DANIELLE CRISTINA FONSECA CANDIAN
Projetos de Pesquisa
Unidades Organizacionais
LIM/35 - Laboratório de Nutrição e Cirurgia Metabólica do Aparelho Digestivo, Hospital das Clínicas, Faculdade de Medicina
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- Potential premalignant status of gastric portion excluded after Roux en-Y gastric bypass in obese women: A pilot study(2019) RAVACCI, Graziela Rosa; ISHIDA, Robson; TORRINHAS, Raquel Suzana; SALA, Priscila; MACHADO, Natasha Mendonca; FONSECA, Danielle Cristina; CANUTO, Gisele Andre Baptista; PINTO, Ernani; NASCIMENTO, Viviane; TAVARES, Marina Franco Maggi; SAKAI, Paulo; FAINTUCH, Joel; SANTO, Marco Aurelio; MOURA, Eduardo Guimaraes Hourneaux; ARTIGIANI NETO, Ricardo; LOGULLO, Angela Flavia; WAITZBERG, Dan LinetzkyWe evaluated whether the excluded stomach (ES) after Roux-en-Y gastric bypass (RYGB) can represent a premalignant environment. Twenty obese women were prospectively submitted to double-balloon enteroscopy (DBE) with gastric juice and biopsy collection, before and 3 months after RYGB. We then evaluated morphological and molecular changes by combining endoscopic and histopathological analyses with an integrated untargeted metabolomics and transcriptomics multiplatform. Preoperatively, 16 women already presented with gastric histopathological alterations and an increased pH (>= 4.0). These gastric abnormalities worsened after RYGB. A 90-fold increase in the concentration of bile acids was found in ES fluid, which also contained other metabolites commonly found in the intestinal environment, urine, and faeces. In addition, 135 genes were differentially expressed in ES tissue. Combined analysis of metabolic and gene expression data suggested that RYGB promoted activation of biological processes involved in local inflammation, bacteria overgrowth, and cell proliferation sustained by genes involved in carcinogenesis. Accumulated fluid in the ES appears to behave as a potential premalignant environment due to worsening inflammation and changing gene expression patterns that are favorable to the development of cancer. Considering that ES may remain for the rest of the patient's life, long-term ES monitoring is therefore recommended for patients undergoing RYGB.
- Gastrointestinal Transcriptomic Response of Metabolic Vitamin B12 Pathways in Roux-en-Y Gastric Bypass(2017) SALA, Priscila; BELARMINO, Giliane; TORRINHAS, Raquel S.; MACHADO, Natasha M.; FONSECA, Danielle C.; RAVACCI, Graziela R.; ISHIDA, Robson K.; GUARDA, Ismael F. M. S.; MOURA, Eduardo G. de; SAKAI, Paulo; SANTO, Marco A.; SILVA, Ismael D. C. G. da; PEREIRA, Claudia C. A.; LOGULLO, Angela F.; HEYMSFIELD, Steven; GIANNELLA-NETO, Daniel; WAITZBERG, Dan L.OBJECTIVES: Vitamin B12 (B12) deficiency after Roux-en-Y gastric bypass (RYGB) is highly prevalent and may contribute to postoperative complications. Decreased production of intrinsic factor owing to gastric fundus removal is thought to have a major role, but other components of B12 metabolism may also be affected. We evaluated changes in the expression levels of multiple B12 pathway-encoding genes in gastrointestinal (GI) tissues to evaluate the potential roles in contributing to post-RYGB B12 deficiency. METHODS: During double-balloon enteroscopy, serial GI biopsies were collected from 20 obese women (age, 46.9 +/- 6.2 years; body mass index, 46.5 +/- 5.3 kg/m(2)) with adult-onset type 2 diabetes (fasting plasma glucose >= 126 mg/dl; hemoglobin A1c >= 6.5%) before and, at the same site, 3 months after RYGB. Gene expression levels were assessed by the Affymetrix Human GeneChip 1.0 ST microarray. Findings were validated by real-time quantitative PCR (RT-qPCR). RESULTS: Gene expression levels with significant changes (P <= 0.05) included: transcobalamin I (TCN1) in remnant (-1.914-fold) and excluded (-1.985-fold) gastric regions; gastric intrinsic factor (GIF) in duodenum (-0.725-fold); and cubilin (CUBN) in duodenum (+0.982-fold), jejunum (+1.311-fold), and ileum (+0.685-fold). Validation by RT-qPCR confirmed (P <= 0.05) observed changes for TCN1 in the remnant gastric region (-0.132-fold) and CUBN in jejunum (+2.833-fold). CONCLUSIONS: RYGB affects multiple pathway-encoding genes that may be associated with postoperative B12 deficiency. Decreased TCN1 levels seem to be the main contributing factor. Increased CUBN levels suggest an adaptive genetic reprogramming of intestinal tissue aiming to compensate for impaired intestinal B12 delivery.
- Genetic reprogramming of rHemnant duodenum may contribute to type 2 diabetes improvement after Roux-en-Y gastric bypass(2022) SALA, Priscila; MACHADO, Natasha Mendonca; TORRINHAS, Raquel Susana Matos de Miranda; FONSECA, Danielle C.; FERREIRA, Beatriz A. M.; ISHIDA, Robson Kiyoshi; GUARDA, Ismael Francisco Mota Siqueira; MOURA, Eduardo Guimaraes Hourneaux de; SAKAI, Paulo; SANTO, Marco Aurelio; HEYMSFIELD, Steven B.; CORREA-GIANNELLA, Maria Lucia; WAITZBERG, Dan LinetzkyObjectives: Type 2 diabetes control occurs within a few days after Roux-en-Y gastric bypass (RYGB) and might be related to intestinal adaptation to the new anatomic arrangement. The aim of this study was to evaluate the intestinal transcriptome response to RYGB and its correlation with markers of glycemic homeostasis. Methods: Global transcriptomic analyses performed by microarray technique were conducted in intestinal biopsies collected from adult women with obesity (N = 20) and T2D before and 3 mo after RYGB. Clinical and biochemical markers of glycemic homeostasis were also evaluated. At 1-y postoperative, patients were clas-sified as responsive (R) or non-responsive (NR) to complete T2D remission according to the American Diabe-tes Association criteria. Intestinal differentially expressed genes (DEGs) were analyzed separately in the two groups, validated by reverse transcription quantitative polymerase chain reaction, and applied in functional enrichment and canonical pathway analysis. Spearman correlations between clinical and biochemical varia-bles with DEGs were conducted. Twelve patients were classified as R and displayed 62 (duodenum), 241 (jejunum), and 63 (ileum) DEGs. Results: Eight of the patients with DEGs presented very strong or strong positive correlations with glycemia or glycated hemoglobin. Duodenal changes of genes involved in the LXR/RXR pathway were more likely to be associated with T2D. Conclusion: In obese women, complete remission of T2D after RYGB might include intestinal transcriptomic changes that suggest a potential role of intracellular cholesterol and lipid homeostasis on glucose control.(c) 2022 Elsevier Inc. All rights reserved.
- Roux-en-Y gastric bypass affects the expression of genes related to the intestinal folate metabolism pathway in obese women(2023) FERREIRA, Beatriz de Azevedo Muner; FONSECA, Danielle Cristina; SALA, Priscila; ALVES, Juliana Tepedino Martins; PRUDENCIO, Ana Paula Aguiar; MACHADO, Natasha Mendonca; MARQUES, Mariane; BARCELOS, Samira; ISHIDA, Robson Kiyoshi; GUARDA, Ismael Francisco Mota Siqueira; MOURA, Eduardo Guimaraes Hourneaux De; SAKAI, Paulo; SANTE, Marco Aurelio; TORRINHAS, Raquel Susana Matos de Miranda; WAITZBERG, Dan LinetzkyObjectives: Roux-en-Y gastric bypass (RYGB) promotes sustained weight loss, and the resulting new gastroin-testinal anatomy can contribute to nutritional depletions. Folate deficiency is one of the most frequently observed nutritional deficiencies after RYGB. The aim of this study was to assess whether RYGB affects the expression of genes related to the intestinal folate metabolism pathway as an additional molecular mecha-nism contributing to its postoperative deficiency. Methods: Biopsies from the duodenum, jejunum, and ileum of 20 obese women were collected before and 3 mo after RYGB. The expression of genes involved in intestinal folate metabolism was assessed by microarray and reverse transcriptase polymerase chain reaction (RT-qPCR). Folate intake (7-d food record) and plasma levels (electrochemiluminescence) also were measured. Results: Compared with the preoperative phase, transcriptomic alterations were observed in all intestinal segments studied after RYBG, mainly marked by decreased expression of genes encoding folate transporters/ receptors and increased expression of genes involved in folate biosynthesis (P < 0.05). Reduced folate intake and plasma folate levels were also observed simultaneously (P < 0.05). Plasma folate concentrations corre-lated inversely with intestinal FOLR2 and SHMT2 genes (P < 0.001). Conclusion: The present findings suggested that impaired expression of genes related to intestinal folate metabolism may contribute to the early systemic deficiency after RYGB and highlight a potential transcrip-tomic reprogramming of the intestine in response to RYGB to compensate for folate depletion induced by this surgical technique.(c) 2023 Elsevier Inc. All rights reserved.
- Intestinal expression of toll-like receptor gene changes early after gastric bypass surgery and association with type 2 diabetes remission(2020) SALA, Priscila; TORRINHAS, Raquel Susana Matos de Miranda; FONSECA, Danielle C.; MACHADO, Natasha Mendonca; SINGER, Joelle; SINGER, Pierre; RAVACCI, Graziela Rosa; BELARMINO, Giliane; FERREIRA, Beatriz A. M.; MARQUES, Mariane; ISHIDA, Robson Kiyoshi; GUARDA, Ismael Francisco Mota Siqueira; MOURA, Eduardo Guimaraes Hourneaux de; SAKAI, Paulo; SANTO, Marco Aurelio; SUNAGA, Daniele Yumi; HEYMSFIELD, Steven B.; BEZERRA, Daniele Pereira dos Santos; CORREA-GIANNELLA, Maria Lucia; WAITZBERG, Dan LinetzkyObjectives: Abnormal activation of toll-like receptors (TLRs) is observed in obese rodents and is correlated with local dysbiosis and increased gut permeability. These purported changes trigger systemic inflammation associated with obesity-related comorbidities, including type 2 diabetes (T2D). Roux-en-Y gastric bypass (RYGB) surgery is an effective treatment for severe obesity and known to induce changes in the gut microbiota and decrease systemic inflammation in humans. This study examined the intestinal expression of TLR-encoding genes in obese women (n = 20) treated with RYGB surgery and the relationship of these genes with T2D remission (T2Dr Methods: Intestinal biopsies were performed before and 3 months after RYGB surgery. Partial and complete T2Dr after 1 year was assessed using the American Diabetes Association criteria. Affymetrix Human GeneChip 1.0 ST array (microarray) and TaqMan assay (real-time quantitative polymerase chain reaction) were used to analyze intestinal gene expression, and associations with systemic markers of energy homeostasis were examined. Results: Patients experienced significant weight loss (P < 0.001) and altered gut TLR gene expression 3 months after surgery. The main effects were a reduction in jejunal TLR4 expression in patients with complete and partial T2Dr (P < 0.05). There was a postoperative decrease in jejunal TLR7 expression in patients with complete T2Dr that correlated inversely with high-density lipoprotein cholesterol and positively with triglyceride concentrations, but not with weight loss. Conclusions: RYGB-induced weight loss-independent changes in the expression of intestinal TLR-encoding genes in obese women and complete T2Dr that was correlated with systemic markers of energy homeostasis. The modulation of intestinal TLRs may mediate inflammatory mechanisms linked to T2Dr after RYGB surgery.
- The SURMetaGIT study: Design and rationale for a prospective pan-omics examination of the gastrointestinal response to Roux-en-Y gastric bypass surgery(2016) SALA, Priscila; BELARMINO, Giliane; MACHADO, Natasha Mendonca; CARDINELLI, Camila Siqueira; ASSAL, Karina Al; SILVA, Mariane Marques; FONSECA, Danielle Cristina; ISHIDA, Robson Kiyoshi; SANTO, Marco Aurelio; MOURA, Eduardo Guimaraes Hourneaux de; SAKAI, Paulo; GUARDA, Ismael Francisco Mota Siqueira; SILVA, Ismael Dale Cotrim Guerreiro da; RODRIGUES, Agatha Sacramento; PEREIRA, Carlos Alberto de Braganca; HEYMSFIELD, Steven; DORE, Joel; TORRINHAS, Raquel Susana Matos de Miranda; GIANNELLA-NETO, Daniel; WAITZBERG, Dan LinetzkyObjective: To describe the protocol of the SURgically induced Metabolic effects on the Human GastroIntestinal Tract (SURMetaGIT) study, a clinical pan-omics study exploring the gastrointestinal tract as a central organ driving remission of type 2 diabetes mellitus (T2DM) after Roux-en-Y gastric bypass (RYGB). The main points considered in the study's design and challenges faced in its application are detailed. Methods: This observational, longitudinal, prospective study involved collection of gastrointestinal biopsy specimens, faeces, urine, and blood from 25 obese women with T2DM who were candidates for RYGB (20 patients for omics assessment and 5 for omics validation). These collections were performed preoperatively and 3 and 24 months postoperatively. Gastrointestinal transcriptomics; faecal metagenomics and metabolomics; plasma proteomics, lipidomics, and metabolomics; and biochemical, nutritional, and metabolic data were assessed to identify their short- and long-term correlations with T2DM remission. Results: Data were collected from 20 patients before and 3 months after RYGB. These patients have nearly completed the 2-year follow-up assessments. The five additional patients are currently being selected for omics data validation. Conclusion: The multi-integrated pan-omics approach of the SURMetaGIT study enables integrated analysis of data that will contribute to the understanding of molecular mechanisms involved in T2DM remission after RYGB.
- Gastrointestinal genetic reprogramming of vitamin A metabolic pathways in response of Roux-en-Y gastric bypass(2024) SAMPAIO, Priscilla; WAITZBERG, Dan Linetzky; MACHADO, Natasha Mendonca; TORRINHAS, Raquel Susana Matos de Miranda; FONSECA, Danielle C.; FERREIRA, Beatriz A. M.; MARQUES, Mariane; BARCELOS, Samira; ISHIDA, Robson Kiyoshi; GUARDA, Ismael Francisco Mota Siqueira; MOURA, Eduardo Guimaraes Hourneaux de; SAKAI, Paulo; SANTO, Marco Aurelio; HEYMSFIELD, Steven B.; CORREA-GIANNELLA, Maria Lucia; PASSADORE, Mariana Doce; SALA, PriscilaRoux-en-Y gastric bypass (RYGB) is one of the most performed bariatric surgical techniques. However, RYGB commonly results, as side effects, in nutritional deficiencies. This study aimed to examine changes in the expression of vitamin A pathway encoding genes in the gastrointestinal tract (GI) and to evaluate the potential mechanisms associated with hypovitaminosis A after RYGB. Intestinal biopsies were obtained through double-balloon endoscopy in 20 women with obesity (age 46.9 +/- 6.2 years; body mass index [BMI] 46.5 +/- 5.3 kg/m(2) [mean +/- SD]) before and three months after RYGB (BMI, 38.2 +/- 4.2 kg/m(2)). Intestinal mucosal gene microarray analyses were performed in samples using a Human GeneChip 1.0 ST array (Affymetrix). Vitamin A intake was assessed from 7-day food records and serum retinot levels were evaluated by electrochemiluminescence immunoassay. Our results showed the following genes with significant downregulation (p <= 0.05): LIPF (-0.60), NPC1L1 (-0.71), BCO1 (-0.45), and RBP4 (-0.13) in duodenum: CD36 (-0.33), and ISX (-0.43) in jejunum and BCO1 (-0.29) in ileum. No significant changes in vitamin A intake were found (784 +/- 694 retinal equivalents [RE] pre-operative vs. 809 +/- 753 RE post-operative [mean +/- SD]). Although patients were routinely supplemented with 3500 international units IU/day (equivalent to 1050 mu gRE/day) of oral retinal palm itate, serum concentrations were lower in the post-operative when compared to pre-operative period (0.35 +/- 0.14 mu g/L vs. 0.52 +/- 0.33 mu g/L respectively - P=0.07), both within the normal range. After RYGB, the simultaneous change in expression of GI genes, may impair carotenoid metabolism in the enterocytes, formation of nascent chylomicrons and transport of retinol, resulting in lower availability of vitamin A.
- Reduced intestinal FADS1 gene expression and plasma omega-3 fatty acids following Roux-en-Y gastric bypass(2019) GARLA, Priscila; SALA, Priscila; TORRINHAS, Raquel Susana Matos; MACHADO, Natasha Mendonca; FONSECA, Danielle Cristina; SILVA, Mariane Marques da; RAVACCI, Graziela Rosa; BELARMINO, Giliane; ISHIDA, Robson Kiyoshi; GUARDA, Ismael Francisco Mota Siqueira; MOURA, Eduardo Guimardes Hourneaux de; SAKAI, Paulo; SANTO, Marco Aurelio; SILVA, Ismael Dale Cotrim Guerreiro da; PEREIRA, Claudia Cristina Alves; HEYMSFIELD, Steven; CORREA-GIANNELLA, Maria Lucia Cardillo; CALDER, Philip C.; WAITZBERG, Dan LinetzkyBackground & aims: Roux-en-Y gastric bypass (RYGB) limits food ingestion and may alter the intestinal expression of genes involved in the endogenous synthesis of polyunsaturated fatty acids (PUFAs). These changes may decrease the systemic availability of bioactive PUFA5 after RYGB. To study the impact of RYGB on the dietary ingestion and plasma concentration of PUFA5 and on the intestinal expression of genes involved in their endogenous biosynthesis in severely obese women with type 2 diabetes. Methods: Before, and 3 and 12 months after RYGB, obese women (n = 20) self-reported a seven-day dietary record, answered a food frequency query and provided plasma samples for alpha-linolenic (ALA), eicosapentaenoic (EPA), docosahexaenoic (DHA) and arachidonic (ARA) acid assessment by gas chromatography. Intestinal biopsies (duodenum, jejunum and ileum) were collected through double balloon endoscopy before and 3 months after RYGB for gene expression analysis by microarray (Human GeneChip 1.0 ST array) and RT-qPCR validation. Results: Compared to the preoperative period, patients had decreased intakes of PUFAs, fish and soybean oil (p < 0.05) and lower plasma concentrations of ALA and EPA (p < 0.001) 3 and 12 months after RYGB. FADS] gene expression was lower in duodenum (RT-qPCR fold change = 1.620, p < 0.05) and jejunum (RT-qPCR fold change = -1.549, p < 0.05) 3 months following RYGB, compared to before surgery. Conclusion: RYGB decreased PUFA ingestion, plasma ALA and EPA levels, and intestinal expression of FADS] gene. The latter encodes a key enzyme involved in endogenous biosynthesis of PUFA5. These data suggest that supplementation of omega-3 PUFAs may be required for obese patients undergoing RYGB. Clinical Trial Registry number and website: www.clinicaltrials.gov NCT01251016; Plataforma Brasil - 19339913.0.0000.0068. (C) 02018 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.