Inflammation: What the current research says about it's role in mental health
Inflammation is defined as the immune system’s response to contact with harmful stimuli including physical injury and pathogens, and involves the amazing communication of immune cells and blood vessels. Inflammation is necessary in order for us to survive and is not a harmful process unless it becomes chronic.
Chronic inflammation can be caused by a variety of things including chronic infections, unrepaired tissue damage, allergens, or indigestible foreign particles. Chronic inflammation contributes to many chronic inflammatory diseases including diabetes, cardiovascular, bowel diseases, and more recently, brain and mental health disorders. It can also be caused by medical conditions, exposure to chemicals or pathogens, as well as lifestyle behaviors including a sedentary lifestyle, poor dietary patterns, and alcohol intake.
Recently, inflammation is thought to be one of the major mechanisms that influence the diet mental health relationship, with several studies concluding strong associations between inflammatory biomarkers (health markers that can be measured in a lab that indicates inflammation in the body) and specific mental health disorders including depression and schizophrenia. But these findings are not always consistent. This article will review the current literature to date elucidating the relationship between inflammation and depression as well as highlight some important nuance and context to help us understand this relationship.
How Inflammation is Measured
Specific molecules called cytokines are classified as type of “biomarker” which can be measured in blood tests that show alterations in the body or tissue fluids. There are both pro-inflammatory cytokines that promote inflammation as well as anti-inflammatory cytokines which help inhibit or stop inflammation. These pro-inflammatory cytokines are used in clinical applications to indicate normal and abnormal biological processes, as well as to properly assess a person’s responses to therapeutic interventions. This helps researchers and clinicians decide if an intervention helped to lower or promote inflammation in the body. Some common pro-inflammatory cytokines used in research include IL-6, CR-P and TNF alpha.
Diet and Inflammation: Current Research
The majority of the current research related to diet and inflammation mostly comes from observational and epidemiological research studies. These kind of studies allow us to see if one factor correlates or has a relationship with another. It is difficult to determine if one nutrient or food itself is inflammatory or anti-inflammatory for multiple reasons. One is simply because of how we eat. We do not eat foods or nutrients in isolation (i.e. only eating avocados every day). We need to eat a variety of foods which themselves include a variety of nutrients (vitamins and minerals). The other is that there is a lot of inter individual differences with regards to how people respond to certain foods. For me, tomatoes and peppers don’t cause any sort of digestive distress, but for others, tomatoes and peppers may cause them a lot of digestive issues, which may indeed affect peripheral measures of inflammation. In this way, labeling a food as “anti inflammatory” or “inflammatory” is futile. Beyond these reasons, one food or nutrient is not “inflammatory” or anti inflammatory” on it’s own. What is more constructive and practical with regards to attempting to make determinations for the public and nutrition recommendations, is looking at overall dietary patterns to assess if that alone affects inflammation. Broadly speaking, dietary factors that have been associated with decreased levels of inflammation are fiber, antioxidants, omega-3 fatty acids and fermented foods, as compared to other nutrients like saturated fat and sodium which have been associated with increased levels of inflammation.
Some of the best research we have on humans is from large epidemiological research studies like the Nurses Health Study. The Nurses Health Study is one of the longest and largest investigations into risk factors for chronic disease in women. One analysis from this long term study includes a more recent look at diet and inflammation in over 40,000 women who were clinically depressed at the start of the study. The purpose of the analysis was to see if consuming a kind of dietary pattern associated with higher levels of inflammatory markers increased the future risk of depression. The participants were followed up for 12 years and during that time there were over 9,000 incident cases of depression. The authors report that an inflammatory dietary pattern was associated with a higher risk of developing depression. Here’s what we can take away from this analysis in particular: there is an association in middle aged women between consuming an inflammatory dietary pattern and developing depression over a period of 12 years. A more obvious limitation with regards to generalizing these results to a broader population is the limited demographic of the population in this analysis as it was mostly Caucasian women working in healthcare age 55-77. More studies like these in more diverse and varied populations would help clarify if these associations occur in most people. This would help benefit more people across the world with the goal of really helping improve public health.
The Mediterranean Diet
I’m sure at this point you have heard and read about the Mediterranean Diet. Full of vegetables, fruits, whole grains, nuts, seeds, legumes, olive oil, seafood and limited dairy and lean meats, this diet has been studied extensively for it’s various health benefits including for brain health.
A recent review looking at over 60 observational studies reports that adherence to a Mediterranean and “anti-inflammatory diet” (as measured by dietary indices such as the Empirical Dietary Inflammatory Index as well as measurements of biomarkers such as C-Reactive Protein) is associated with lower levels of inflammation. The majority of analyses in the review report a positive association between a healthier diet and lower pro-inflammatory marker CRP, indicating less inflammation. These results again means that there seems to be an association between closer adherence to a Mediterranean diet in an adult population and lower levels of a pro-inflammatory cytokine (CRP). One of the limitations in this review and among all of the studies included was that only one inflammatory biomarker (CRP) was assessed and at only one time-point. Future research needs to focus on examining multiple inflammatory markers in order to better understand these complex biological inflammatory mechanisms and how diet influences this. Also, the studies included in the review were mostly cross-sectional, which only allows us to say that there is an association between diet and inflammation, not that diet necessarily causes inflammatory markers to increase. Additionally, there are many different disease states and variables that influence inflammation and hence, measures of inflammatory markers and mediators in the blood. These factors (like chronic medical diseases including Type 2 diabetes and rheumatoid arthritis) were not controlled for in the data analysis. This is important because trying to control for these variables will allow us to better understand the relationship between inflammation and diet alone. Future research needs to focus on longitudinal methods as well as methodological designs that get us closer to seeing if diet alone is enough to cause and maintain chronic inflammation in particular.
Recent Research on Inflammation and Depression
One recent hypothesis is that diet mediates chronic inflammation and that poor diet in some people, may lead to both inflammation as well as contribute to the development of depression. Meaning, that diet directly influences chronic inflammation.
Interestingly, there is some newer research that suggests that certain depressive symptoms may be associated with specific inflammatory biomarkers. For example, one review reports that there is an association between the neurovegetative symptoms of depression and inflammation, such as fatigue, disturbed appetite, sleep problems (specifically hypersomnia), and depressed mood. This review is also interesting because it analyzed data from a very large sample of people. The data was retrospectively analyzed with over100,000 individuals from the UK Biobank and NESDA cohort. The researchers report that CRP and IL-6 levels (two inflammatory cytokines) were associated with specific symptoms of depression including fatigue, sleeping problems, changes in appetite, and depressed mood. This study adds new information to the existing literature and if this is found repeatedly in depressive populations, this may be able to help clinicians tailor treatment based on these assessments. But I think these results need to be interpreted with caution as there is a ton of difficulty involved in helping to determine if certain subtypes of depression are related to inflammation status. There are also some limitations to consider as well in that although this study used elevated CRP as the criteria, a one time measurement of CRP may not be sufficient to identify patients with persistent inflammation.
A recent study from 2020 assessed and measured absolute numbers of 14 immune cell subsets from peripheral blood samples in 206 participants with depression and 77 healthy controls (as defined by not having any history of MDD or other psychiatric illness). Researchers tested the hypothesis that a subgroup of depressed cases would have peripheral inflammation using what’s called a top down analysis, dividing the cases into 2 subgroups based on their immune cell profiles. They then tested for significant differences between the groups in terms of inflammatory proteins and clinical variables. In terms of the characteristics of the participants in the MDD group: 114 had moderate to severe depressive symptoms, of whom 61% were taking an antidepressant medication, 50 with mild depressive symptoms of whom 90% were currently taking medication and 42 with minimal depressive symptoms of whom 100% were currently taking medication.
Results showed that CRP and IL-6 concentrations as well as absolute counts of neutrophils, intermediate monocytes, and CD4+ T cells (various immune cells) were significantly increased in the depressed group. They further defined 4 different subggroups within the MDD patients: an uninflamed group which had low levels of immune cells measured, and 3 other subgroups with elevated levels of different immune cells. The subgroup of cases with increased immune cell counts also had significantly increased inflammatory protein concentrations compared with the second subgroup with decreased immune cell counts. The researchers called this group the inflamed depression group. Cases of inflamed depression had significantly higher severity of observer related depressive symptoms as measured on the Ham-D and self reported depressive symptoms from the BDI, compared with the uninflamed depression cases. Inflamed vs. uninflamed cases had twice the rate of unemployment, were slightly older, and were more likely to be smokers. They still did not differ significantly on other variables like sex, current antidepressant use, alcohol use, and BMI.
Some limitations to consider are the methodological design in that case control designs are vulnerable to the effects of uncontrolled confounding variables, and there are many factors that could have effects on peripheral immune biomarkers. But these results are interesting and help us understand that not all cases of MDD are necessarily driven or are associated with increased levels of inflammation.
Another study published earlier this year that included older adults with late life depression MDD, sought to disassociate the links among depression, medical illness, and inflammation by carefully screening out patients with known inflammatory-associated illness. This approach allowed the researchers to determine, in the absence of known comorbid illness, whether depression was associated with higher rates of inflammation when compared to healthy adults without a diagnosis of MDD. They found that there were very low levels of circulating cytokines and inflammatory mediators in individuals with MDD and in healthy controls, when study participants in both groups were carefully screened to exclude medical causes of inflammation. The researchers report that there was no observable difference in inflammatory markers between patients with MDD and controls, which included levels of 29 different circulating cytokines and chemokines. The authors also note that a large number of patients had to be excluded which highlights the high rates of physical illness in most patients with MDD. In fact, one review estimates that the prevalence of MDD in those with chronic medical diseases is at least twice as high and often more than four times higher than the prevalence in the general population. This is extremely important as other medical conditions that are inflammatory driven (like IBS and rhemutoid arthritis) significantly increase the risk for depression and also will affect the number of plasma inflammatory proteins.
These two recent studies in tandem tell us that inflammation is not necessarily a central component when it comes to the pathophysiology of depression, but that it may be for some individuals. It provides further support that depression is a heterogenous disorder in that there is a lot of variability with regards to how depression develops, it’s time course, as well as ways in which people respond to treatments. Hopefully more research can done to replicate the findings that there may be subgroups of patients with depression where inflammation may be the primary driver. In this way, treatment potentially can be tailored to focus on ways to help lowers these levels of inflammation.
Takeaways
While most of the research on diet and inflammation in humans are from correlational studies, there is growing evidence that dietary patterns influence inflammation. More research needs to be done with more diverse populations as well as with more diverse dietary patterns to help understand the complexity of this relationship and what to relay to the public. Indeed the Mediterranean diet isn’t the only dietary pattern that helps to support our mental health. It’s just that is has been the dietary pattern that has been most studied thus far and therefore has been recommended to promote health more than other dietary patterns.
Food is more than just nutrients, it’s pleasurable, comforting, social, cultural, and emotional. The most consistent finding shown thus far is that it is your dietary pattern that is what seems to matter most when it comes to diet and overall health. Which means it’s not about finding magic brain healthy nutrients, it’s about eating a spectrum of food that both satisfies the soul as well as nourishes our brain. Sticking with sustainable basics like increasing your fruits, vegetables, fiber, and water intake, ensures you are feeding and supporting your mental health as best as you can. And remember, inflammation has not been shown to be a central component when it comes to the pathophysiology of complex mental health disorders, which means you do not need to be obsessive about focusing on lowering inflammation if you have a mental illness. It’s a lot more complicated than that :)
References
Colditz, G. A., Manson, J. E., & Hankinson, S. E. (1997). The Nurses' Health Study: 20-year contribution to the understanding of health among women. Journal of women's health, 6(1), 49–62. https://doi.org/10.1089/jwh.1997.6.49
Hart, M.J., Torres, S.J., McNaughton, S.A. et al. Dietary patterns and associations with biomarkers of inflammation in adults: a systematic review of observational studies. Nutr J 20, 24 (2021). https://doi.org/10.1186/s12937-021-00674-9
Melo, H. M., Santos, L. E., & Ferreira, S. T. (2019). Diet-Derived Fatty Acids, Brain Inflammation, and Mental Health. Frontiers in neuroscience, 13, 265. https://doi.org/10.3389/fnins.2019.00265
Salari-Moghaddam, A., Keshteli, A. H., Afshar, H., Esmaillzadeh, A., & Adibi, P. (2019). Association between dietary inflammatory index and psychological profile in adults. Clinical nutrition (Edinburgh, Scotland), 38(5), 2360–2368.
Zhao, H., Wu, L., Yan, G. et al. Inflammation and tumor progression: signaling pathways and targeted intervention. Sig Transduct Target Ther 6, 263 (2021). https://doi.org/10.1038/s41392-021-00658-5
