat, Prem; Matern, Dietrich; Ganapathy, Vadivel; Ignatowicz, Leszek

doi:10.1371/journal.pone.0047729

Cited by 24 publications

(26 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…) and carnitine deficiency has been associated with intestinal inflammation and apoptosis in neonatal mice (Sonne et al . ). Host–microbial interactions modulate metabolism (Nicholson et al .…”

Section: Discussionmentioning

confidence: 97%

High‐fat diet intake modulates maternal intestinal adaptations to pregnancy and results in placental hypoxia, as well as altered fetal gut barrier proteins and immune markers

Gohir

Kennedy

Wallace

et al. 2019

The Journal of Physiology

109

View full text Add to dashboard Cite

Key points Maternal obesity has been associated with shifts in intestinal microbiota, which may contribute to impaired barrier function Impaired barrier function may expose the placenta and fetus to pro‐inflammatory mediators We investigated the impacts of diet‐induced obesity in mice on maternal and fetal intestinal structure and placental vascularization Diet‐induced obesity decreased maternal intestinal short chain fatty acids and their receptors, impaired gut barrier integrity and was associated with fetal intestinal inflammation. Placenta from obese mothers showed blood vessel immaturity, hypoxia, increased transcript levels of inflammation, autophagy and altered levels of endoplasmic reticulum stress markers. These data suggest that maternal intestinal changes probably contribute to adverse placental adaptations and also impart an increased risk of obesity in the offspring via alterations in fetal gut development. Abstract Shifts in maternal intestinal microbiota have been implicated in metabolic adaptations to pregnancy. In the present study, we generated cohorts of female C57BL/6J mice fed a control (17% kcal fat, n = 10–14) or a high‐fat diet (HFD 60% kcal from fat, n = 10–14; ad libitum) aiming to investigate the impact on the maternal gut microbiota, intestinal inflammation and gut barrier integrity, placental inflammation and fetal intestinal development at embryonic day 18.5. HFD was associated with decreased relative abundances of short‐chain fatty acid (SCFA) producing genera during pregnancy. These diet‐induced shifts paralleled decreased maternal intestinal mRNA levels of SCFA receptor Gpr41, modestly decreased cecal butyrate, and altered mRNA levels of inflammatory cytokines and immune cell markers in the maternal intestine. Maternal HFD resulted in impaired gut barrier integrity, with corresponding increases in circulating maternal levels of lipopolysaccharide (LPS) and tumour necrosis factor. Placentas from HFD dams demonstrated blood vessel immaturity and hypoxia; decreased free carnitine, acylcarnitine derivatives and trimethylamine‐N‐oxide; and altered mRNA levels of inflammation, autophagy, and ER stress markers. HFD exposed fetuses had increased activation of nuclear factor‐kappa B and inhibition of the unfolded protein response in the developing intestine. Taken together, these data suggest that HFD intake prior to and during pregnancy shifts the composition of the maternal gut microbiota and impairs gut barrier integrity, resulting in increased maternal circulating LPS, which may ultimate contribute to changes in placental vascularization and fetal gut development.

show abstract

Section: Discussionmentioning

confidence: 97%

High‐fat diet intake modulates maternal intestinal adaptations to pregnancy and results in placental hypoxia, as well as altered fetal gut barrier proteins and immune markers

Gohir

Kennedy

Wallace

et al. 2019

The Journal of Physiology

109

View full text Add to dashboard Cite

show abstract

“…The SLC22A5 gene is therefore an important regulator of fatty acid metabolism, and is necessary for the maintenance of skeletal and cardiac muscle function (Steiber et al, 2004). Mutations in the SLC22A5 gene can cause systemic primary carnitine deficiency (Sonne et al, 2012). Alcohol has the capacity to upregulate genes involved in fatty acid metabolism similar to effects of glucagon when blood sugar is low.…”

Section: Resultsmentioning

confidence: 99%

Gene expression signatures affected by alcohol-induced DNA methylomic deregulation in human embryonic stem cells

Khalid

Kim

et al. 2014

Stem Cell Research

View full text Add to dashboard Cite

Stem cells, especially human embryonic stem cells (hESCs), are useful models to study molecular mechanisms of human disorders that originate during gestation. Alcohol (ethanol, EtOH) consumption during pregnancy causes a variety of prenatal and postnatal disorders collectively referred to as fetal alcohol spectrum disorders (FASDs). To better understand the molecular events leading to FASDs, we performed a genome-wide analysis of EtOH's effects on the maintenance and differentiation of hESCs in culture. Gene Co-expression Network Analysis showed significant alterations in gene profiles of EtOH-treated differentiated or undifferentiated hESCs, particularly those associated with molecular pathways for metabolic processes, oxidative stress, and neuronal properties of stem cells. A genome-wide DNA methylome analysis revealed widespread EtOH-induced alterations with significant hypermethylation of many regions of chromosomes. Undifferentiated hESCs were more vulnerable to EtOH's effect than their differentiated counterparts, with methylation on the promoter regions of chromosomes 2, 16 and 18 in undifferentiated hESCs most affected by EtOH exposure. Combined transcriptomic and DNA methylomic analysis produced a list of differentiation-related genes dysregulated by EtOH-induced DNA methylation changes, which likely play a role in EtOH-induced decreases in hESC pluripotency. DNA sequence motif analysis of genes epigenetically altered by EtOH identified major motifs representing potential binding sites for transcription factors. These findings should help in deciphering the precise mechanisms of alcohol-induced teratogenesis.

show abstract

“…Carnitine deficiency led to severe gut injury accompanied by a severe immune phenotype and pro-inflammatory status in OCTN2 (SLC22A5) carnitine transporter (-/-) newborn mice [67]. Very recently a significant impairment in the β-oxidation pathway was reported in mucosal biopsies of 26 patients with active ulcerative colitis.…”

Section: Discussionmentioning

confidence: 99%

The role of L-carnitine in acetyl salicylic acid-induced acute gastric mucosal injury in rats

Uz¹,

Türkay²,

Uyar³

et al. 2017

Arch Med Sci Civil Dis

View full text Add to dashboard Cite

A b s t r a c tIntroduction: The aim of this study was to determine the protective effects of L-carnitine on acetyl salicylic acid (ASA)-induced acute gastric mucosal injury through oxidant/antioxidant parameters and histopathological alterations in rat gastric tissues. Material and methods: Forty-two rats were randomly assigned to six groups: The control group received 1 mg/kg distilled water, while the other groups were pretreated with L-carnitine 50 mg/kg/day (LC), pantoprazole 40 mg/ kg/day (PPI), ASA + LC (50 mg/kg/day), and ASA + PPI (40 mg/kg/day), for 21 days, respectively. On day 23, gastric mucosal injury was induced by a single intragastric administration of 600 mg/kg aspirin in ASA, ASA + LC, and ASA + PPI groups. The animals were killed 60 min after the administration of aspirin. The stomach of each animal was removed. Gastric mucosal injury was scored histopathologically (ulcer score). Tissue catalase (CAT), glutathione peroxidase (GSH-Px), and superoxide dismutase (SOD) activities, and malondialdehyde (MDA) and nitric oxide (NO) levels were also measured. Results: The ulcer score increased significantly in the ASA group, but this increase was not significantly inhibited by the administration of L-carnitine (2.71 ±1.0 vs. 2.57 ±0.5, p = 0.965). The CAT and GSH-Px activities were significantly reduced, whereas MDA and NO levels were significantly increased in the ASA group. Pretreatment with L-carnitine did not alter CAT or GSH-Px activities, but reduced MDA and NO levels insignificantly (p = 0.204 and p = 0.277, respectively). Conclusions: Long-term administration of L-carnitine did not improve the oxidative and histological parameters of acute gastric mucosal injury induced by ASA.

show abstract

Carnitine Deficiency in OCTN2−/− Newborn Mice Leads to a Severe Gut and Immune Phenotype with Widespread Atrophy, Apoptosis and a Pro-Inflammatory Response

Cited by 24 publications

References 59 publications

High‐fat diet intake modulates maternal intestinal adaptations to pregnancy and results in placental hypoxia, as well as altered fetal gut barrier proteins and immune markers

High‐fat diet intake modulates maternal intestinal adaptations to pregnancy and results in placental hypoxia, as well as altered fetal gut barrier proteins and immune markers

Gene expression signatures affected by alcohol-induced DNA methylomic deregulation in human embryonic stem cells

The role of L-carnitine in acetyl salicylic acid-induced acute gastric mucosal injury in rats

Contact Info

Product

Resources

About