Intestinal accumulation of microbiota-produced succinate caused by loss of microRNAs leads to diarrhea in weanling piglets

Zhou, Xin; Liu, Yonghui; Xiong, Xia; Chen, Jingqing; Tang, Wenjie; He, Liuqin; Zhang, Zhigang; Yin, Yulong; Li, Fengna

doi:10.1080/19490976.2022.2091369

Cited by 30 publications

(28 citation statements)

References 49 publications

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“…Fixed liver samples were paraffin embedded and sectioned into 8-μm thick sections; then, the samples were either subjected to H&E (hematoxylin–eosin) staining for histological observation or Oil Red O staining for the determination of lipid content as previously described ( 20 ).…”

Section: Methodsmentioning

confidence: 99%

Chlorogenic acid improves glucose tolerance, lipid metabolism, inflammation and microbiota composition in diabetic db/db mice

Yan¹,

Shen³

et al. 2022

Front. Endocrinol.

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IntroductionChronic and acute chlorogenic acid (CGA) can improve glucose tolerance (GT) and insulin sensitivity (IS). However, whether acute administration of CGA has beneficial effects on hepatic lipid metabolism and cecal microbiota composition remains unclear.MethodsIn the current study, diabetic db/db mice were administered CGA or metformin, and db/m mice were used as controls to explore the effects of CGA on hepatic lipid metabolism, including fatty acid oxidation and transportation and triglyceride (TG) lipolysis and synthesis. Moreover, alterations in the inflammatory response and oxidative stress in the liver and gut microbe composition were evaluated.ResultsThe results showed that CGA decreased body weight and improved glucose tolerance and insulin resistance, and these effects were similar to those of metformin. CGA decreased hepatic lipid content by increasing the expression of CPT1a (carnitine palmitoyltransferase 1a), ACOX1 (Acyl-CoA oxidase 1), ATGL (adipose triglyceride lipase), and HSL (hormone-sensitive lipase) and decreasing that of MGAT1 (monoacylglycerol O-acyltransferase 1), DGAT1 (diacylglycerol O-acyltransferase), DGAT2, CD36, and FATP4 (fatty acid transport protein 4). Additionally, CGA restored the expression of inflammatory genes, including TNF-α (tumor necrosis factor-alpha), IL-1β (interleukin-1beta), IL-6, and IL-10, and genes encoding antioxidant enzymes, including SOD1 (superoxide dismutases 1), SOD2 (superoxide dismutases 2), and GPX1 (glutathione peroxidase 1). Furthermore, CGA improved the bacterial alpha and beta diversity in the cecum. Moreover, CGA recovered the abundance of the phylum Bacteroidetes and the genera Lactobacillus, Blautia, and Enterococcus.DiscussionCGA can improve the antidiabetic effects, and microbes may critically mediate these beneficial effects.

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Section: Methodsmentioning

confidence: 99%

Chlorogenic acid improves glucose tolerance, lipid metabolism, inflammation and microbiota composition in diabetic db/db mice

Yan¹,

Shen³

et al. 2022

Front. Endocrinol.

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“…The db/db diabetic mice were first orally gavaged with 0.2 mg ampicillin, 0.1 mg vancomycin, 0.2 mg neomycin, 0.2 mg streptomycin and 0.2 mg metronidazole dissolved in 0.2 mL PBS for 7 consecutive days as previously described ( Zhou X. et al, 2022 ). Then, the db/db mice were gavaged with 5 mg freshly collected feces suspended in 0.2 mL PBS, either from mice in the db/db group or from those in the SeSer group.…”

Section: Methodsmentioning

confidence: 99%

Administration of selenomethionine in combination with serine benefits diabetes via gut microbiota

Cui

Chen²,

Yang³

2022

Front. Microbiol.

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Either selenium or serine could modulate glucose homeostasis, however, whether there are synergistic effects of selenium with serine on diabetes remains to be unknown. In the present study, eight male db/m mice were used as a control, and 24 male diabetic db/db mice were either orally gavaged with PBS, or with selenomethionine alone, or with both selenomethionine and serine, to investigate the effects of selenomethionine and serine on body weight and glucose level. Furthermore, intestinal microbiota composition was analyzed and fecal microbiota transplantation (FMT) was performed to explore whether microbes mediate the beneficial effects of selenomethionine and serine. The results showed that administration of selenomethionine decreased body weight, adipose tissue weight and serum glucose level in db/db diabetic mice. Importantly, administration of selenomethionine in combination with serine exerted better effects than selenomethionine alone did. Furthermore, a combined administration of selenomethionine and serine restored the microbial composition in diabetic mice. Corynebacterium glutamicum, Bifidobacterium pseudolongum, and Aerococcus urinaeequi were significantly decreased, whereas Lactobacillus murinus was increased in mice in the selenomethionine group and selenomethionine in combination with serine group, when compared with those in the db/db group. FMT decreased body weight and glucose level in db/db mice, further indicating that microbes play critical roles in the beneficial effects of selenomethionine and serine. Thus, we concluded that administration of selenomethionine in combination with serine benefits diabetes via gut microbes. Our results suggested that the synergic application of selenomethionine and serine could be potentially used for the treatment of diabetes.

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“…The role of an intestinal gluconeogenic substrate in maintaining intestinal energy metabolism has also been studied ( De Vadder et al., 2016 ). On the other hand, numerous studies point to succinate as a danger signal that can aggravate intestinal mucosal damage and promote the development of inflammation ( Fremder et al., 2021 ; Zhou et al., 2022b ). Therefore, we can speculate that succinate may plays its role as a signal molecule depending on the specific cell types or disease states.…”

Section: Discussionmentioning

confidence: 99%

“…For example, several studies have demonstrated the effect of short-chain fatty acids on the progression of intestinal health in patients with NEC and demonstrated that they show predictive value for NEC development (Roy et al, 2018;Sun et al, 2021;Liu et al, 2022a). Succinate, widely regarded as an intermediate molecule of the mitochondrial tricarboxylic acid cycle, has recently emerged as a key player in maintaining intestinal homeostasis, intestinal energy metabolism, and immune regulation (De Vadder et al, 2016;Banerjee et al, 2020;Zhou et al, 2022b). A study pointed out that succinate can alter bacterial virulence while increasing bacterial invasion in inflammatory bowel disease (Zaidi et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

“…Succinate, widely regarded as an intermediate molecule of the mitochondrial tricarboxylic acid cycle, has recently emerged as a key player in maintaining intestinal homeostasis, intestinal energy metabolism, and immune regulation ( De Vadder et al., 2016 ; Banerjee et al., 2020 ; Zhou et al., 2022b ). A study pointed out that succinate can alter bacterial virulence while increasing bacterial invasion in inflammatory bowel disease ( Zaidi et al., 2020 ).…”

Section: Introductionmentioning

confidence: 99%

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Succinate aggravates intestinal injury in mice with necrotizing enterocolitis

Yan

Liu²,

Zhang³

et al. 2022

Front. Cell. Infect. Microbiol.

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BackgroundNecrotizing enterocolitis (NEC) is the most prevalent gastrointestinal disorder that predominantly threatens preterm newborns. Succinate is an emerging metabolic signaling molecule that was recently studied in relation to the regulation of intestinal immunity and homeostasis. We aimed to investigate the relationship between NEC and gut luminal succinate and preliminarily explored the effect of succinate on NEC pathogenesis.MethodsFecal samples from human neonates and mouse pups were analyzed by HPLC – MS/MS and 16S rRNA gene sequencing. C57BL/6 mice were randomly divided into four groups: control, NEC, Lsuc, and Hsuc. The mortality, weight gain, and intestinal pathological changes in four mouse groups were observed. Inflammatory cytokines and markers of macrophages were identified by quantitative real-time PCR. Succinate receptor 1 (SUCNR1) localization was visualized by immunohistochemistry. The protein levels of SUCNR1 and hypoxia-inducible factor 1a (HIF-1a) were quantified by western blotting.ResultsThe levels of succinate in feces from NEC patients were higher than those in feces from non-NEC patients (P <0.05). In the murine models, succinate levels in intestinal content samples were also higher in the NEC group than in the control group (P <0.05). The change in succinate level was closely related to intestinal flora composition. In samples from human neonates, relative to the control group, the NEC group showed a higher abundance of Enterobacteriaceae and a lower abundance of Lactobacillaceae and Lactobacillus (P <0.05). In the murine models, relative to the control group, increased abundance was observed for Clostridiaceae, Enterococcaceae, Clostridium_sensu_stricto_1, and Enterococcus, whereas decreased abundance was observed for Lactobacillaceae and Lactobacillus (P <0.05). Increased succinate levels prevented mice from gaining weight, damaged their intestines, and increased their mortality; upregulated the gene expression of interleukin-1β (IL-1β), IL-6, IL-18 and tumor necrosis factor (TNF); and downregulated the gene expression of IL-10 and transforming growth factor (TGF)-β. Exogenous succinic acid increased inducible nitric oxide synthase (iNOS) gene expression but decreased Arginase-1 (Arg1) gene expression; and increased the protein expression of SUCNR1 and HIF-1a.ConclusionSuccinate plays an important role in the development of necrotizing enterocolitis severity, and the activation of the HIF-1a signaling pathway may lead to disease progression.

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Intestinal accumulation of microbiota-produced succinate caused by loss of microRNAs leads to diarrhea in weanling piglets

Cited by 30 publications

References 49 publications

Chlorogenic acid improves glucose tolerance, lipid metabolism, inflammation and microbiota composition in diabetic db/db mice

Chlorogenic acid improves glucose tolerance, lipid metabolism, inflammation and microbiota composition in diabetic db/db mice

Administration of selenomethionine in combination with serine benefits diabetes via gut microbiota

Succinate aggravates intestinal injury in mice with necrotizing enterocolitis

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