Blautia Coccoides is a Newly Identified Bacterium Increased by Leucine Deprivation and has a Novel Function in Improving Metabolic Disorders.

Gut microbiota is linked to human metabolic diseases. The previous work showed that leucine deprivation improved metabolic dysfunction, but whether leucine deprivation alters certain specific species of bacterium that brings these benefits remains unclear. Here, this work finds that leucine deprivation alters gut microbiota composition, which is sufficient and necessary for the metabolic improvements induced by leucine deprivation. Among all the affected bacteria, B. coccoides is markedly increased in the feces of leucine-deprived mice. Moreover, gavage with B. coccoides improves insulin sensitivity and reduces body fat in high-fat diet (HFD) mice, and singly colonization of B. coccoides increases insulin sensitivity in gnotobiotic mice. The effects of B. coccoides are mediated by metabolizing tryptophan into indole-3-acetic acid (I3AA) that activates the aryl hydrocarbon receptor (AhR) in the liver. Finally, this work reveals that reduced fecal B. coccoides and I3AA levels are associated with the clinical metabolic syndrome. These findings suggest that B. coccoides is a newly identified bacterium increased by leucine deprivation, which improves metabolic disorders via metabolizing tryptophan into I3AA.

Constructing Heterogeneous Interface by Growth of Carbon Nanotubes on the Surface of MoB2 for Boosting Hydrogen Evolution Reaction in a Wide pH Range.

Transition metal diborides represented by MoB2 have attracted widespread attention for their excellent acidic hydrogen evolution reaction (HER). Nevertheless, their electrocatalytic performance is generally unsatisfactory in high-pH electrolytes. Heterogeneous interface engineering is one of the most promising methods for optimizing the composition and structure of electrocatalysts, thereby greatly affecting their electrochemical performance. Herein, a heterostructure, composed of MoB2 and carbon nanotubes (CNTs), is rationally constructed by boronizing precursors including (NH4 )4 [NiH6 Mo6 O24 ]·5H2 O (NiMo6 ) and Co complexes on the carbon cloth (Co,Ni-MoB2 @CNT/CC). In this method, NiMo6 is boronized to form MoB2 by a modified molten-salt-assisted borothermal reduction. Meanwhile, Co catalyzes extra carbon sources to grow CNTs on the surface of MoB2 . Thanks to the successful production of the heterostructure, Co,Ni-MoB2 @CNT/CC exhibits remarkable HER performance with a low overpotential of 98.6, 113.0, and 73.9 mV at 10 mA cm-2 in acidic, neutral, and alkaline electrolytes, respectively. Notably, even at 500 mA cm-2 , the electrochemical activity of Co,Ni-MoB2 @CNT/CC exceeds that of Pt/C/CC in an alkaline solution and maintains over 50 h. Theoretical calculations reveal that the construction of the heterostructure is beneficial to both water dissociation and reactive intermediate adsorption, resulting in superior alkaline HER performance.

The Comparison of Biomolecular Changes of Epstein-Barr Virus Infection in Nasopharyngeal Epithelial Cells Using Confocal Raman Microspectroscopy.

BACKGROUND: Due to its unique fingerprinting properties, Confocal Raman microscopy (CRM) can be used to examine the biomolecular changes of viruses invading and manipulating host cells. Recently, the biochemical changes due to the invasion and infection of B lymphocyte cells, nerve cells, and epithelial cells by Epstein-Barr virus (EBV) have been reported. However, biomolecular changes in nasopharyngeal epithelial cells that result from EBV infection are still poorly understood. METHODS: In continuation of our prior investigation of EBV infection in nasopharyngeal epithelial cells, we tried to expound on biomolecular changes in EBV-infected nasopharyngeal epithelial cells using Raman microspectroscopy. EBV has two life cycles, latent infection and lytic replication. We have established latent and lytic infection models at the cellular level. In order to understand the characteristics of the two patterns of EBV infection, we used Raman spectroscopy to identify the changes in biomolecules of EBV latent cells (CNE2, CNE2-EBV) and lytic cells (NPEC1-BMI1-CN, NPEC1-BMI1-EBV). RESULTS: During latent infection, levels of glycogen, protein, and lipid molecules in the cell increased while levels of nucleic acid and collagen molecules decreased. Molecular levels of glycogen, proteins, and nucleic acids are reduced during lytic infection. We found that molecular levels of nucleic acid decreased during two different periods of infection, whereas levels of other biomolecules showed the opposite trend. Glycogen, proteins, lipids, nucleic acids, and other molecules are associated with alterations in cellular biochemical homeostasis. These changes correspond to unique Raman spectra in infected and uninfected cells associated with specific biomolecules that have been proven. These molecules are mainly responsible for cellular processes such as cell proliferation and apoptosis. The Raman signatures of these biomolecular changes depend on the different phases of viral infection. CONCLUSIONS: Therefore, by using CRM, it is possible to discern details in the progression of EBV infection in nasopharyngeal epithelial cells at the molecular level.

Transcriptional and epigenetic decoding of the microglial aging process.

As important immune cells, microglia undergo a series of alterations during aging that increase the susceptibility to brain dysfunctions. However, the longitudinal characteristics of microglia remain poorly understood. In this study, we mapped the transcriptional and epigenetic profiles of microglia from 3- to 24-month-old mice. We first discovered unexpected sex differences and identified age-dependent microglia (ADEM) genes during the aging process. We then compared the features of aging and reactivity in female microglia at single-cell resolution and epigenetic level. To dissect functions of aged microglia excluding the influence from other aged brain cells, we established an accelerated microglial turnover model without directly affecting other brain cells. By this model, we achieved aged-like microglia in non-aged brains and confirmed that aged-like microglia per se contribute to cognitive decline. Collectively, our work provides a comprehensive resource for decoding the aging process of microglia, shedding light on how microglia maintain brain functions.

Efficient detection of metronidazole by a glassy carbon electrode modified with a composite of a cyclotriveratrylene-based metal-organic framework and multi-walled carbon nanotubes.

Constructing a sensitive and efficient sensor for determination of metronidazole (MNZ) is crucial in food field. Herein, a new cyclotriveratrylene-based metal-organic framework (MOF), namely, [Cd6L2(cyclen)2(H2O)2] (1), was constructed by self-assembly of functionalized 5,6,12,13,19,20-hexacarboxy-propoxy-cyclotriveratrylene (H6L), 1,4,7,10-tetraazacyclododecane (cyclen) and Cd(II) cation under solvothermal condition. In 1, adjacent Cd(II) cations are linked by L6- to produce a 2D polymeric structure with carboxylate and phenolic oxygen atoms. To enhance conductivity of 1, it was combined with conducting carbon materials, including mesoporous carbon (MC), reduced graphene oxide (RGO) and multi-walled carbon nanotubes (MWCNT), respectively, producing a series of composite materials. Remarkably, electrochemical tests showed that 1@MWCNT(1:1) featured a much better electrochemical detection performance for metronidazole (MNZ) than 1@MC and 1@RGO. The linear range for the detection of MNZ is up to 0.4-500 µM and the limit of detection (LOD) for MNZ reached 0.25 µM. Importantly, the fabricated sensor 1@MWCNT(1:1) was employed for the detection of MNZ in honey and egg with satisfactory result. High-performance liquid chromatography (HPLC) validated the high accuracy of the electrochemical method for the determination of honey and egg.

Reduced hepatic bradykinin degradation accounts for cold-induced BAT thermogenesis and WAT browning in male mice.

An important role for liver in the regulation of adipose tissue thermogenesis upon cold exposure has been suggested; however, the underlying mechanisms remain incompletely defined. Here, we identify elevated serum bradykinin levels in response to acute cold exposure in male mice. A bolus of anti-bradykinin antibodies reduces body temperature during acute cold exposure, whereas bradykinin has the opposite effect. We demonstrate that bradykinin induces brown adipose tissue thermogenesis and white adipose tissue browning, and bradykinin increases uncoupling protein 1 (UCP1) expression in adipose tissue. The bradykinin B2 receptor (B2R), adrenergic signaling and nitric oxide signaling are involved in regulating bradykinin-increased UCP1 expression. Moreover, acute cold exposure inhibits hepatic prolyl endopeptidase (PREP) activity, causing reduced liver bradykinin degradation and increased serum bradykinin levels. Finally, by blocking the breakdown of bradykinin, angiotensin-converting enzyme inhibitors (ACEIs) increase serum bradykinin levels and induce brown adipose tissue thermogenesis and white adipose tissue browning via B2R. Collectively, our data provide new insights into the mechanisms underlying organ crosstalk in whole-body physiology control during cold exposure and also suggest bradykinin as a possible anti-obesity target.

Direct medical costs of ischemic heart disease in urban Southern China: a 5-year retrospective analysis of an all-payer health claims database in Guangzhou City.

Introduction: This study aimed to estimate the direct medical costs and out-of-pocket (OOP) expenses associated with inpatient and outpatient care for IHD, based on types of health insurance. Additionally, we sought to identify time trends and factors associated with these costs using an all-payer health claims database among urban patients with IHD in Guangzhou City, Southern China. Methods: Data were collected from the Urban Employee-based Basic Medical Insurance (UEBMI) and the Urban Resident-based Basic Medical Insurance (URBMI) administrative claims databases in Guangzhou City from 2008 to 2012. Direct medical costs were estimated in the entire sample and by types of insurance separately. Extended Estimating Equations models were employed to identify the potential factors associated with the direct medical costs including inpatient and outpatient care and OOP expenses. Results: The total sample included 58,357 patients with IHD. The average direct medical costs per patient were Chinese Yuan (CNY) 27,136.4 [US dollar (USD) 4,298.8] in 2012. The treatment and surgery fees were the largest contributor to direct medical costs (52.0%). The average direct medical costs of IHD patients insured by UEBMI were significantly higher than those insured by the URBMI [CNY 27,749.0 (USD 4,395.9) vs. CNY 21,057.7(USD 3,335.9), P < 0.05]. The direct medical costs and OOP expenses for all patients increased from 2008 to 2009, and then decreased during the period of 2009-2012. The time trends of direct medical costs between the UEBMI and URBMI patients were different during the period of 2008-2012. The regression analysis indicated that the UEBMI enrollees had higher direct medical costs (P < 0.001) but had lower OOP expenses (P < 0.001) than the URBMI enrollees. Male patients, patients having percutaneous coronary intervention operation and intensive care unit admission, patients treated in secondary hospitals and tertiary hospitals, patients with the LOS of 15-30 days, 30 days and longer had significantly higher direct medical costs and OOP expenses (all P < 0.001). Conclusions: The direct medical costs and OOP expenses for patients with IHD in China were found to be high and varied between two medical insurance schemes. The type of insurance was significantly associated with direct medical costs and OOP expenses of IHD.

Intestinal activating transcription factor 4 regulates stress-related behavioral alterations via paraventricular thalamus in male mice.

Chronic stress induces depression- and anxiety-related behaviors, which are common mental disorders accompanied not only by dysfunction of the brain but also of the intestine. Activating transcription factor 4 (ATF4) is a stress-induced gene, and we previously show that it is important for gut functions; however, the contribution of the intestinal ATF4 to stress-related behaviors is not known. Here, we show that chronic stress inhibits the expression of ATF4 in gut epithelial cells. ATF4 overexpression in the colon relieves stress-related behavioral alterations in male mice, as measured by open-field test, elevated plus-maze test, and tail suspension test, whereas intestine-specific ATF4 knockout induces stress-related behavioral alterations in male mice. Furthermore, glutamatergic neurons are inhibited in the paraventricular thalamus (PVT) of two strains of intestinal ATF4-deficient mice, and selective activation of these neurons alleviates stress-related behavioral alterations in intestinal ATF4-deficient mice. The highly expressed gut-secreted peptide trefoil factor 3 (TFF3) is chosen from RNA-Seq data from ATF4 deletion mice and demonstrated decreased in gut epithelial cells, which is directly regulated by ATF4. Injection of TFF3 reverses stress-related behaviors in ATF4 knockout mice, and the beneficial effects of TFF3 are blocked by inhibiting PVT glutamatergic neurons using DREADDs. In summary, this study demonstrates the function of ATF4 in the gut-brain regulation of stress-related behavioral alterations, via TFF3 modulating PVT neural activity. This research provides evidence of gut signals regulating stress-related behavioral alterations and identifies possible drug targets for the treatment of stress-related behavioral disorders.

Intestinal Epithelial Cell-specific Deletion of Cytokine-inducible SH2-containing Protein Alleviates Experimental Colitis in Ageing Mice.

BACKGROUND AND AIMS: The incidence of inflammatory bowel disease [IBD] in the elderly has increased in recent years. However, the mechanisms underlying the ageing-related IBD susceptibility remain elusive. Cytokine-inducible SH2-containing protein [CISH] is involved in regulating metabolism, the expansion of intestinal tuft cells and type-2 innate lymphoid cells, and ageing-related airway inflammation. Here, we investigated the role of CISH in ageing-related colitis susceptibility. METHODS: CISH and phosphorylated signal transducer and activator of transcription-3 [p-STAT3] levels were evaluated in the colons of ageing mice and older ulcerative colitis [UC] patients. Mice with intestinal epithelial cell-specific knockout of Cish [CishΔIEC] and Cish-floxed mice were administered dextran sodium sulphate [DSS] or trinitrobenzene sulphonic acid [TNBS] to induce colitis. Colonic tissues were analysed in quantitative real-time polymerase chain reaction, immunoblotting, immunohistochemical, and histological staining experiments. Differentially expressed genes from colonic epithelia were analysed by RNA sequencing. RESULTS: Ageing increased the severity of DSS-induced colitis and the expression of colonic epithelial CISH in mice. CishΔIEC prevented DSS- or TNBS-induced colitis in middle-aged mice but not in young mice. RNA-sequencing analysis revealed that CishΔIEC significantly suppressed DSS-induced oxidative stress and proinflammatory responses. During ageing in the CCD841 cell model, knockdown of CISH decreased ageing-induced oxidative stress and proinflammatory responses, whereas these effects were compromised by knocking down or inhibiting STAT3. The increase in CISH expression was higher in the colonic mucosa of older patients with UC than in that of healthy controls. CONCLUSIONS: CISH might be a proinflammatory regulator in ageing; therefore, targeted therapy against CISH may provide a novel strategy for treating ageing-related IBD.

SLC7A14 imports GABA to lysosomes and impairs hepatic insulin sensitivity via inhibiting mTORC2.

Lysosomal amino acid accumulation is implicated in several diseases, but its role in insulin resistance, the central mechanism to type 2 diabetes and many metabolic diseases, is unclear. In this study, we show the hepatic expression of lysosomal membrane protein solute carrier family 7 member 14 (SLC7A14) is increased in insulin-resistant mice. The promoting effect of SLC7A14 on insulin resistance is demonstrated by loss- and gain-of-function experiments. SLC7A14 is further demonstrated as a transporter resulting in the accumulation of lysosomal γ-aminobutyric acid (GABA), which induces insulin resistance via inhibiting mTOR complex 2 (mTORC2)'s activity. These results establish a causal link between lysosomal amino acids and insulin resistance and suggest that SLC7A14 inhibition may provide a therapeutic strategy in treating insulin resistance-related and GABA-related diseases and may provide insights into the upstream mechanisms for mTORC2, the master regulator in many important processes.

Inhibition of c-Jun in AgRP neurons increases stress-induced anxiety and colitis susceptibility.

Psychiatric disorders, such as anxiety, are associated with inflammatory bowel disease (IBD), however, the neural mechanisms regulating this comorbidity are unknown. Here, we show that hypothalamic agouti-related protein (AgRP) neuronal activity is suppressed under chronic restraint stress (CRS), a condition known to increase anxiety and colitis susceptibility. Consistently, chemogenic activation or inhibition of AgRP neurons reverses or mimics CRS-induced increase of anxiety-like behaviors and colitis susceptibility, respectively. Furthermore, CRS inhibits AgRP neuronal activity by suppressing the expression of c-Jun. Moreover, overexpression of c-Jun in these neurons protects against the CRS-induced effects, and knockdown of c-Jun in AgRP neurons (c-Jun∆AgRP) promotes anxiety and colitis susceptibility. Finally, the levels of secreted protein thrombospondin 1 (THBS1) are negatively associated with increased anxiety and colitis, and supplementing recombinant THBS1 rescues colitis susceptibility in c-Jun∆AgRP mice. Taken together, these results reveal critical roles of hypothalamic AgRP neuron-derived c-Jun in orchestrating stress-induced anxiety and colitis susceptibility.

Comprehensive analysis of aberrantly expressed circRNAs, mRNAs and lncRNAs in patients with nasopharyngeal carcinoma.

BACKGROUND: The location of nasopharyngeal cancer is hidden, so it is difficult to diagnose at an early stage. In this study, we aimed to investigate the expression profiles of circRNAs, mRNAs and IncRNAs and to provide some basis for further studies. METHODS: Expression profiles of circRNAs, mRNAs, and lncRNAs were analyzed using microarray techniques. The differentially expressed ncRNA was calculated by bioinformatics. RESULTS: A total of 3048 circRNAs, 2179 lncRNAs, and 2015 mRNAs were detected to be significantly differentially expressed in NPC. The most upregulated circRNAs, lncRNAs, and mRNAs were hsa-circ-0067562, NONHSAT232922.1, and HOXB13, respectively. And, the most downregulated circRNAs, lncRNAs, and mRNAs were hsa_circ_0078837, lnc-TTC8-4:3, and LTF, respectively. The number of upregulated DE lncRNAs was more than twice than those downregulated. Our data showed that 80.44% of pairs of lncRNAs and cis-mRNAs demonstrated positive correlations. For lncRNAs and trans-mRNAs pairs, 53.7% of pairs showed positive correlation. LncRNA-mediated cis regulation is a prevalent regulatory mode in the development of nasopharyngeal carcinoma. CR1, LRMP and SORBS2 are predicted to be mediated not only by cis-acting lncRNA modes of action, but also by trans-acting lncRNA mechanisms. Additionally, we constructed a diagnostic prediction model with a high sensitivity and specificity. CONCLUSION: Our study characterized the landscape of circRNAs, mRNAs and lncRNAs in NPC tissue and provided novel insights into the molecular mechanisms of NPC.

Functional Autapses Form in Striatal Parvalbumin Interneurons but not Medium Spiny Projection Neurons.

Autapses selectively form in specific cell types in many brain regions. Previous studies have also found putative autapses in principal spiny projection neurons (SPNs) in the striatum. However, it remains unclear whether these neurons indeed form physiologically functional autapses. We applied whole-cell recording in striatal slices and identified autaptic cells by the occurrence of prolonged asynchronous release (AR) of neurotransmitters after bursts of high-frequency action potentials (APs). Surprisingly, we found no autaptic AR in SPNs, even in the presence of Sr2+. However, robust autaptic AR was recorded in parvalbumin (PV)-expressing neurons. The autaptic responses were mediated by GABAA receptors and their strength was dependent on AP frequency and number. Further computer simulations suggest that autapses regulate spiking activity in PV cells by providing self-inhibition and thus shape network oscillations. Together, our results indicate that PV neurons, but not SPNs, form functional autapses, which may play important roles in striatal functions.

High-protein diet prevents fat mass increase after dieting by counteracting Lactobacillus-enhanced lipid absorption.

Dietary restriction is widely used to reduce fat mass and lose weight in individuals with or without obesity; however, weight regain after dieting is still a big challenge, and the underlying mechanisms remain largely elusive. Here we show that refeeding after various types of dieting induces quick fat accumulation in mice and enhanced intestinal lipid absorption contributes to post-dieting fat mass increase. Moreover, refeeding after short-term dietary restriction is accompanied by an increase in intestinal Lactobacillus and its metabolites, which contributes to enhanced intestinal lipid absorption and post-dieting fat mass increase; however, refeeding a high-protein diet after short-term dietary restriction attenuates intestinal lipid absorption and represses fat accumulation by preventing Lactobacillus growth. Our results provide insight into the mechanisms underlying fat mass increase after dieting. We also propose that targeting intestinal Lactobacillus to inhibit intestinal lipid absorption via high-protein diet or antibiotics is likely an effective strategy to prevent obesity after dieting.

Microglial debris is cleared by astrocytes via C4b-facilitated phagocytosis and degraded via RUBICON-dependent noncanonical autophagy in mice.

Microglia are important immune cells in the central nervous system (CNS) that undergo turnover throughout the lifespan. If microglial debris is not removed in a timely manner, accumulated debris may influence CNS function. Clearance of microglial debris is crucial for CNS homeostasis. However, underlying mechanisms remain obscure. We here investigate how dead microglia are removed. We find that although microglia can phagocytose microglial debris in vitro, the territory-dependent competition hinders the microglia-to-microglial debris engulfment in vivo. In contrast, microglial debris is mainly phagocytosed by astrocytes in the brain, facilitated by C4b opsonization. The engulfed microglial fragments are then degraded in astrocytes via RUBICON-dependent LC3-associated phagocytosis (LAP), a form of noncanonical autophagy. Interference with C4b-mediated engulfment and subsequent LAP disrupt the removal and degradation of microglial debris, respectively. Together, we elucidate the cellular and molecular mechanisms of microglial debris removal in mice, extending the knowledge on the maintenance of CNS homeostasis.

Performance comparison of two nucleic acid amplification systems for SARS-CoV-2 detection: A multi-center study.

BACKGROUND: Many rapid nucleic acid testing systems have emerged to halt the development and spread of COVID-19. However, so far relatively few studies have compared the diagnostic performance between these testing systems and conventional detection systems. Here, we performed a retrospective analysis to evaluate the clinical detection performance between SARS-CoV-2 rapid and conventional nucleic acid detection system. METHODS: Clinical detection results of 63,352 oropharyngeal swabs by both systems were finally enrolled in this analysis. Sensitivity (SE), specificity (SP), and positive and negative predictive value (PPV, NPV) of both systems were calculated to evaluate their diagnostic accuracy. Concordance between these two systems were assessed by overall, positive, negative percent agreement (OPA, PPA, NPA) and κ value. Sensitivity of SARS-CoV-2 rapid nucleic acid detection system (Daan Gene) was further analyzed with respect to the viral load of clinical specimens. RESULTS: Sensitivity of Daan Gene was slightly lower than that of conventional detection system (0.86 vs. 0.979), but their specificity was equivalent. Daan Gene had ≥98.0% PPV and NPV for SARS-CoV-2. Moreover, Daan Gene demonstrated an excellent test agreement with conventional detection system (κ = 0.893, p = 0.000). Daan Gene was 99.31% sensitivity for specimens with high viral load (Ct < 35) and 50% for low viral load (Ct ≥ 35). CONCLUSIONS: While showing an analytical sensitivity slightly below than that of conventional detection system, rapid nucleic acid detection system may be a diagnostic alternative to rapidly identify SARS-CoV-2-infected individuals with high viral loads and a powerful complement to current detection methods.

Hepatic cytokine-inducible SH2-containing protein (CISH) regulates gluconeogenesis via cAMP-responsive element binding protein (CREB).

Impairment of gluconeogenesis is a key factor responsible for hyperglycemia in patients with type 2 diabetes. As an important member of the suppressors of cytokine signaling (SOCS) protein family, many physiological functions of cytokine-inducible SH2-containing protein (CISH) have been described; however, the role of hepatic CISH in gluconeogenesis is poorly understood. In the present study, we observed that hepatic CISH expression was reduced in fasted wild-type (WT) mice. Overexpression of CISH decreased glucose production in mouse primary hepatocytes, while silencing of CISH had the opposite effects. In addition, adenovirus-mediated hepatic CISH overexpression resulted in improved glucose tolerance and decreased gluconeogenesis in WT and leptin receptor-deficient diabetic (db/db) mice. In contrast, adenovirus-mediated hepatic CISH knockdown impaired glucose tolerance and increased gluconeogenesis in WT mice. We also generated liver-specific CISH knockout (LV-CISH KO) mice and discovered that these mice had a similar phenotype in glucose tolerance and gluconeogenesis as mice injected with adenoviruses that knockdown CISH expression. Mechanistically, we found that CISH overexpression decreased and CISH knockdown increased the mRNA and protein levels of glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase 1 (PEPCK), two key enzymes involved in gluconeogenesis, in vitro, and in vivo. Moreover, we discovered that the phosphorylation of cAMP-responsive element binding protein 1 (CREB), a transcription factor of G6pase and Pepck, was required for regulating gluconeogenesis by CISH. Taken together, this study identifies hepatic CISH as an important regulator of gluconeogenesis. Our results also provide important insights into the metabolic functions of the SOCS protein family and the potential targets for the treatment of diabetes.

Amino acid sensor GCN2 promotes SARS-CoV-2 receptor ACE2 expression in response to amino acid deprivation.

Angiotensin-converting enzyme 2 (ACE2) has been identified as a primary receptor for severe acute respiratory syndrome coronaviruses 2 (SARS-CoV-2). Here, we investigated the expression regulation of ACE2 in enterocytes under amino acid deprivation conditions. In this study, we found that ACE2 expression was upregulated upon all or single essential amino acid deprivation in human colonic epithelial CCD841 cells. Furthermore, we found that knockdown of general control nonderepressible 2 (GCN2) reduced intestinal ACE2 mRNA and protein levels in vitro and in vivo. Consistently, we revealed two GCN2 inhibitors, GCN2iB and GCN2-IN-1, downregulated ACE2 protein expression in CCD841 cells. Moreover, we found that increased ACE2 expression in response to leucine deprivation was GCN2 dependent. Through RNA-sequencing analysis, we identified two transcription factors, MAFB and MAFF, positively regulated ACE2 expression under leucine deprivation in CCD841 cells. These findings demonstrate that amino acid deficiency increases ACE2 expression and thereby likely aggravates intestinal SARS-CoV-2 infection.