Racial disparities in obesity are prevalent in America, with minority groups experiencing disproportionately higher rates. While genetics, diet, physical activity, and psychological factors are considered, the role of discrimination experiences in increasing obesity risk remains understudied. Discrimination, a psychosocial stressor, is linked to various adverse health outcomes. It can stimulate ingestive behavior by increasing appetite and cravings for palatable foods, contributing to stress-related weight gain. Neuroimaging studies show stress alters food-cue reactivity to highly palatable foods, suggesting discrimination may increase obesity risk via altered reactivity to hypercaloric and hyperpalatable foods common in Western diets. A potential mechanism involves alterations in the brain–gut–microbiome (BGM) system. Discrimination-related stress influences brain-gut communication via pathways involving the vagus nerve, immune-inflammatory mechanisms, microbial metabolites, neurotransmitters, and the hypothalamic–pituitary–adrenal axis. Brain pathways associated with discrimination-related stress responses include reward and cognitive control networks. Chronic stress alters responses in prefrontal regions (executive control, emotion/impulse regulation) and limbic regions (reward processing, appetitive responses), impacting food-reward processing and cravings. Stress can deactivate frontal executive modulation and potentiate limbic activity, biasing preference toward unhealthy foods. Discrimination can also alter the gut microbiome; stress causes gut dysbiosis and increased gut-barrier permeability, leading to inflammation. Stress-induced unhealthy dietary patterns can result in gut dysbiosis and dysregulated eating behaviors. Dysregulation of glutamate metabolism is important in inflammatory CNS processes associated with stress-related disorders and obesity. Early life stress alters gut metabolites in the glutamate pathway, potentially via glutamatergic excitotoxicity and oxidative stress. This study hypothesized that increased stress from discrimination would be associated with altered brain reactivity to highly palatable unhealthy foods and altered glutamate metabolites implicated in inflammation and oxidative stress. Interactions between discrimination-related neural reactivity to unhealthy sweet foods and glutamate pathway metabolites were also predicted.

Existing research highlights the correlation between discrimination and negative health outcomes, including obesity. Studies have explored the role of genetics, diet, and physical activity in obesity disparities, but the contribution of discrimination has received less attention. The literature demonstrates that stress, particularly chronic stress, impacts the brain's reward system and executive functions, potentially leading to increased consumption of palatable, energy-dense foods. Furthermore, research indicates that stress significantly affects the gut microbiome, leading to dysbiosis and inflammation. The interaction between the brain, gut, and microbiome is increasingly understood to play a crucial role in various health conditions, including obesity. Studies have begun to investigate the link between psychosocial stressors and alterations in the gut microbiome, and several studies have shown a relationship between chronic stress and changes in gut metabolites, particularly those involved in the glutamate pathway.

This study used a multi-omics approach, combining neuroimaging (fMRI) and fecal metabolomics with clinical and behavioral measures. 107 participants (87 women) were recruited from the Los Angeles community. Exclusion criteria included major medical/neurological conditions, psychiatric illnesses, comorbidities, weight-loss/abdominal surgeries, substance use disorders, tobacco dependence, metal implants, medication use interfering with the CNS, analgesic use, pregnancy, breastfeeding, and strenuous exercise. Participants completed the Everyday Discrimination Scale (EDS) to measure chronic experiences of unfair treatment. EDS scores were dichotomized into high (EDS > 10) and low (EDS ≤ 10) discrimination exposure groups. Participants underwent fMRI scans during a food-cue task, viewing images of unhealthy sweet, unhealthy savory, healthy sweet, healthy savory, and non-food items. Brain reactivity was assessed in response to each food category. Fecal samples were collected from a subsample (n=62) for metabolomic analysis, focusing on glutamate pathway metabolites. Participants also rated their willingness to eat the foods presented during the fMRI scan. Data analysis included whole-brain analyses to identify brain regions showing discrimination-related differences in food-cue reactivity. A composite region of interest (ROI) mask was created to analyze discrimination effects on brain signal change in a linear fashion. Generalized linear modeling was used to compare glutamate pathway metabolites between high and low discrimination groups, adjusting for confounders. Structural equation modeling (SEM) was employed to assess the relationships between discrimination exposure, brain reactivity, and gut metabolites, accounting for BMI, race, diet, and socioeconomic status. All statistical maps were corrected for multiple comparisons.

Participants with high discrimination exposure (n=50) exhibited greater food-cue reactivity compared to the low discrimination exposure group (n=57) in brain regions associated with reward processing and executive control, particularly for unhealthy sweet and savory foods. These regions included the insula, inferior frontal gyrus, lateral orbitofrontal cortex, frontal operculum, caudate, putamen, and frontal pole. For healthy foods, heightened reactivity was observed in the superior frontal gyrus and middle frontal gyrus. The high discrimination group showed higher levels of N-acetylglutamate (P = 0.04) and N-acetylglutamine (P = 0.002), metabolites from the glutamate pathway linked to inflammation and oxidative stress. After multiple correction, N-acetylglutamine levels remained significantly different (q = 0.025). The high discrimination group also reported a significantly higher willingness to eat unhealthy foods (P = 0.048) compared to the low discrimination group. Structural equation modeling revealed a positive association between high discrimination exposure and brain reactivity to unhealthy sweet foods (standardized coefficient = 0.31, P = 0.009), as well as between discrimination and glutamate metabolism (standardized coefficient = 0.42, P = 0.004). A significant bidirectional association between brain and gut was observed for unhealthy sweet foods (standardized coefficient = 0.34, P = 0.048), but not for unhealthy savory or healthy foods. Similar patterns were observed with unhealthy savory foods but not with healthy food. In unhealthy sweet food model, the RMSEA was 0.0, CFI was 1.0, GFI was 0.955 and SRMR was 0.071. In unhealthy savory food model, RMSEA was 0.0, CFI was 1.0, GFI was 0.964 and SRMR was 0.058. In healthy food model, RMSEA was 0.0, CFI was 1.0, GFI was 0.969 and SRMR was 0.058.

This study demonstrates a link between self-reported discrimination exposure and disruptions in the brain-gut-microbiome (BGM) system. Increased discrimination is associated with heightened brain reactivity to unhealthy food cues, particularly sweet foods, in regions crucial for reward processing and executive control. These findings support the hypothesis that discrimination-related stress enhances reward responses and impairs self-regulation of food intake. The observed alterations in gut glutamate metabolites suggest an inflammatory component contributing to the link between discrimination and obesity risk. The strong bidirectional association between brain and gut observed specifically for unhealthy sweet foods highlights the role of these foods in the BGM interaction. These findings suggest that interventions targeting both brain-based reward pathways and gut-based inflammation might be beneficial for individuals experiencing discrimination-related stress.

This study provides evidence for a systems-biology perspective linking discrimination to obesity risk, emphasizing the interplay between brain reward pathways, gut microbiome, and glutamate metabolism. Future research should investigate causal relationships using longitudinal studies and examine potential sex and race/ethnicity-specific effects. Targeting brain reward systems and reducing gut inflammation may offer therapeutic strategies for individuals experiencing discrimination-related stress.

This study is correlational, limiting causal inferences. Men were underrepresented, and sufficient samples of specific racial/ethnic groups were lacking for stratified analyses. Future studies need larger, more balanced samples to address these limitations and explore potential moderating effects of sex and race/ethnicity. The study relied on self-reported discrimination and dietary information.