Tryptophan Metabolic Pathways Are Altered in Obesity and Are Associated With Systemic Inflammation

Cussotto, Sofia; Delgado, Inês; Anesi, Andrea; Dexpert, Sandra; Aubert, Agnès; Beau, Cédric; Forestier, Damien; Ledaguenel, Patrick; Magne, Eric; Mattivi, Fulvio; Capuron, Lucile

doi:10.3389/fimmu.2020.00557

Cited by 120 publications

(102 citation statements)

References 38 publications

(52 reference statements)

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“…Notably, lower SLC6A19 levels are selectively associated with lower tryptophan levels in small bowel CD [37, 40] (Figure 7, adapted from prior literature on RAAS pathway [11, 35, 41, 42]). Dysregulated tryptophan metabolism has been linked to systemic inflammation [43, 44]. The biologic mechanisms that link levels of tryptophan to disease intestinal inflammation and obesity are complex, including host and microbial production of bioactive tryptophan metabolites [40, 45, 46] and the selective roles of these metabolites on molecular processes such as energy checkpoint [37, 47, 48] and transcriptional controls of inflammation pathways [49, 50].…”

Section: Discussionmentioning

confidence: 99%

Reduced expression of COVID-19 host receptor,ACE2is associated with small bowel inflammation, more severe disease, and response to anti-TNF therapy in Crohn’s disease

Potdar

Dube

Naito

et al. 2020

Preprint

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Angiotensin-Converting Enzyme 2 (ACE2) has been identified as the host receptor for SARScoronavirus 2 (SARS-CoV-2) which has infected millions world-wide and likely caused hundreds of thousands of deaths. Utilizing transcriptomic data from four cohorts taken from Crohn's disease (CD) and non-inflammatory bowel disease (IBD) subjects, we observed evidence of increased ACE2 mRNA in ileum with demographic features that have been associated with poor outcomes in COVID-19 including age and raised BMI. ACE2 was downregulated in CD compared to controls in independent cohorts. Within CD, ACE2 expression was reduced in inflamed ileal tissue and also remarkably, from un-involved tissue in patients with a worse prognosis in both adult and pediatric cohorts. In active CD, small bowel ACE2 expression was restored by anti-TNF therapy particularly in anti-TNF responders. Collectively our data suggest that ACE2 downregulation is associated with inflammation and worse outcomes in CD. Methods Tissue Samples and Study SubjectsWe investigated association of ACE2 mRNA with age at collection, gender, smoking, BMI, diagnosis, CD sub-phenotypes and cytokine levels in 4 independent transcriptomic datasets of SB gene expression contingent on availability of meta-data for each cohort (see Table 1). Three of these cohorts have been described previously. In all 4 cohorts the small bowel specimens were taken from macroscopically normal appearing tissue.The 'SB139' [13] dataset was generated using whole Human Genome 4x44k Microarrays (Agilent) from formalin fixed paraffin embedded (FFPE) tissue taken from the unaffected margin of SB tissue resected during ileo-cecal or SB resection for complicated CD. Median age at time of surgery, which were all performed at Cedars-Sinai Medical Center, Los Angeles, was 32 years. The 'WashU' dataset [14] was generated by RNA-seq and similarly was generated from FFPE tissue from the unaffected proximal margin of resected CD tissues and also from FFPE from non-IBD control subjects. These subjects had a median age of 51 years at time of surgery which were all performed at the University of Washington, St Louis. The 'RISK' [15, 16] dataset was generated by RNA-seq from ileal biopsies taken from pediatric subjects in a CD inception cohort from multiple centers across North America (median age at time of biopsy 12 years). Being an inception cohort the age of diagnosis and age at specimen collection are the same. The CD subjects in RISK cohort were divided into two groups: those that had no small bowel/ileal disease (cCD) and those where the ileum was involved (iCD). The 'Cedars100' [17] dataset has not been previously published but similarly, utilized FFPE from un-involved proximal resection margins from complicated CD surgeries (performed at Cedars-Sinai Medical Center) and transcriptomics were generated by RNA-seq. All study subjects in SB139 and Cedars100 were CD; the WashU cohort consisted of CD and non-IBD controls and RISK cohort is a mix of CD, UC, and non-IBD controls.In addition we looked at the effect ...

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Section: Discussionmentioning

confidence: 99%

Reduced expression of COVID-19 host receptor,ACE2is associated with small bowel inflammation, more severe disease, and response to anti-TNF therapy in Crohn’s disease

Potdar

Dube

Naito

et al. 2020

Preprint

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“…Inflammatory factors IFN-gamma, IL-1, LPS and TNF-alpha stimulate the expression of IDO, which is the rate-limiting enzyme of the Kyn pathway [ 53 , 54 , 55 ]. Kyn can cause inflammation in various organs and Kyn/Trp has been used as an indicator of the progression of inflammation [ 56 , 57 , 58 ].…”

Section: Gut Microbiota Metabolites In the Pathogenesis Of Nafldmentioning

confidence: 99%

Gut Microbiota Metabolites in NAFLD Pathogenesis and Therapeutic Implications

Chen¹,

Vitetta

2020

IJMS

179

137

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Gut microbiota dysregulation plays a key role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) through its metabolites. Therefore, the restoration of the gut microbiota and supplementation with commensal bacterial metabolites can be of therapeutic benefit against the disease. In this review, we summarize the roles of various bacterial metabolites in the pathogenesis of NAFLD and their therapeutic implications. The gut microbiota dysregulation is a feature of NAFLD, and the signatures of gut microbiota are associated with the severity of the disease through altered bacterial metabolites. Disturbance of bile acid metabolism leads to underactivation of bile acid receptors FXR and TGR5, causal for decreased energy expenditure, increased lipogenesis, increased bile acid synthesis and increased macrophage activity. Decreased production of butyrate results in increased intestinal inflammation, increased gut permeability, endotoxemia and systemic inflammation. Dysregulation of amino acids and choline also contributes to lipid accumulation and to a chronic inflammatory status. In some NAFLD patients, overproduction of ethanol produced by bacteria is responsible for hepatic inflammation. Many approaches including probiotics, prebiotics, synbiotics, faecal microbiome transplantation and a fasting-mimicking diet have been applied to restore the gut microbiota for the improvement of NAFLD.

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“…Compared to lean individuals, obese patients display reduced circulating levels of Trp 117 , increased kynurenine/Trp ratio [117][118][119] indicating increased IDO activity. The increased kynureine/Trp ratio is confirmed in overweight/obese individuals with the metabolic syndrome 118 .…”

Section: Kynureninementioning

confidence: 99%

Metabolism and Metabolic Disorders and the Microbiome: The Intestinal Microbiota Associated With Obesity, Lipid Metabolism, and Metabolic Health—Pathophysiology and Therapeutic Strategies

et al. 2021

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Changes in the intestinal microbiome have been associated with obesity and type 2 4 diabetes, in epidemiological studies and studies of the effects of fecal transfer in germ-free mice. We review the mechanisms by which alterations in the intestinal microbiome contribute to development of metabolic diseases, and recent advances, such as the effects of the microbiome on lipid metabolism. Strategies have been developed to modify the intestinal microbiome and reverse metabolic alterations, which might be used as therapies. We discuss approaches that have shown effects in mouse models of obesity and metabolic disorders, and how these might be translated to humans to improve metabolic health.

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Tryptophan Metabolic Pathways Are Altered in Obesity and Are Associated With Systemic Inflammation

Cited by 120 publications

References 38 publications

Reduced expression of COVID-19 host receptor,ACE2is associated with small bowel inflammation, more severe disease, and response to anti-TNF therapy in Crohn’s disease

Reduced expression of COVID-19 host receptor,ACE2is associated with small bowel inflammation, more severe disease, and response to anti-TNF therapy in Crohn’s disease

Gut Microbiota Metabolites in NAFLD Pathogenesis and Therapeutic Implications

Metabolism and Metabolic Disorders and the Microbiome: The Intestinal Microbiota Associated With Obesity, Lipid Metabolism, and Metabolic Health—Pathophysiology and Therapeutic Strategies

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