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From 2013 to 2014, a nested sub-study of 207 women from the NHS2, the Mind Body Study (MBS), collected up to four stool samples, a fasting blood sample, dietary information, and detailed depression symptom questionnaires.", "x": "/html/body/div[4]/div[4]/main/article/section[4]/div/div/div[1]/figure/div[1]/div[2]/p/b"}]}, "tags": ["img", "b"], "label": "content", "web_segment_id": 81, "global_sentence_id": 203, "edu_l1_label": "IOS"}, {"txt": " Stool samples were then profiled through metagenomics (MGX), and blood was analyzed by untargeted metabolomics (MBX).", "language": "english", "position": {"atoms": [{"position_id": 2256, "txt": " Stool samples were then profiled through metagenomics (MGX), and blood was analyzed by untargeted metabolomics (MBX).", "x": "/html/body/div[4]/div[4]/main/article/section[4]/div/div/div[1]/figure/div[1]/div[2]/p/b"}]}, "tags": ["b", "img"], "label": "content", "web_segment_id": 81, "global_sentence_id": 204, "edu_l1_label": "IOS"}, {"txt": " In the 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Greater intake of citrus is prospectively associated with a decreased risk of depression (p-trend 0.001) after adjustment for covariates including age, BMI, activity, smoking status, menopausal hormone therapy, total caloric intake, intake of alcohol, comorbidities (history of diabetes mellitus, hypertension, and dyslipidemia), social network level, median family income, overall diet quality, and sleep hours.", "language": "english", "position": {"atoms": [{"position_id": 2308, "txt": " ", "x": "/html/body/div[4]/div[4]/main/article/section[4]/div/div/div[2]/figure/div[1]/div[2]/p/i[1]"}, {"position_id": 2310, "txt": "A", "x": "/html/body/div[4]/div[4]/main/article/section[4]/div/div/div[2]/figure/div[1]/div[2]/p/b[1]"}, {"position_id": 2312, "txt": " Greater intake of citrus is prospectively associated with a decreased risk of depression (", "x": "/html/body/div[4]/div[4]/main/article/section[4]/div/div/div[2]/figure/div[1]/div[2]/p/b[1]"}, {"position_id": 2314, "txt": "p", "x": 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independent MLVS cohort, greater abundance of ", "x": "/html/body/div[4]/div[4]/main/article/section[4]/div/div/div[2]/figure/div[1]/div[2]/p/b[5]"}, {"position_id": 2383, "txt": "F. prausnitzii", "x": "/html/body/div[4]/div[4]/main/article/section[4]/div/div/div[2]/figure/div[1]/div[2]/p/i[12]"}, {"position_id": 2385, "txt": " was associated with a composite biomarker score for depression (", "x": "/html/body/div[4]/div[4]/main/article/section[4]/div/div/div[2]/figure/div[1]/div[2]/p/i[12]"}, {"position_id": 2387, "txt": "β", "x": "/html/body/div[4]/div[4]/main/article/section[4]/div/div/div[2]/figure/div[1]/div[2]/p/i[13]"}, {"position_id": 2389, "txt": " = 5.78, ", "x": "/html/body/div[4]/div[4]/main/article/section[4]/div/div/div[2]/figure/div[1]/div[2]/p/i[13]"}, {"position_id": 2391, "txt": "p", "x": "/html/body/div[4]/div[4]/main/article/section[4]/div/div/div[2]/figure/div[1]/div[2]/p/i[14]"}, {"position_id": 2393, "txt": "-value 0.04)", "x": "/html/body/div[4]/div[4]/main/article/section[4]/div/div/div[2]/figure/div[1]/div[2]/p/i[14]"}]}, "tags": ["b", "img"], "label": "figure_title", "web_segment_id": 87, "global_sentence_id": 231, "edu_l1_label": "EDU_O"}, {"txt": "Full size image", "language": "english", "position": {"atoms": [{"position_id": 2395, "txt": "Full size image", "x": "/html/body/div[4]/div[4]/main/article/section[4]/div/div/div[2]/figure/div[2]/a/span"}]}, "tags": ["img"], "label": "O", "web_segment_id": 88, "global_sentence_id": 232, "edu_l1_label": "EDU_O"}, {"txt": "To demonstrate specificity in the relationship between citrus intake and depression risk, we then investigated the associations between total fruit, total vegetable, apple, and banana intake with risk of depression.", "language": "english", "position": {"atoms": [{"position_id": 2397, "txt": "To demonstrate specificity in the relationship between citrus intake and depression risk, we then investigated the associations between total fruit, 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"edu_l1_label": "IOS"}, {"txt": " Among these, only naringenin and formononetin, two flavonoids found in citrus peels and expressed juice, were linked with depression (HR 0.79, 95% CI 0.69–0.91, HR 0.83, 95% CI 0.72–0.96, respectively, Supplementary Table 8).", "language": "english", "position": {"atoms": [{"position_id": 2404, "txt": " Among these, only naringenin and formononetin, two flavonoids found in citrus peels and expressed juice, were linked with depression (HR 0.79, 95% CI 0.69–0.91, HR 0.83, 95% CI 0.72–0.96, respectively, Supplementary Table 8).", "x": "/html/body/div[4]/div[4]/main/article/section[4]/div/div/p[4]/i"}]}, "tags": [], "label": "content", "web_segment_id": 89, "global_sentence_id": 236, "edu_l1_label": "IOS"}, {"txt": " By contrast, vitamin C intake was not linked with depression.", "language": "english", "position": {"atoms": [{"position_id": 2405, "txt": " By contrast, vitamin C intake was not linked with depression.", "x": 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"F. prausnitzii", "x": "/html/body/div[4]/div[4]/main/article/section[4]/div/div/p[9]/i[1]"}, {"position_id": 2641, "txt": " in two independent cohorts.", "x": "/html/body/div[4]/div[4]/main/article/section[4]/div/div/p[9]/i[1]"}]}, "tags": [], "label": "content", "web_segment_id": 96, "global_sentence_id": 280, "edu_l1_label": "IOS"}, {"txt": " In turn, the abundance of F. prausnitzii is inversely associated with depression in both cohorts.", "language": "english", "position": {"atoms": [{"position_id": 2642, "txt": " In turn, the abundance of ", "x": "/html/body/div[4]/div[4]/main/article/section[4]/div/div/p[9]/i[1]"}, {"position_id": 2644, "txt": "F. prausnitzii", "x": "/html/body/div[4]/div[4]/main/article/section[4]/div/div/p[9]/i[2]"}, {"position_id": 2646, "txt": " is inversely associated with depression in both cohorts.", "x": "/html/body/div[4]/div[4]/main/article/section[4]/div/div/p[9]/i[2]"}]}, "tags": [], "label": "content", "web_segment_id": 96, "global_sentence_id": 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[{"position_id": 2654, "txt": "Having linked citrus intake with a greater abundance of ", "x": "/html/body/div[4]/div[4]/main/article/section[4]/div/div/p[10]"}, {"position_id": 2656, "txt": "F. prausnitzii,", "x": "/html/body/div[4]/div[4]/main/article/section[4]/div/div/p[10]/i[1]"}, {"position_id": 2658, "txt": " and having found that, in turn, ", "x": "/html/body/div[4]/div[4]/main/article/section[4]/div/div/p[10]/i[1]"}, {"position_id": 2660, "txt": "F. prausnitzii", "x": "/html/body/div[4]/div[4]/main/article/section[4]/div/div/p[10]/i[2]"}, {"position_id": 2662, "txt": " was associated with a lower risk of depression, we next investigated the mechanisms by which this association may occur.", "x": "/html/body/div[4]/div[4]/main/article/section[4]/div/div/p[10]/i[2]"}]}, "tags": [], "label": "content", "web_segment_id": 98, "global_sentence_id": 283, "edu_l1_label": "IOS"}, {"txt": " Using linear mixed effects models with multivariable adjustment, we agnostically related all 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[{"position_id": 2668, "txt": " Of these, we found 48 meeting our threshold (", "x": "/html/body/div[4]/div[4]/main/article/section[4]/div/div/p[10]/i[3]"}, {"position_id": 2670, "txt": "q", "x": "/html/body/div[4]/div[4]/main/article/section[4]/div/div/p[10]/i[4]"}, {"position_id": 2672, "txt": " < 0.05) that were contributed by ", "x": "/html/body/div[4]/div[4]/main/article/section[4]/div/div/p[10]/i[4]"}, {"position_id": 2674, "txt": "F. prausnitzii", "x": "/html/body/div[4]/div[4]/main/article/section[4]/div/div/p[10]/i[5]"}, {"position_id": 2676, "txt": " (Supplementary Table 10).", "x": "/html/body/div[4]/div[4]/main/article/section[4]/div/div/p[10]/i[5]"}]}, "tags": [], "label": "content", "web_segment_id": 98, "global_sentence_id": 285, "edu_l1_label": "IOS"}, {"txt": " To minimize the odds of finding “passenger” functions, which merely correlate with an abundance of F. prausnitzii, we first took a data-driven approach and used prespecified criteria to filter out pathways with extremely high function-species abundance correlations (rho > 0.9, “Methods”).", "language": "english", "position": {"atoms": [{"position_id": 2677, "txt": " To minimize the odds of finding “passenger” functions, which merely correlate with an abundance of ", "x": "/html/body/div[4]/div[4]/main/article/section[4]/div/div/p[10]/i[5]"}, {"position_id": 2679, "txt": "F. prausnitzii", "x": "/html/body/div[4]/div[4]/main/article/section[4]/div/div/p[10]/i[6]"}, {"position_id": 2681, "txt": ", we first took a data-driven approach and used prespecified criteria to filter out pathways with extremely high function-species abundance correlations (rho > 0.9, “Methods”).", "x": "/html/body/div[4]/div[4]/main/article/section[4]/div/div/p[10]/i[6]"}]}, "tags": [], "label": "content", "web_segment_id": 98, "global_sentence_id": 286, "edu_l1_label": "IOS"}, {"txt": " Then, we reviewed the remaining subset of 25 pathways and found that an abundance of the S-adenosyl-L-methionine (SAM) cycle I pathway 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" 3B).", "language": "english", "position": {"atoms": [{"position_id": 2691, "txt": " ", "x": "/html/body/div[4]/div[4]/main/article/section[4]/div/div/p[10]/i[8]"}, {"position_id": 2693, "txt": "3", "x": "/html/body/div[4]/div[4]/main/article/section[4]/div/div/p[10]/a[1]"}, {"position_id": 2695, "txt": "B).", "x": "/html/body/div[4]/div[4]/main/article/section[4]/div/div/p[10]/a[1]"}]}, "tags": [], "label": "content", "web_segment_id": 98, "global_sentence_id": 288, "edu_l1_label": "IOS"}, {"txt": " A growing body of evidence suggests that SAM supplementation in clinical trials lowers depression symptoms [60,61,62,63].", "language": "english", "position": {"atoms": [{"position_id": 2696, "txt": " A growing body of evidence suggests that SAM supplementation in clinical trials lowers depression symptoms [", "x": "/html/body/div[4]/div[4]/main/article/section[4]/div/div/p[10]/a[1]"}, {"position_id": 2698, "txt": "60", "x": 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98, "global_sentence_id": 292, "edu_l1_label": "IOS"}, {"txt": "Fig.", "language": "english", "position": {"atoms": [{"position_id": 2725, "txt": "Fig.", "x": "/html/body/div[4]/div[4]/main/article/section[4]/div/div/div[3]/figure/figcaption/b"}]}, "tags": ["b", "figcaption", "img"], "label": "figure_title", "web_segment_id": 99, "global_sentence_id": 293, "edu_l1_label": "EDU_O"}, {"txt": " 3", "language": "english", "position": {"atoms": [{"position_id": 2726, "txt": " 3", "x": "/html/body/div[4]/div[4]/main/article/section[4]/div/div/div[3]/figure/figcaption/b"}]}, "tags": ["b", "figcaption", "img"], "label": "figure_title", "web_segment_id": 99, "global_sentence_id": 294, "edu_l1_label": "EDU_O"}, {"txt": "<img img", "language": "english", "position": {"atoms": [{"position_id": 701, "txt": "<img img", "x": "/html/body/div[4]/div[4]/main/article/section[4]/div/div/div[3]/figure/div[1]/div[1]/a/picture/img"}]}, "tags": ["img"], "label": "figure", "web_segment_id": 100, "global_sentence_id": 295, "edu_l1_label": "EDU_O"}, {"txt": "Metabolic pathways by which F. prausnitzii may influence depression.", "language": "english", "position": {"atoms": [{"position_id": 2728, "txt": "Metabolic pathways by which ", "x": "/html/body/div[4]/div[4]/main/article/section[4]/div/div/div[3]/figure/div[1]/div[2]/p"}, {"position_id": 2730, "txt": "F. prausnitzii", "x": "/html/body/div[4]/div[4]/main/article/section[4]/div/div/div[3]/figure/div[1]/div[2]/p/i[1]"}, {"position_id": 2732, "txt": " may influence depression.", "x": "/html/body/div[4]/div[4]/main/article/section[4]/div/div/div[3]/figure/div[1]/div[2]/p/i[1]"}]}, "tags": ["img"], "label": "figure_title", "web_segment_id": 101, "global_sentence_id": 296, "edu_l1_label": "IOS"}, {"txt": " A Volcano plot demonstrating metagenomic carriage by 4098 pathways from all microbial species in relation to depression.", "language": "english", "position": {"atoms": [{"position_id": 2733, "txt": " ", "x": "/html/body/div[4]/div[4]/main/article/section[4]/div/div/div[3]/figure/div[1]/div[2]/p/i[1]"}, {"position_id": 2735, "txt": "A", "x": "/html/body/div[4]/div[4]/main/article/section[4]/div/div/div[3]/figure/div[1]/div[2]/p/b[1]"}, {"position_id": 2737, "txt": " Volcano plot demonstrating metagenomic carriage by 4098 pathways from all microbial species in relation to depression.", "x": "/html/body/div[4]/div[4]/main/article/section[4]/div/div/div[3]/figure/div[1]/div[2]/p/b[1]"}]}, "tags": ["img", "b"], "label": "figure_title", "web_segment_id": 101, "global_sentence_id": 297, "edu_l1_label": "EDU_O"}, {"txt": " S-Adenosyl-L-methionine cycle I pathway, encoded by F. prausnitzii, was among the strongest hits.", "language": "english", "position": {"atoms": [{"position_id": 2738, "txt": " S-Adenosyl-L-methionine cycle I pathway, encoded by ", "x": "/html/body/div[4]/div[4]/main/article/section[4]/div/div/div[3]/figure/div[1]/div[2]/p/b[1]"}, {"position_id": 2740, "txt": "F. prausnitzii", "x": "/html/body/div[4]/div[4]/main/article/section[4]/div/div/div[3]/figure/div[1]/div[2]/p/i[2]"}, {"position_id": 2742, "txt": ", was among the strongest hits.", "x": "/html/body/div[4]/div[4]/main/article/section[4]/div/div/div[3]/figure/div[1]/div[2]/p/i[2]"}]}, "tags": ["b", "img"], "label": "figure_title", "web_segment_id": 101, "global_sentence_id": 298, "edu_l1_label": "EDU_O"}, {"txt": " B S-Adenosyl-L-methionine cycle I pathway of F. prausnitzii is reduced in depression (generalized linear mixed effects model, FDR q = 0.01).", "language": "english", "position": {"atoms": [{"position_id": 2743, "txt": " ", "x": "/html/body/div[4]/div[4]/main/article/section[4]/div/div/div[3]/figure/div[1]/div[2]/p/i[2]"}, {"position_id": 2745, "txt": "B", "x": "/html/body/div[4]/div[4]/main/article/section[4]/div/div/div[3]/figure/div[1]/div[2]/p/b[2]"}, {"position_id": 2747, "txt": " S-Adenosyl-L-methionine cycle I pathway of ", "x": "/html/body/div[4]/div[4]/main/article/section[4]/div/div/div[3]/figure/div[1]/div[2]/p/b[2]"}, {"position_id": 2749, "txt": "F. prausnitzii", "x": "/html/body/div[4]/div[4]/main/article/section[4]/div/div/div[3]/figure/div[1]/div[2]/p/i[3]"}, {"position_id": 2751, "txt": " is reduced in depression (generalized linear mixed effects model, FDR ", "x": "/html/body/div[4]/div[4]/main/article/section[4]/div/div/div[3]/figure/div[1]/div[2]/p/i[3]"}, {"position_id": 2753, "txt": "q", "x": "/html/body/div[4]/div[4]/main/article/section[4]/div/div/div[3]/figure/div[1]/div[2]/p/i[4]"}, {"position_id": 2755, "txt": " = 0.01).", "x": "/html/body/div[4]/div[4]/main/article/section[4]/div/div/div[3]/figure/div[1]/div[2]/p/i[4]"}]}, "tags": ["b", "img"], "label": "figure_title", "web_segment_id": 101, "global_sentence_id": 299, "edu_l1_label": "EDU_O"}, {"txt": " C In the SAM cycle pathway, S-adenosyl-L-homocysteine (SAH) is hydrolyzed to S-ribosyl-L-homocysteine by adenosylhomocysteine nucleosidase (EC 3.2.2.9) and then converted to L-homocysteine by S-ribosylhomocysteine lyase (EC 4.4.1.21). L-homocysteine is methylated to L-methionine using a methyl group from methylated folate, catalyzed by cobalamin-independent methionine synthase (EC 2.1.1.14).", "language": "english", "position": {"atoms": [{"position_id": 2756, "txt": " ", "x": "/html/body/div[4]/div[4]/main/article/section[4]/div/div/div[3]/figure/div[1]/div[2]/p/i[4]"}, {"position_id": 2758, "txt": "C", "x": "/html/body/div[4]/div[4]/main/article/section[4]/div/div/div[3]/figure/div[1]/div[2]/p/b[3]"}, {"position_id": 2760, "txt": " In the SAM cycle pathway, S-adenosyl-L-homocysteine (SAH) is hydrolyzed to S-ribosyl-L-homocysteine by adenosylhomocysteine nucleosidase (EC 3.2.2.9) and then converted to L-homocysteine by S-ribosylhomocysteine lyase (EC 4.4.1.21). L-homocysteine is methylated to L-methionine using a methyl group from methylated folate, catalyzed by cobalamin-independent methionine synthase (EC 2.1.1.14).", "x": "/html/body/div[4]/div[4]/main/article/section[4]/div/div/div[3]/figure/div[1]/div[2]/p/b[3]"}]}, "tags": ["img", "b"], "label": "figure_title", "web_segment_id": 101, "global_sentence_id": 300, "edu_l1_label": "EDU_O"}, {"txt": " The SAM cycle is completed with the regeneration of SAM by SAM synthetase (EC 2.5.1.6). Abundance of the EC 3.2.2.9, EC 4.4.1.21, and EC 2.5.1.6 were significantly associated with depression (FDR q 0.004, 0.006, and 0.004, respectively).", "language": "english", "position": {"atoms": [{"position_id": 2761, "txt": " The SAM cycle is completed with the regeneration of SAM by SAM synthetase (EC 2.5.1.6). Abundance of the EC 3.2.2.9, EC 4.4.1.21, and EC 2.5.1.6 were significantly associated with depression (FDR q 0.004, 0.006, and 0.004, respectively).", "x": "/html/body/div[4]/div[4]/main/article/section[4]/div/div/div[3]/figure/div[1]/div[2]/p/b[3]"}]}, "tags": ["b", "img"], "label": "figure_title", "web_segment_id": 101, "global_sentence_id": 301, "edu_l1_label": "EDU_O"}, {"txt": " D Naringenin, a flavonoid specific to citrus fruit, was associated with an increased abundance of SAM synthetase, the rate-limiting step in SAM production (β = 0.00001, p-value = 0.038).", "language": "english", "position": {"atoms": [{"position_id": 2762, "txt": " ", "x": "/html/body/div[4]/div[4]/main/article/section[4]/div/div/div[3]/figure/div[1]/div[2]/p/b[3]"}, {"position_id": 2764, "txt": "D", "x": "/html/body/div[4]/div[4]/main/article/section[4]/div/div/div[3]/figure/div[1]/div[2]/p/b[4]"}, {"position_id": 2766, "txt": " Naringenin, a flavonoid specific to citrus fruit, was associated with an increased abundance of SAM synthetase, the rate-limiting step in SAM production (", "x": "/html/body/div[4]/div[4]/main/article/section[4]/div/div/div[3]/figure/div[1]/div[2]/p/b[4]"}, {"position_id": 2768, "txt": "β", "x": "/html/body/div[4]/div[4]/main/article/section[4]/div/div/div[3]/figure/div[1]/div[2]/p/i[5]"}, {"position_id": 2770, "txt": " = 0.00001, ", "x": "/html/body/div[4]/div[4]/main/article/section[4]/div/div/div[3]/figure/div[1]/div[2]/p/i[5]"}, {"position_id": 2772, "txt": "p", "x": "/html/body/div[4]/div[4]/main/article/section[4]/div/div/div[3]/figure/div[1]/div[2]/p/i[6]"}, {"position_id": 2774, "txt": "-value = 0.038).", "x": "/html/body/div[4]/div[4]/main/article/section[4]/div/div/div[3]/figure/div[1]/div[2]/p/i[6]"}]}, "tags": ["b", "img"], "label": "figure_title", "web_segment_id": 101, "global_sentence_id": 302, "edu_l1_label": "EDU_O"}, {"txt": " E Greater abundance of S-adenosyl-L-methionine pathway was associated with lower monoamine oxidase A (MAOA) gene 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# F. prausnitzii potentially modulates the association between citrus intake and depression
## Abstract
### Background
### Results
### Conclusions
## Introduction
## Materials and methods
### Study population
### Assessment of citrus intake
### Assessment of depression
### Covariate assessment
### Blood collection and metabolomics profiling
### Stool collection and metagenomic sequencing
### Statistical analysis
#### Prospective association between citrus consumption and risk of depression
#### Prospective association of citrus consumption with overall microbiome communities and specific microbial species
#### Association of specific microbial species with depression status
#### The association of microbial genes, enzymes, and pathways with depression status
#### Validation of gut microbial species on biomarker-related depression in Men’s Lifestyle Validation Study (MLVS)
### Study population
### Blood collection and metabolomics profile
### Stool collection and metagenomic sequencing
### Biomarker-based definition of depression
### Association between gut microbial RNA expression and host gene expression in the rectum
### Statistical analysis
## Results
### Integration of long-term dietary, depression, and multi-omics data in an ongoing cohort study
### Citrus consumption is prospectively associated with decreased risk of depression
### Citrus consumption is prospectively associated with abundance of gut microbial species
### Faecalibacterium prausnitzii, modulated by citrus intake, is associated with lower risk of depression
### S-Adenosyl-L-methionine production by F. prausnitzii may influence gut-brain transmission
### Citrus and its micronutrients are also prospectively associated with a specific microbial gene in F. prausnitzii
### Expression of SAM cycle I is associated with lower intestinal serotonin and dopamine degradation activity in the colon
## Discussion
## Conclusions
