Men's Health

Diet, microbial metabolites, and cytokine levels correlate with depression and anxiety symptoms in obese individuals


In a recent study published in the American Journal of Clinical Nutrition, researchers determine the association between diet, microbe-derived metabolites, such as fecal short-chain fatty acids (SCFAs), and serological inflammatory cytokine levels with anxiety and depression among adult individuals with depression and obesity.

Study: Associations between fecal short-chain fatty acids, plasma inflammatory cytokines, and dietary markers with depression and anxiety: post-hoc analysis of the ENGAGE-2 pilot trial. Image Credit: New Africa /

Mental health and the gut microbiome

Several studies have indicated that the microbiota-gut-brain-axis (MGBA) has essential mechanistic associations between nutrition and mental well-being. However, the effects of MGBA modifiers, such as intestinal microbe-derived metabolites and inflammation, among obese and depressed individuals have not been well-characterized.

The ENGAGE-2 trial aimed to elucidate the MGBA pathways of comorbid depression and obesity. The trial findings provide important insights into the impact of therapy on anxiety and depression symptoms, but not on body mass index (BMI) after six months.

About the study

Researchers utilized serological and fecal samples obtained from ENGAGE-2 trial participants to explore the mechanistic basis of diet-associated behavioral changes, MGBA, and symptoms of anxiety and depression.

The study investigated whether alterations in stool-derived SCFAs and serological pro-inflammatory cytokine levels at two months were related to changes in anxiety and depression symptoms at two months and six months. Furthermore, the researchers assessed whether nutritional markers at two months were related to changes in stool-derived SCFAs and serological pro-inflammatory cytokines at two months and whether these biomarkers were related to symptoms of anxiety and depression at two and six months.

Pearson partial correlation and partial least squares (PLS) analyses were performed to determine the relationships between alterations in stool-derived SCFAs including butyric, propionic, isovaleric, and acetic acids, serological cytokines such as C-reactive protein (CRP), interleukin 1RA (IL-1RA), IL-1β, IL-6, and tumor necrosis factor-alpha (TNF-α), and nutritional biomarkers over 14 months. Symptomatic changes in anxiety and depression were assessed based on generalized anxiety disorder 7.0-item (GAD-7) and depression symptom checklist 20.0-item (SCL-20) scores over six months.

The ENGAGE-2 clinical trial was performed between March 1, 2019, and August 31, 2020, and included adults from outpatient care centers of the University of Illinois Hospital and health sciences system in Chicago. Individuals were included if they were depressed, which was defined as Patient Health Questionnaire-9 (PHQ-9) scores greater than or equal to 10.0, and obese, which was defined as a BMI greater than or equal to 30.0 among the general population, or greater than or equal to 27.0 for Asians.

Psychotic individuals or those with bipolar disorders, diabetes, cardiovascular diseases, pregnancy, and contraindications for magnetic resonance imaging (MRI) were excluded from the analysis.

Seventy-one individuals received Integrated Coaching for Better Mood and Weight version 2 (I-CARE2) therapy, whereas 35 indiviudals recieved regular care. Fecal samples and serological samples were analyzed by liquid chromatography-mass spectrometry (LC-MS/MS) and enzyme-linked immunosorbent assay (ELISA), respectively.

Nutritional intake was recorded based on 24.0-hour diet recalls. Nutritional quality was evaluated based on the DASH index.

Study findings

A total of 34 adults completed the analysis, 68% of whom were female with an average age of 47 years.

Altered levels of butyric acid, TNF-α, isovaleric acid, acetic acid and propionic acid correlated positively with anxiety and depression symptom scores. Conversely, altered CRP and IL-1RA correlated negatively with alterations in GAD-7 and SCL-20 scores.

Fourteen nutritional biomarkers including vegetable and fruit intake, Dietary Approaches to Stop Hypertension (DASH) scores, animal-derived protein, calories, added sugar, beta-cryptoxanthin, monounsaturated fat, soluble-type fiber, ascorbic acid, vitamin D, glycitein, alpha-carotene, genistein, and daidzein were selected for PLS analysis. Each of these nutritional biomarkers were significantly associated with anxiety and depression symptoms at two and six months.

Negative correlations were observed with altered butyric acid, TNF-α, isovaleric acid, acetic acid, and propionic acid levels in relation to 12 nutritional markers including DASH score, fruit and vegetable intake, animal protein, monosaturated fat, added sugar, vitamin C, vitamin D, beta-cryptoxanthin, alpha-carotene, daidzein, genistein, and glycitein by two months. Comparatively, these SCFAs and serological biomarkers were positively associated with added sugar and monounsaturated fatty acids at two months.

Alterations in the levels of monounsaturated fats, intake of fruits and vegetables, glycitein, beta-cryptoxanthin, and ascorbic acid correlated negatively. Comparatively, DASH scores, vitamin D, animal-derived proteins, genistein, added sugar, daidzein, and alpha-carotene were positively correlated with altered IL-1RA levels.

Altered DASH scores, vitamin D, soluble-type fiber, animal-based protein, genistein, glycitein, and daidzein levels at two months were negatively correlated with altered GAD-7 and SCL-20 scores at six months. Contrastingly, altered levels of monounsaturated fats, added sugar, and calories at two months correlated positively with GAD-7 and SCL-20 score changes at six months. The levels of animal-based proteins and monounsaturated fats most significantly correlated with clinical outcomes.


After six months, both fecal SCFA and serum TNF-α levels were found to positively correlate with depressive scores and negatively correlate with IL-1RA levels. Furthermore, several nutritional biomarkers, including the consumption of animal protein, also correlated with depressive symptoms at this time point.

Taken together, the current study highlights the potential benefit of incorporating dietary modifications and anti-inflammatory medications for the concomitant treatment of obesity, anxiety, and depression. However, further research is needed to validate these findings.

Journal reference:

  • Burton, T. C. J., Lv, N., Tsai, P., et al. (2023). Associations between fecal short-chain fatty acids, plasma inflammatory cytokines, and dietary markers with depression and anxiety: post-hoc analysis of the ENGAGE-2 pilot trial. The American Journal of Clinical Nutrition. doi:10.1016/ j.ajcnut.2023.01.018

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