Abstract
The potential therapeutic effect of probiotic/prebiotic on depression remains a concern. Our study aimed to explore the relationship between probiotic/prebiotic consumption and the severity of depressive symptoms and to further analyze the potential mediating role of chronic obstructive pulmonary disease (COPD) in this association. The study included 5025 individuals with depression who participated in the National Health and Nutrition Examination Survey between 2009 and 2018. Weighted multiple logistic regression analyses were used to evaluate the associations between probiotic/prebiotic intake and the severity of depressive symptoms, between COPD and severity of depressive symptoms, and between probiotic/prebiotic consumption and COPD. In addition, we also carried out hierarchical, mediation and sensitivity analyses. Our results revealed that probiotic/prebiotic consumption is negatively associated with the severity of depressive symptoms, and subgroup analyses and interaction tests revealed that this relationship is stable. We also found a positive correlation between COPD and the severity of depressive symptoms and a negative correlation between probiotic/prebiotic consumption and COPD. Further mediation analysis revealed that COPD weakly mediated the effect of probiotic/prebiotic consumption on the severity of depressive symptoms (mediation effect: 2.30%). These findings reveal that probiotic/prebiotic consumption is associated with a reduction in the severity of depressive symptoms, and the presence of COPD comorbidity should be taken into account in the nutritional management of depression.
Keywords: COPD, depression, mediation, NHANES, probiotic/prebiotic
1. Introduction
Depression is a prevalent psychological disorder that has become one of the major public health challenges worldwide. According to the World Health Organization, the prevalence of depression is currently estimated to be 4.4%, affecting more than 320 million people globally. A Bayesian Age-Period-Cohort model predicted that between 2020 and 2030, the number of instances of depression worldwide will increase.[1] Individuals with depression frequently have comorbid diseases such as diabetes, metabolic syndrome, cardiovascular disease (CVD) and respiratory disease, and they may even be more likely to commit suicide.[2-4] This may have significant negative impacts on health, the economy, and society, including lower life expectancy, lower quality of life, higher healthcare costs, and lower productivity in both work and education.[5]
Different approaches have been used to treat depression, ranging from traditional remedies such as acupuncture and ancient botanicals to modern psychotherapy, medication, and developed therapies; however, treatment coverage is still insufficient. In high-income countries, the percentage of individuals who do not receive treatment for depression ranges from 34% to 77%, while in low-income countries, this percentage is only 8%.[5] There are a number of negative effects linked to antidepressant use, such as headaches, gastrointestinal problems, libido loss, and sexual dysfunction. Moreover, approximately one-third of patients do not respond well to antidepressants.[6] Furthermore, the comorbidity of depression with multiple diseases makes treatment more complex and challenging. Therefore, improving existing treatments and exploring innovative therapies that are effective for more patients will be critical to developing effective prevention and control strategies.
In this context, probiotics and prebiotics have drawn much interest as supplemental treatments for depression. Probiotics are live bacteria present in nutritional supplements, dairy and nondairy fermented foods and beverages, which confer health benefits when consumed in moderation.[7,8] Prebiotics are substrates that host microorganisms for selective application.[9] They usually include dietary fibres or other carbohydrates, such as inulin, fructooligosaccharides (FOSs), and galactooligosaccharides (GOSs), which are essential for supporting the growth and activity of good gut bacteria.[10] Animal studies have demonstrated that some probiotics and prebiotics can regulate the composition of the intestinal flora, inhibit the inflammatory response, lower corticosterone levels, and alter the concentrations of neural metabolites. These mechanisms promote the growth of neurites in the dentate gyrus of the hippocampus, ultimately alleviating depression-like symptoms.[11,12] A growing number of clinical studies suggest that probiotics and prebiotics may have antidepressant effects when included in a balanced diet. A meta-analysis of 786 individuals revealed that, in comparison with patients in placebo groups, patients who took probiotics and prebiotics experienced a significant improvement in their depression symptoms.[13] In addition, for patients with depression accompanied by physical illness, the effect of probiotic treatment was better than that of patients with depression alone.[14] These findings provide an important basis for the potential application of probiotics and prebiotics in the comprehensive treatment of depression. However, due to factors such as small sample sizes, the heterogeneity of doses and strains, and inconsistencies in intervention timing, studies on the associations between probiotic or prebiotic supplements and depressive states remain insufficient.
Chronic obstructive pulmonary disease (COPD) is one of the most common chronic respiratory diseases. According to epidemiological data, there were 480 million COPD patients worldwide among people 40 years of age and older in 2020. By 2050, the disease burden will rise to 592 million.[15] Depression is a common comorbidity in COPD, with its prevalence ranging from 16% to 40%.[16] Respiratory diseases are often accompanied by intestinal flora disorders, and probiotics or prebiotics can alleviate or treat diseases by restoring intestinal flora homeostasis.[10] In an experimental animal model of COPD, the application of probiotics reduced pulmonary inflammation and improved airway remodeling.[17] The beneficial effects of probiotics are thought to stem in part from their ability to regulate the production of anti-inflammatory and pro-inflammatory cytokines and the balance between T-cell response types.[18] In addition, by reducing intestinal permeability and stabilizing neuromuscular connections, probiotics improve muscle strength and functional performance in patients with COPD.[19] Notably, when COPD is effectively treated, accompanying depressive symptoms also tend to improve.[20] However, research on the relationships among probiotic or prebiotic consumption, COPD, and depression is still limited.
Therefore, this study aimed to explore the associations between probiotic or prebiotic intake and depressive symptoms on the basis of 2009 to 2018 National Health and Nutrition Examination Survey (NHANES) data and to further analyze the potential mediating role of COPD in this association. Through this study, we intend to provide a new scientific basis for nutritional intervention strategies for depression, thereby facilitating the development of more effective personalized treatment options.
2. Methods
2.1. Data sources
The study utilized data from the NHANES, a nationally representative survey administered by the National Center for Health Statistics. The National Health and Nutrition Examination Survey employs a complex multistage probability sampling design to capture a diverse array of information, including demographic data, dietary data, examination data, laboratory data, and other health-related data collected through standardized questionnaires. These publicly available data facilitate comprehensive assessments of the health and nutritional status of the noninstitutionalized U.S. population. The NHANES is conducted in adherence with rigorous ethical standards, with approval from the Research Ethics Review Board of the National Center for Health Statistics. Informed consent is obtained from all participants (https://www.cdc.gov/nchs/nhanes/irba98.htm).
2.2. Study population
The study included 30,352 adults aged ≥18 years who participated in the NHANES from 2009 to 2018. After individuals with missing Patient Health Questionnaire-9 (PHQ-9) depression score data were excluded, 6571 participants with PHQ-9 depression scores ≥5 points were included. Participants with missing data on COPD, education level, alcohol consumption, body mass index (BMI), CVD, sleep duration and gastrointestinal disorder were also excluded. Finally, participants without dietary two-day sample weight data were excluded. The final analytic sample comprised 5025 participants. The design flowchart of the screening process is shown in Figure 1.
Figure 1.
Design flowchart of the screening process. BMI = body mass index, COPD = chronic obstructive pulmonary disease, NHANES = National Health and Nutrition Examination Survey, PHQ-9 = Patient Health Questionnaire-9.
2.3. Assessment of depression
Depression was assessed using the PHQ-9, a well-established screening tool for detecting depression. The PHQ-9 comprises 9 questions, each scored from 0 (“Not at all”) to 3 (“Nearly every day”), designed to evaluate the presence and severity of depressive symptoms. The participants were categorized on the basis of their scores: scores of 5 to 9 points indicated mild depression; and scores of 10 points or greater indicated moderate-to-severe depression.[21]
2.4. Assessment of probiotic/prebiotic supplements
Currently, the only Food and Drug Administration-regulated prebiotic product is lactulose, but no probiotic products have been approved by the Food and Drug Administration. Relevant information is available online at https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm. Based on the probiotic and prebiotic search information used by previous researchers [22] we collected data via the Dietary Supplement Use 30-Day Individual Dietary Supplement (DSQIDS) questionnaire. We extracted information using phrases containing probiotics or prebiotics to assess the participants’ intake of these substances. In addition, previous studies have reported that probiotics are mainly present in food products (such as yogurt) and probiotic supplements.[23] Therefore, the intake of yogurt was included in the assessment of probiotic/probiotic prebiotic dietary exposure. The participants underwent two 24-hour dietary recall interviews: the first was conducted in person at a Mobile Examination Center, and the second was conducted by telephone 3 to 10 days later. The participants were classified into the probiotic/prebiotic intake group if they reported probiotic/prebiotic intake on the DSQIDS or yogurt consumption on the dietary interview questionnaires; otherwise, they were classified into the nonprobiotic/prebiotic intake group.
2.5. Assessment of COPD
Based on previous literature, participants who were told that they had chronic bronchitis or emphysema were considered to have COPD.[24] Chronic bronchitis and emphysema data were extracted from the questionnaire data. Participants were considered to have chronic bronchitis and emphysema if they answered yes to the question “Ever told you had chronic bronchitis” or “Ever told you had emphysema.” If the answer was no, the participant was not considered to have the disease.
2.6. Covariates
The demographic characteristics included age, gender, race, marital status, and education level. Age was categorized into <30 years, 30 to 55 years, and >55 years. Race was classified as Mexican American, Non-Hispanic Black, Non-Hispanic White, and Others. Marital status was divided into Married (including married and living with a partner), Unmarried (including never married), and others (including widowed, divorced, and separated). Educational level was categorized as Below High School, High School, and Above High School.
Lifestyle-related variables included smoking status, alcohol consumption, BMI and sleep duration. Smoking status was derived from the SMQ data in the Questionnaire Data, with a history of smoking defined as Yes and no history of smoking defined as No. Alcohol consumption was determined if DR1IALCO or DR2IALCO in the Dietary Interview - Total Nutrient Intakes was >0, or if the average number of alcoholic drinks per day over the past 12 months in the ALQ data from the Questionnaire Data was ≥1. Participants meeting either criterion were classified as drinking; otherwise, they were classified as nondrinking. BMI was extracted from the Body Measures in the Examination Data and was classified as <25 kg/m2, 25 to 30 kg/m2 and ≥30.0 kg/m2. Sleep duration data were derived from the SLQ data in the Questionnaire Data and assessed by asking participants about their average sleep duration on weeknights and classifying sleep duration as short (<7 hours), normal (7 to <9 hours), and long (>9 hours).
The health-related variables included diabetes, hypertension, hyperlipidemia, and CVD, sleep disorder, and gastrointestinal disorders. Diabetes and hyperlipidemia data were extracted from the Questionnaire Data and Laboratory Data. Diabetes was defined as a response of Yes to “Doctor told you have diabetes,” “Taking insulin now,” or “Take diabetic pills to lower blood sugar,” or if Plasma Fasting Glucose was ≥126 mg/dL or Glycohemoglobin was ≥6.5. Hyperlipidemia was defined as a response of Yes to “Doctor told you - high cholesterol level,” “Told to take prescription for cholesterol” or “Now taking prescribed medicine” or if TC was >200 mg/dL, TG was >150 mg/dL, HDL was <40 mg/dL for men or <50 mg/dL for women, or LDL was ≥130 mg/dL. Hypertension data were also extracted from the Questionnaire Data and Examination Data. Hypertension was defined as a response of Yes to “Ever told you had high blood pressure,” “Taking prescription for hypertension,” or “Now taking prescribed medicine for HBP,” or if SBP was ≥140 or DBP was ≥90. CVD data were extracted from the Medical Conditions in the Questionnaire Data. CVD was defined as a response of Yes to “Ever told had congestive heart failure,” “Ever told you had coronary heart disease,” “Ever told you had angina/angina pectoris” or “Ever told you had heart attack.” Sleep disorder data was derived from the SLQ data in the Questionnaire Data. Sleep disorder was defined as a response of Yes to “Ever told doctor had trouble sleeping.” Stomach or intestinal illness data was derived from the HSQ data in the Questionnaire Data. Stomach or intestinal illness was defined as a response of Yes to “SP have stomach or intestinal illness.”
2.7. Statistical analysis
The NHANES adopts a stratified, multistage complex sampling design, with each survey cycle lasting for 2 years. Data from 5 consecutive cycles spanning a total of 10 years were used in this study. The two-day dietary weights (WTDR2D) corresponding to each cycle were used to weight the dietary recall interview data. According to the recommended weighting method, when combining multiple survey cycles, to ensure the representativeness of the sample for the entire 10-year survey population, the single-cycle weight was calculated as 2/10 * WTDR2D.[25] Finally, the weighted coefficient obtained was 1/5 * WTDR2D, which served as the sampling weight for this study. Initially, the baseline characteristics of the participants were statistically described. Categorical variables are presented as frequencies and percentages, whereas continuous variables with nonnormal distributions are reported as medians and interquartile ranges. The Rao–Scott chi-square test was used to analyze the weighted percentages of categorical variables, and the Wilcoxon rank-sum test was employed for continuous variables. Subsequently, adjusted binary logistic regression models, reported as odds ratios (ORs) and 95% confidence intervals (95% CIs), were used to assess the relationships between probiotic/prebiotic consumption and the severity of depression. Three covariate models were evaluated: an unadjusted model; adjusted Model 1: adjusted for age, gender, race, marital status, and education level; adjusted Model 2: adjusted for the covariates in adjusted Model 1 plus smoking status, alcohol consumption, BMI and sleep duration; and adjusted Model 3: adjusted for all covariates in Model 2 plus diabetes, hypertension, hyperlipidemia, CVD, sleep disorder, gastrointestinal disorder, and COPD. We performed stratified analyses to examine whether the associations varied by population characteristics. Additionally, we performed a mediation analysis to further explore whether COPD affects the relationship between probiotic/prebiotic consumption and depression. The mediation analysis was conducted using the mediation effect analysis method based on regression models, and the “mediation” package in R 4.2.2 software. After adjusting for different potential confounding factors, we separately evaluated the association between probiotic/probiotic prebiotic intake and COPD, as well as the association between COPD and the severity of depressive symptoms. Subsequently, regression models were constructed for the independent variables with the mediator variables, and regression models for the independent variables and the mediator variables together with the dependent variable were also constructed. The direct effect, indirect effect, and total effect were estimated. The bootstrap method was used for 1000 repeated samplings to enhance the robustness of the results and reduce sampling bias. The statistical significance of the mediation effect was determined by whether the 95% CI crossed 0. We also conducted a sensitivity analysis using unweighted data to evaluate the robustness of the research results. Statistical analyses were conducted using R software (version 4.2.2) and MSTATA software (www.mstata.com).
3. Results
3.1. Baseline characteristics of the study participants
Table 1 presents the baseline characteristics of the participants with depression, comparing those who consumed probiotic/prebiotic with those who did not. The study included 4321 nonprobiotic/prebiotic consumers and 704 probiotic/prebiotic consumers. Probiotic/prebiotic consumers were more frequently female, older than 30 years, non-Hispanic white, married, and had an above high school education. In terms of lifestyle factors, probiotic/prebiotic consumers were less likely to smoke. There were no significant differences between the 2 groups concerning alcohol consumption, BMI, sleep duration, or comorbidities such as diabetes, hypertension, hyperlipidemia, CVD, sleep disorders, and gastrointestinal disorders. However, a significantly greater proportion of individuals who consumed probiotics/prebiotics did not have COPD. In this study, 65.63% (PHQ-9 score <10 points) of the participants were classified as having mild depression, whereas 34.37% (PHQ-9 score ≥10 points) had moderate-to-severe depression. Notably, compared with nonconsumers, probiotic/prebiotic consumers presented lower depression scores (7.00 [5.00, 10.00] vs 8.0 [6.00, 11.00]) and a lower proportion of moderate-to-severe depression (26.37% vs 36.00%).
Table 1.
Baseline characteristics of the study participants.
| Characteristic | Probiotic/prebiotic consumption | P-value | ||
|---|---|---|---|---|
| Overall, 50,271,891* | No Weighted N = 41,763,537 Unweighted n = 4,321* |
Yes Weighted N = 8508,354 Unweighted n = 704* |
||
| Gender | <.001† | |||
| Female | 29,943,455 (59.56%) | 23,722,054 (56.80%) | 6221,400 (73.12%) | |
| Male | 20,328,436 (40.44%) | 18,041,483 (43.20%) | 2286,954 (26.88%) | |
| Age | .020† | |||
| ˂30 | 10,873,884 (21.63%) | 9287,370 (22.24%) | 1586,514 (18.65%) | |
| 30–55 | 22,921,112 (45.59%) | 19,369,422 (46.38%) | 3551,690 (41.74%) | |
| ˃55 | 16,476,895 (32.78%) | 13,106,745 (31.38%) | 3370,149 (39.61%) | |
| Race | <.001† | |||
| Mexican American | 4580,306 (9.11%) | 3890,967 (9.32%) | 689,339 (8.10%) | |
| Non-Hispanic Black | 6290,607 (12.51%) | 5730,534 (13.72%) | 560,073 (6.58%) | |
| Non-Hispanic White | 31,993,045 (63.64%) | 25,959,353 (62.16%) | 6033,692 (70.91%) | |
| Others | 7407,933 (14.74%) | 6182,684 (14.80%) | 1225,249 (14.40%) | |
| Marital status | .009† | |||
| Married | 26,933,291 (53.58%) | 21,863,659 (52.35%) | 5069,632 (59.58%) | |
| Others | 12,427,098 (24.72%) | 10,302,855 (24.67%) | 2124,244 (24.97%) | |
| Unmarried | 10,911,502 (21.70%) | 9597,024 (22.98%) | 1314,479 (15.45%) | |
| Educational level | <.001† | |||
| Above high school | 27,938,261 (55.57%) | 21,951,602 (52.56%) | 5986,658 (70.36%) | |
| Below high school | 9086,996 (18.08%) | 8241,861 (19.73%) | 845,135 (9.93%) | |
| High School | 13,246,634 (26.35%) | 11,570,074 (27.70%) | 1676,560 (19.70%) | |
| Smoke | .003† | |||
| No | 22,700,058 (45.15%) | 18,194,565 (43.57%) | 4505,494 (52.95%) | |
| Yes | 27,571,833 (54.85%) | 23,568,972 (56.43%) | 4002,860 (47.05%) | |
| Alcohol | .541† | |||
| No | 35,473,228 (70.56%) | 29,614,758 (70.91%) | 5858,470 (68.86%) | |
| Yes | 14,798,663 (29.44%) | 12,148,779 (29.09%) | 2649,884 (31.14%) | |
| BMI | .682† | |||
| ˂25 | 12,518,241 (24.90%) | 10,421,019 (24.95%) | 2097,222 (24.65%) | |
| 25 to ˂30 | 13,930,505 (27.71%) | 11,404,905 (27.31%) | 2525,600 (29.68%) | |
| ≥30 | 23,823,145 (47.39%) | 19,937,613 (47.74%) | 3885,532 (45.67%) | |
| Sleep duration | .266† | |||
| Long | 4068,189 (8.09%) | 3524,709 (8.44%) | 543,479 (6.39%) | |
| Normal | 26,528,270 (52.77%) | 21,689,278 (51.93%) | 4838,992 (56.87%) | |
| Short | 19,675,432 (39.14%) | 16,549,550 (39.63%) | 3125,883 (36.74%) | |
| Diabetes | .818† | |||
| No | 41,768,470 (83.09%) | 34,669,060 (83.01%) | 7099,410 (83.44%) | |
| Yes | 8503,421 (16.91%) | 7094,477 (16.99%) | 1408,944 (16.56%) | |
| Hypertension | .793† | |||
| No | 28,197,345 (56.09%) | 23,480,718 (56.22%) | 4716,627 (55.44%) | |
| Yes | 22,074,546 (43.91%) | 18,282,819 (43.78%) | 3791,727 (44.56%) | |
| Hyperlipidaemia | .035† | |||
| No | 13,261,547 (26.38%) | 11,438,322 (27.39%) | 1823,224 (21.43%) | |
| Yes | 37,010,344 (73.62%) | 30,325,215 (72.61%) | 6685,129 (78.57%) | |
| Cardiovascular disease | .719† | |||
| No | 45,357,090 (90.22%) | 37,635,233 (90.12%) | 7721,857 (90.76%) | |
| Yes | 4914,801 (9.78%) | 4128,304 (9.88%) | 786,497 (9.24%) | |
| Sleep disorder | .200† | |||
| No | 24,330,400 (48.40%) | 20,471,965 (49.02%) | 3858,434 (45.35%) | |
| Yes | 25,941,491 (51.60%) | 21,291,572 (50.98%) | 4649,920 (54.65%) | |
| Gastrointestinal disorder | .301† | |||
| No | 44,028,794 (87.58%) | 36,455,304 (87.29%) | 7573,491 (89.01%) | |
| Yes | 6243,097 (12.42%) | 5308,234 (12.71%) | 934,863 (10.99%) | |
| Chronic obstructive pulmonary disease | .009† | |||
| No | 44,286,654 (88.09%) | 36,433,874 (87.24%) | 7852,780 (92.29%) | |
| Yes | 5985,237 (11.91%) | 5329,663 (12.76%) | 655,574 (7.71%) | |
| PHQ-9 score | 8.00 (6.00, 11.00) | 8.00 (6.00, 11.00) | 7.00 (5.00, 10.00) | .001‡ |
| Depressive symptoms | .003† | |||
| <10 | 32,992,280 (65.63%) | 26,727,764 (64.00%) | 6264,517 (73.63%) | |
| ≥10 | 17,279,611 (34.37%) | 15,035,774 (36.00%) | 2243,837 (26.37%) | |
n (%); Median (IQR).
Chi-squared test with Rao & Scott’s second-order correction.
Wilcoxon rank-sum test for complex survey samples.
3.2. Association between probiotic/prebiotic consumption and the severity of depressive symptoms
We performed binary logistic regression analysis to investigate the relationship between probiotic/prebiotic consumption and the severity of depressive symptoms. As detailed in Table 2, the unadjusted model (Model 1) revealed a negative correlation between probiotic/prebiotic consumption and the severity of depression, yielding an OR of 0.64 (95% CI: 0.47, 0.86). This protective effect remained consistent in the adjusted models: Model 2 (adjusted for gender, age, race, marital status, and education level) had an OR of 0.66 (95% CI: 0.49, 0.88), Model 3 (furtherly adjusted for smoking, alcohol, BMI, and sleep duration) had an OR of 0.67 (95% CI: 0.51, 0.89), and Model 4 (additionally adjusted for diabetes, hypertension, hyperlipidemia, CVD, sleep disorders, gastrointestinal disorders and COPD) had an OR of 0.68 (95% CI: 0.50, 0.92). The results from both unadjusted and adjusted models indicated that probiotic/prebiotic consumers were more likely to exhibit mild depressive symptoms.
Table 2.
Association between probiotic/prebiotic consumption and the severity of depressive symptoms.
| Probiotic/prebiotic consumption | P-value | ||
|---|---|---|---|
| No | Yes | ||
| Mode l | Ref. | 0.64 (0.47, 0.86) | .003 |
| Mode 2 | Ref. | 0.66 (0.49, 0.88) | .006 |
| Mode 3 | Ref. | 0.67 (0.51, 0.89) | .008 |
| Mode 4 | Ref. | 0.68 (0.50, 0.92) | .017 |
Values are odds ratios (95% confidence intervals).
Model 1: no covariates were adjusted.
Model 2: adjusted for Gender, Age, Race, Marital status, and Educational level.
Model 3: adjusted for Gender, Age, Race, Marital status, Educational level, Smoke,
Alcohol, BMI, and Sleep duration.
Model 4: adjusted for Gender, Age, Race, Marital status, Educational level, Smoke, Alcohol, BMI, Sleep duration, Diabetes, Hypertension, Hyperlipidemia, CVD, Sleep disorder, Gastrointestinal disorder and COPD.
3.3. Subgroup analysis
We performed stratified analyses based on gender, marital status, education level, smoking, sleep duration, hypertension, CVD, sleep disorder, gastrointestinal disorder, and COPD to assess the consistency of the associations between probiotic/prebiotic consumption and depression across subgroups. As shown in Figure 2, the interaction test results revealed that gender, marital status, education level, smoking, sleep duration, hypertension, CVD, sleep disorder, gastrointestinal disorder, and COPD did not significantly affect this association (P > .05). These findings suggest that the relationship between probiotic/prebiotic consumption and the severity of depressive symptoms is consistent across subgroups and that the results are robust.
Figure 2.
Association between probiotic/prebiotic consumption and the severity of depressive symptoms in different subgroups. CI = confidence interval, OR = odds ratio.
3.4. Mediation analysis
We observed a significant association between COPD and the severity of depressive symptoms. Specifically, individuals with COPD were more likely to have moderate-to-severe depression symptoms in both unadjusted and multivariable-adjusted models. As shown in Table 3, the unadjusted model showed an OR of 1.97 (95% CI: 1.54, 2.51), indicating that patients with COPD had 1.97 times the odds of moderate-to-severe depressive symptoms compared with those without COPD. After adjusting for multiple covariates, this association remained statistically significant across all the models, although it weakened.
Table 3.
Association between COPD and the severity of depressive symptoms.
| COPD | P-value | ||
|---|---|---|---|
| No | Yes | ||
| Mode l | Ref. | 1.97 (1.54, 2.51) | <.001 |
| Mode 2 | Ref. | 1.90 (1.45, 2.50) | <.001 |
| Mode 3 | Ref. | 1.74 (1.33, 2.28) | <.001 |
| Mode 4 | Ref. | 1.54 (1.15, 2.07) | .005 |
Values are odds ratios (95% confidence intervals).
Model 1: no covariates were adjusted.
Model 2: adjusted for Gender, Age, Race, Marital status, and Educational level.
Model 3: adjusted for Gender, Age, Race, Marital status, Educational level, Smoke, Alcohol, BMI, and Sleep duration.
Model 4: adjusted for Gender, Age, Race, Marital status, Educational level, Smoke, Alcohol, BMI, Sleep duration, Diabetes, Hypertension, Hyperlipidemia, CVD, Sleep disorder, and Gastrointestinal disorder.
Furthermore, we observed a significant association between probiotic/prebiotic consumption and the presence of COPD. In multiple unadjusted and multivariable-adjusted models, probiotic/prebiotic consumers had more than 40% lower odds of COPD than nonconsumers (Table 4).
Table 4.
Association between probiotic/prebiotic consumption and COPD.
| Probiotic/prebiotic consumption | P-value | ||
|---|---|---|---|
| No | Yes | ||
| Mode l | Ref. | 0.57 (0.38, 0.86) | .010 |
| Mode 2 | Ref. | 0.53 (0.34, 0.82) | .005 |
| Mode 3 | Ref. | 0.55 (0.35, 0.85) | .010 |
| Mode 4 | Ref. | 0.56 (0.36, 0.87) | .013 |
Values are odds ratios (95% confidence intervals).
Model 1: no covariates were adjusted.
Model 2: adjusted for Gender, Age, Race, Marital status, and Educational level.
Model 3: adjusted for Gender, Age, Race, Marital status, Educational level, Smoke, Alcohol, BMI, and Sleep duration.
Model 4: adjusted for Gender, Age, Race, Marital status, Educational level, Smoke, Alcohol, BMI, Sleep duration, Diabetes, Hypertension, Hyperlipidemia, CVD, Sleep Disorder, and Gastrointestinal disorder.
On the basis of the above findings, we further explored the potential mediating role of COPD in the association between probiotic/prebiotic consumption and the severity of depressive symptoms. The results showed that COPD weakly but significantly mediated the association between probiotic/prebiotic consumption and the severity of depressive symptoms. Specifically, in the model that was not adjusted for covariates, the mediating effect was 5.52%, whereas in the multiple models adjusted for different covariates, the mediating effect was reduced but remained significant, with values of 4.34%, 3.94% and 2.30%, respectively (Table 5).
Table 5.
The mediation analysis of COPD on the relationship between probiotic/prebiotic consumption and the severity of depressive symptoms.
| ACME | ADE | TE | PM | |
|---|---|---|---|---|
| Model 1 | −0.00702 (−0.01595, −0.00074)* | −0.12021 (−0.15172, −0.02271)* | −0.12723 (−0.15987, −0.03033)** | 0.05521 (0.00607, 0.25843)* |
| Model 2 | −0.00583 (−0.01572, −0.00130)* | −0.12841 (−0.14094, −0.01532)* | −0.13424 (−0.14963, −0.02426)** | 0.04341 (0.01054, 0.35360)* |
| Model 3 | −0.00529 (−0.01312, −0.00064)* | −0.12907 (−0.13782, −0.01036)* | −0.13435 (−0.14330, −0.01738)* | 0.03936 (0.00393, 0.31838)* |
| Model 4 | −0.00313 (−0.01087, −0.00036)* | −0.13307 (−0.13686, −0.01275)* | −0.13620 (−0.14097, −0.01747)** | 0.02295 (0.00257, 0.25631)* |
ACME: average causal mediation effects; ADE: Average Direct Effect; TE: Total.
Model 1: no covariates were adjusted.
Model 2: adjusted for Gender, Age, Race, Marital status, and Educational level.
Model 3: adjusted for Gender, Age, Race, Marital status, Educational level, Smoke, Alcohol, BMI, and Sleep duration.
Model 4: adjusted for Gender, Age, Race, Marital status, Educational level, Smoke, Alcohol, BMI, Sleep duration, Diabetes, Hypertension, Hyperlipidemia, CVD, Sleep disorder, and Gastrointestinal disorder.
P < .05.
P < .01.
3.5. Sensitivity analyses
We conducted regression analysis, subgroup analysis and mediation analysis using unweighted data to evaluate the robustness of the original results. The results showed that the association directions and magnitude among probiotic/prebiotic consumption, the severity of depressive symptoms and the incidence of COPD remained unchanged. The results are summarized in Supplement Table S1–S5, Supplemental Digital Content 1 and Supplement Figure S1, Supplemental Digital Content 2.
4. Discussion
The purpose of our study was to investigate the potential relationships among probiotic/prebiotic consumption, depressive symptoms, and COPD. First, our results revealed a significant negative correlation between probiotic/prebiotic consumption and depressive symptoms. Individuals who consumed probiotics/prebiotics tended to exhibit milder depressive symptoms, and this relationship was consistent and stable across demographic characteristics, lifestyle habits, and health-status subgroups. We subsequently confirmed that patients with COPD were more likely to experience moderate-to-severe depressive symptoms, while those who consumed probiotics/prebiotics were less likely to suffer from COPD. Finally, mediated effects analysis revealed that COPD weakly mediated the relationship between probiotic/prebiotic consumption and depressive symptoms. It is worth noting that this study is a cross-sectional study, and the observed results mainly reflect the cross-sectional differences among different groups with varying degrees of depression, rather than the true longitudinal progression of the occurrence and development of depression. Therefore, to clarify the temporal causal relationship between the two, further prospective cohort studies are still needed for verification.
Alterations in the composition and function of the gut microbiota are now recognized as key factors contributing to gut–brain axis dysfunction and are implicated in the onset and progression of depression.[26] Research has revealed significant dysbiosis in the gut microbiome of patients with depression, characterized by reduced microbial diversity. At the phylum level, notable differences were observed in Bacteroidetes, Firmicutes, Actinobacteria, Clostridia, and Archaea. At the genus level, the abundance of Anaerostipes, Blautia, and Clostridium increased in patients with depression, while the abundance of Bifidobacterium, Faecalibacterium, and Ruminococcus decreased.[27] Studies on fecal microbiota transplantation have further confirmed that germ-free mice transplanted with gut microbiota from patients with depression exhibit depression-like behaviors, such as anhedonia and anxiety, whereas mice transplanted with microbiota from healthy individuals do not exhibit such changes.[28] These results suggest that the composition of the gut microbiota may have a direct effect on host mood and behavior. In addition, a study has shown that HAMD-24 scores in patients with depressive episodes are significantly correlated with gut microbiota abundance at various taxonomic levels.[29] It suggested that changes in the composition of the gut microbiota not only increase susceptibility to depression but also increase depression severity. Moreover, alterations in the gut microbiota disrupt the normal permeability of the intestinal barrier, stimulating inflammatory and immune responses[30] and leading to imbalances in metabolites such as short-chain fatty acids, neurotransmitters, bile acids, and lipopolysaccharides.[31] These changes affect the function of the HPA axis; lead to abnormal production of dopamine, adrenaline, and norepinephrine; and interfere with the concentrations of neurotransmitters such as 5-HT, glutamine, glutamate and GABA, thus affecting mental health.[31]
The effects of probiotics and prebiotics on the gut microbiota and their potential role in depression have been of concern. A new study based on 2005 to 2016 NHANES data revealed that probiotics, prebiotics, synthetic bacteria or yogurt supplements significantly reduced the prevalence of depression and relieved depressive symptoms such as sadness, anhedonia, sleep problems, fatigue, appetite changes, and psychomotor disorders.[32] This antidepressant effect may be related to its ability to maintain the ecological balance of the gut microbiome.[33] A recent meta-analysis indicates that specific probiotics significantly alleviate depressive symptoms. In particular, Lactobacillus and Bifidobacterium strains have shown favorable antidepressant effects.[34] Merkouris et al[35] reviewed literature over the past decade and found that prebiotics, psychoprobiotics, and synthetic probiotics can alleviate depressive symptoms. Approximately two-thirds of the studies confirmed that probiotic supplementation provides modest benefits in patients with depression. This effect may be attributed to probiotics increasing the abundance of Lactobacillus casei, Lactobacillus rhamnosus, Lactobacillus plantarum, and other strains, thereby regulating mental and stress-related behaviors. Furthermore, in a rat depression model induced by chronic unpredictable mild stress, the combined application of Lactobacillus rhamnosus HN001 (HN001) and Bifidobacterium animalis subsp. lactis HN019 (HN019) significantly decreased the ACE and Chao1 indices, which represent microbial abundance and diversity. This intervention subsequently improved depressive-like symptoms in the rats.[36] Similarly, prebiotics, as nutrients for microorganisms, can restore stress-induced changes in the intestinal microbiota of mice, improve intestinal barrier function, and reduce depression-like symptoms.[30] These findings support the protective effects of probiotics or prebiotics against depressive symptoms, which depend in part on the maintenance of the ecological stability of the gut microbiota. The present study conducted a cross-sectional survey of depression patients selected from the NHANES database from 2008 to 2017 and reported that the consumption of probiotics/prebiotics was associated with less severe depressive symptoms, and this relationship was consistent and stable across different demographic characteristics, lifestyle habits, and health-status subgroups. These findings suggest that patients with milder symptoms of depression may benefit more from probiotic supplements.
The mediating role of COPD in the association between probiotic/prebiotic consumption and the severity of depression symptoms was further evaluated in our study. First, we observed a significant association between COPD and the severity of depressive symptoms. This conclusion is supported by numerous studies. A Veterans Affairs-based database population cohort study revealed that patients with COPD have a significantly increased risk of depression symptoms.[37] Other findings indicate that the presence of COPD increases the PHQ-9 depression score by an average of 1 to 2 points.[38] This was also confirmed by a large-scale study conducted using the UK-based General Practice Research Database. In the study of 35,722 patients with COPD and 35,722 patients without COPD, the incidence of new depression after a first COPD diagnosis was 16.2 cases/1000 person-years, whereas it was only 9.4 cases/1000 person-years in the control group.[39] We subsequently examined the relationship between probiotic/prebiotic consumption and COPD, and observed that individuals who consumed probiotics/prebiotics were less likely to suffer from COPD. This finding is consistent with the findings of a previous cross-sectional study based on data from 3 consecutive NHANES cycles from 2007 to 2012, which confirmed the beneficial role of probiotic, prebiotic, or yogurt intake in preventing COPD.[40] Given the positive effect of COPD on depressive symptoms and the negative effect of probiotic/prebiotic consumption on COPD, we further analyzed whether COPD mediated the association between probiotic/prebiotic consumption and the severity of depressive symptoms. Our study suggested that COPD plays a weak but significant mediating role in the association between probiotic/prebiotic consumption and the severity of depressive symptoms. This mediating effect may be related to the regulation of systemic immunity by probiotics/prebiotics. Research has shown that high levels of the inflammatory cytokines IL-1β, IL-2, IL-6, IL-8, IL-10, and TNF-α are risk factors for depression in elderly patients with COPD. Elevated cytokine levels in patients with COPD can activate microglia, causing intracellular inflammatory signals. Long-term inflammatory factors overactivate the HPA axis, leading to glucocorticoid resistance and further worsening depression.[41] Moreover, in patients with lung disease, dysregulation of the gut microbiota leads to decreased secretion of SCFAs, increased Th17/Treg ratios, and the secretion of pro-inflammatory cytokines, which are strongly associated with lung inflammation. The addition of probiotics and prebiotics can restore the immunity of the intestinal microflora, restore the balance of cytokine and chemokine generation, reduce the number of white blood cells, and increase the SCFA concentration, thereby reducing respiratory inflammation.[42] Notably, the effect of probiotics/prebiotics on the severity of depressive symptoms in our study occurred mainly through direct pathways (97.7%), whereas the indirect effect through COPD as a mediating variable was relatively small (2.3%). These results may be directly related to the intricate reciprocal relationship between depression and COPD. Patients with COPD are prone to severe sleep disturbances because of long-term airflow limitation and chronic hypoxia. However, sleep disturbances can also cause or worsen anxiety, which in turn can lead to the beginning and advancement of depressive symptoms.[43] At the same time, recurrent hospital stays and frequent acute exacerbations of COPD can greatly exacerbate anxiety and depressive symptoms, and the frequency of hospital stays worsens the severity of depression.[44] Conversely, depression may also reduce self-management ability, treatment adherence, and participation in pulmonary rehabilitation, while increasing unhealthy behaviors such as smoking and alcohol consumption, which in turn worsens COPD and forms a vicious cycle.[45] This bidirectional and potentially vicious relationship may result in the weak mediating role of COPD in the association between probiotics/prebiotics and depressive severity. Nevertheless, given their potential in regulating inflammation and the gut-brain axis, they may act as promising adjunctive therapies for patients with depression comorbid with COPD.
5. Conclusions
Taken together, to our knowledge, this study is the first to explore the relationship between probiotic/prebiotic consumption and the severity of depressive symptoms using NHANES data. Studies have shown that the consumption of probiotics/prebiotics was correlated with the severity of depressive symptoms. Individuals who consumed probiotic/prebiotic tended to exhibit milder depressive symptoms. We also found that COPD played a weak mediating role in this relationship. These results provide epidemiological evidence for the consumption of probiotics or prebiotic-related products in depressed people in the United States and support a potential therapeutic direction for the use of probiotics or prebiotics as adjunct treatments for depression.
However, there are several limitations to this study. First, as a cross-sectional study based on the US population, our findings have limited generalizability. Second, this study focused only on the overall intake of probiotic/prebiotic, without distinguishing specific sources, types, and intake doses. Although this reflects overall dietary exposure, variations in strain composition and biological activity may introduce exposure heterogeneity and non-differential misclassification bias. Moreover, further subgroup analyses by source were not performed due to sample size, which may limit detailed, comprehensive, and accurate recommendations. Third, NHANES data rely mainly on questionnaires. Specifically, the diagnosis of COPD is based only on the individuals’ self-reported results, without confirmation by clinical gold standards such as pulmonary function tests, which may lead to recall bias and disease misclassification. Finally, as a cross-sectional study, it is difficult to establish causality between probiotic/prebiotic consumption and the severity of depressive symptoms. Moreover, the possibility of reverse causality cannot be ruled out. Additionally, residual confounding may remain despite multivariate adjustment, particularly regarding dietary patterns, socioeconomic status, and healthcare access. Therefore, future studies are needed to further confirm the effects of the consumption of probiotics or prebiotics on depression with high-quality, large-sample randomized controlled trials and optimize treatment strategies by combining data from more extensive sources.
Acknowledgments
We would like to thank all participants and contributors of NHANES.
Author contributions
Conceptualization: Tao Fang, Na Shen.
Writing – original draft: Tao Fang, Na Shen.
Writing – review & editing: Tao Fang, Na Shen.
Abbreviations:
- BMI
- body mass index
- CI
- confidence interval
- COPD
- chronic obstructive pulmonary disease
- CVD
- cardiovascular disease
- NHANES
- National Health and Nutrition Examination Survey
- OR
- odds ratio
- PHQ-9
- Patient Health Questionnaire-9.
This work was supported by grants from the Exceptional Young Talents Fostering Foundation of the Tianjin 4th Central Hospital (tjdszxyy20220021) and the Tianjin Education Commission scientific research project (2023KJ031).
This study used open data from the NHANES database, which had been approved by the Research Ethics Review Board of the National Center for Health Statistics and obtained informed consent from all participants (https://www.cdc.gov/nchs/nhanes/irba98.htm).
The authors have no conflicts of interest to declare.
All data generated or analyzed during this study are included in this published article (and its supplementary information files).
Supplemental Digital Content is available in the online version of this article (http://dx.doi.org/10.1097/MD.0000000000050042).
How to cite this article: Shen N, Fang T. Associations among probiotic/prebiotic consumption, depression and chronic obstructive pulmonary disease: A cross-sectional study. Medicine 2026;105:31(e50042).
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