Edited by: Fulvio D’Acquisto, Queen Mary University of London, United Kingdom
Reviewed by: Angela Ianaro, University of Naples Federico II, Italy; Ana Maria Teixeira, University of Coimbra, Portugal
Specialty section: This article was submitted to Inflammation, a section of the journal Frontiers in Immunology
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There is considerable evidence for the effectiveness of mind–body interventions (MBIs) in improving mental and physical health, but the molecular mechanisms of these benefits remain poorly understood. One hypothesis is that MBIs reverse expression of genes involved in inflammatory reactions that are induced by stress. This systematic review was conducted to examine changes in gene expression that occur after MBIs and to explore how these molecular changes are related to health. We searched PubMed throughout September 2016 to look for studies that have used gene expression analysis in MBIs (i.e., mindfulness, yoga, Tai Chi, Qigong, relaxation response, and breath regulation). Due to the limited quantity of studies, we included both clinical and non-clinical samples with any type of research design. Eighteen relevant studies were retrieved and analyzed. Overall, the studies indicate that these practices are associated with a downregulation of nuclear factor kappa B pathway; this is the opposite of the effects of chronic stress on gene expression and suggests that MBI practices may lead to a reduced risk of inflammation-related diseases. However, it is unclear how the effects of MBIs compare to other healthy interventions such as exercise or nutrition due to the small number of available studies. More research is required to be able to understand the effects of MBIs at the molecular level.
In the past two decades, mind–body interventions (MBIs; refer to Table
The search for potential mechanisms of MBIs should not stop at the neural level. The development of gene expression analysis techniques in recent year makes this one important tool for psychologists to gain a deeper understanding of biological mechanisms that underpin, or interact with, psychological variables. Over the past decade, studies that implement gene expression analysis in MBIs research have begun to appear. In addition to being an objective measure of evaluating and comparing the effectiveness of MBIs, the analysis of gene expression changes has considerably theoretical value, as it reveals the underlying mechanisms of the psychological and physical effects of MBIs.
In this systematic review, we will explore (1) if MBIs can affect physical health by causing observable molecular changes in the form of differential gene expression and (2) what are the molecular changes underpinning psychological benefits in MBIs. By implementing a biological approach to the study of MBIs, there is an opportunity to fill a crucial gap concerning the underlying mechanisms that give rise to their reported beneficial effects. We have included a range of MBIs in our analysis, such as mindfulness and other forms of meditation, yoga, RR, Tai Chi, and Qigong, all interventions for which there is evidence suggesting similar beneficial effects on mental and physical health (
Below we start by outlining the principles of gene expression analyses and how they have been applied to MBIs; then we move into a systematic review of the evidence for their effects on gene expression, and what changes in gene expression underpin the psychological benefits of MBIs. Finally, we will discuss the implications of the reviewed studies, their limitations, and offer guidance for future studies.
Gene expression detection techniques produce an enormous amount of quantitative data—a long list of genes. But because genes are most often team players—they work together as a network to produce an observable trait or a measurable biological function—a long list of genes is hard to contextualize and interpret. To make matters more complicated, some genes regulate the activity of other genes. One way to deal with this is to start with statistical analysis, followed by bioinformatics analyses; this one is used to identify which of the genes are in the same pathway (i.e., network) and, therefore, have the same function.
The most common bioinformatics analysis in MBIs research is the Transcription Element Listening System (TELiS). This analysis will assess which transcription factor is regulating gene expression amid a set of genes. It does so by scanning the promoters for transcription factor binding motifs that are overrepresented, in relation to their usual prevalence across the genome (
Stress can be regarded as a bodily response to events that are perceived as a threat or a challenge. This response may precipitate a health risk when stress is severe or it occurs over a long period of time without adequate coping mechanisms. It has been found that exposure to severe stressors can have a profound influence on the body and can lead to detrimental changes in its biology, such as reduced gray matter in several brain regions (
To understand the impact of environmental factors on the body’s immune system through CTRA, we first need to unpack the underlying molecular mechanisms. Consider the path linking a stressful event to an observable psychobiological change, such as the onset of depression. Slavich and Irwin (
In the first stage of modulation, the SNS initiates the production of the neuromodulators epinephrine and norepinephrine. These will, in turn, promote inflammation by activating the production of molecules called transcription factors that then bind to and activate pro-inflammatory genes and translate them into proteins cytokines that can inhibit or initiate inflammation. Cytokines will travel back to the brain and initiate symptoms of depression [e.g., low mood, fatigue, and anhedonia (
In the second stage of modulation, the HPA initiates the production of metabolic agents (glucocorticoids) and the neurotransmitter acetylcholine that, in normal conditions, suppress inflammation. In the case of long-term stress, the body adapts to their continuous secretion and becomes less sensitive to their anti-inflammatory effects. These processes lead to CTRA and, if this condition is maintained for years, there is a high risk of inflammation-related diseases, infection, accelerated biological aging, and early mortality. It is likely that CTRA played an important role in our hunter-gatherer prehistory, as it linked fight-or-flight response with pro-inflammatory gene expression that provided protection when there was a higher risk of bacterial infections from wounds (
We will now review studies on MBIs (mindfulness, yoga, RR, Tai Chi, and Qigong) that include gene expression analysis as an outcome measure, in order to assess the evidence for their effects on gene expression, and what changes in gene expression underpin the psychological benefits of MBIs. Studies were identified by searching PubMed through September 2016 using the following combination of keywords: The population studied should only contain adults. Both clinical and non-clinical samples were allowed (for example, students, cancer patients, and caregivers) and studies with all sample sizes were included. Studies with experienced practitioners or non-experienced practitioners were allowed, making both cross-sectional and longitudinal studies eligible. Gene expression changes had to be one of the outcome variables (any number of analyzed genes, cell type and any gene expression technology were eligible). The independent variables had to be any type of MBI. Articles should be written in English. Only research papers were included. Review papers, meta-analyses, commentaries, and conference proceedings were excluded.
PRISMA flow chart: the process of selecting relevant studies.
The screening narrowed the search results to 18 articles (Figure
A summary of the results of MBI and gene expression.
Study | Research design | Type of population (experimental group sample size) | Control group type (size) | Meditation or meditation-related type of practice | Practice frequency, training time | Gene expression technology (bioinformatics analysis) | Cell type | Biological outcome | Psychological and other outcomes |
---|---|---|---|---|---|---|---|---|---|
Li et al. ( |
CS | Experienced practitioners ( |
Naïve ( |
Qigong | 60–120 min/day, 1–5 years | Genome-wide: Affymetrix Human Genome U95 (N/A) | Peripheral blood neutrophils | Genes related to: |
N/A |
Sharma et al. ( |
CS | Experienced practitioners ( |
Naïve ( |
Sudarshan Kriya (breath regulation) | >60 min/day, at least 1 year | RT-PCR of 9 genes (N/A) | Peripheral blood lymphocytes | Genes related to: oxidative stress ns, DNA damage ns, cell cycle control ns, aging ns, apoptosis+ | N/A |
Kumar and Balkrishna ( |
CS | Leukemia patients ( |
Naïve ( |
Pranayama (breath regulation) | N/A | Genome-wide: Expression Array System of Applied Biosystems (N/A) | Peripheral blood lymphocytes | Genes related to: immune regulation+ |
N/A |
Creswell et al. ( |
LG | Normal older adults ( |
Wait list ( |
Mindfulness-based stress reduction, 8 weeks | 30 min/day, 8 weeks | Genome-wide: Illumina HT 12 BeadChip (TELiS, NF-κB) | PBMC | Transcription factors: NF-κB−; |
Loneliness− |
Black et al. ( |
LG | Dementia caregivers ( |
Relaxing music ( |
Kirtan Kriya Meditation | 12 min/day, 8 weeks | Genome-wide: Illumina HT 12 BeadChip (TELiS, NF-κB, and IRF) | PBMC | NF-κB−, IRF+ |
Depression−, mental health+ |
Irwin et al. ( |
LG | Breast cancer survivors with insomnia ( |
Cognitive behavioral therapy ( |
Tai Chi | 2 h/week, 12 weeks | Genome-wide: Illumina HT 12 BeadChip (TELiS, NF-κB) | PBMC | NF-κB− |
N/A |
Bower et al. ( |
LG | Breast cancer survivors with fatigue ( |
Health education ( |
Iyengar yoga | 90 min/twice a week, 12 weeks | Genome-wide: Illumina HT 12 BeadChip (TELiS: NF-κB, GR, and CREB) | PBMC | NF-κB−, CREB−, GR+ |
N/A |
Bower et al. ( |
LG | Breast cancer survivors ( |
Wait list ( |
Mindful awareness practice | 2 h/week, 6 weeks | Genome wide: Illumina HT 12 BeadChip(TELiS: NF-κB, GR, CREB, IRF) | PBMC | NF-κB− |
Stress−. Fatigue−, sleep disturbance−, hot flashes−, depression− (marginal), positive affect+, peace and meaning+, intrusive thought ns, fear of recurrence ns |
Duraimani et al. ( |
LG | Hypertensive adults ( |
Extensive health education ( |
Transcendental meditation | 40 min/day, 16 weeks | 2 genes related to telomeres: RT-PCR | Whole blood | hTR ns, hTERT ns, |
Blood pressure ns, healthy lifestyle ns, anger ns |
Irwin et al. ( |
LG | Older adults with insomnia ( |
Cognitive behavioral therapy for insomnia ( |
Tai Chi | 2 h/week, 16 weeks | Genome-wide: Illumina HT 12 BeadChip (TELiS: NF-κB, CREB, GR, AP, IRF1, IRF2) | PBMC | NF-κB−, CREB−, GR+, AP−, IRF1 ns, IRF2 ns; |
N/A |
Kuo et al. ( |
LG | Irritable bowel syndrome and inflammatory bowel disease ( |
None | Relaxation response–mind–body intervention | 20 min/day, 9 weeks | Genome-wide: Affymetrix HG U133 Plus (Interactive network analysis: NF-κB) | PBMC | NF-κB− |
Quality of life+, symptoms of IBS/IBD−, pain catastrophizing−, pain interference with daily life ns, anxiety− |
Ho et al. ( |
LG | Caregivers ( |
None | MBSR | 1.5 h/week (8 weeks) | Genome-wide: Affymetrix HuGene 1.0 ST arrays (WebGestalt2) | PBMC | Genes related to inflammation−, |
Psychological stress+, mindfulness+ |
Ravnik-Glavač et al. ( |
RR | Experienced practitioners ( |
None | Buddhist forms of meditation | N/A, more than 23 years of experience | Genome-wide: Affymetrix HG U133 Plus, ArrayStar Human LncRNA Array (Gene Enrichment Analysis) | PBMC | Genes related to metabolism and cell cycle processes−, immune system ns, apoptosis ns, stress response ns |
N/A |
Qu et al. ( |
RR | Experienced practitioners ( |
Within-subject controls (relaxation) | Sudarshan Kriya and yoga | 2 days for 2 h, 1.5 months to 5 years of experience | Genome-wide: Illumina Human WG-6 v3 Bead Chip, 9 genes: qPCR (Gene ontology) | Peripheral blood lymphocytes | All pathways ns | N/A |
Dusek et al. ( |
CS + L | Experienced practitioners ( |
Naïve ( |
Relaxation response | 20 min/day, 8 weeks | Genome-wide: Affymetrix HG U133 Plus (GSEA) | PBMC | CS: ubiquitin−, proteasome−, stress response−, ribosomal protein+ |
N/A |
Bhasin et al. ( |
CS + L + RR | Experienced practitioners ( |
Naïve ( |
Relaxation response | 20 min/day, 8 weeks | Genome-wide:HR U133A (GSEA) | PBMC | ATP+, INS+, NF-kb− |
N/A |
Kaliman et al. ( |
CS + RR | Experienced practitioners ( |
Naïve ( |
Mindfulness meditation | >30 min/day, 3 years | RT-PCR of 23 genes | PBMC | CS: ns |
Stress reactivity− |
Epel et al. ( |
CS + L + RR | Experienced practitioners ( |
Naïve ( |
Meditation and yoga retreat | 4 h of meditation and 3 h of yoga per day, 4 days | Genome-wide: RNA-Seq (Gene ontology) | PBMC | All groups: stress response−, wound healing−, injury− |
Depression−, stress−, vitality−, mindfulness− |
Summary | CS = 17% |
M (participants per group) = 23.55 |
No control group = 22% |
Mindfulness = 22% |
46% of interventions lasted 8–12 weeks; 33% of interventions had only weekly meetings | 44% of studies used TELiS and all found a downregulation of NF-κB | 72% of studies did gene expression analysis from PBMC, 17% from lymphocytes | 81% of studies found a reduction inflammation related genes and/or transcription factors | 56% of studies did not measure any psychological outcomes |
In Table
The very first study of mind–body therapies that included gene expression compared gene profiles of six long-term Falun Gong Qigong practitioners and six healthy controls (
Sharma and colleagues (
Kumar and Balkrishna (
Creswell and colleagues (
They tested if increased inflammation is a mechanism by which loneliness promotes disease in older adults. Inflammation was measured through changes in transcriptome and in protein markers of inflammation [C-reactive protein (CRP) and IL-6]. Blood samples were taken at baseline and after completion of MBSR. There also were self-report measures of loneliness and mindfulness. MBSR class attendances and minutes of daily home practice were measured as control variables.
Genome-wide transcriptional profiling was done from peripheral blood mononuclear cells (PBMCs) controlling for sex, age, ethnicity, BMI, as well as the contribution of sleep quality and exercise. Effect size cutoff of 25% was used in statistical analysis, which was followed with bioinformatics analysis of differentially expressed genes to see how many of them are targeted with NF-κB transcription factors (TELiS transcription factor search). They were interested in NF-κB because previous studies found that genes targeted with this transcription factor are more expressed in people who are lonely (
At baseline, older adults who reported more loneliness showed higher expression of pro-inflammatory genes targeted with NF-κB transcription factor. After MBSR participants reported reduced loneliness and gene analysis showed a reversal of pro-inflammatory gene expression pattern. Further analysis showed that genes that changed expression originated mostly from monocytes and B lymphocytes. Regarding protein biomarkers of inflammation, there were no significant changes in CRP and IL-6 after MBSR.
Black and colleagues (
There was a significantly greater reduction of depressive symptoms and an improvement in mental health in the meditation group. Furthermore, 49 genes were downregulated and 19 upregulated in the KKM group in relation to the relaxation group. These differentially expressed genes were further analyzed with TELiS, which confirmed the hypothesis that there is a decrease in pro-inflammatory gene expression (related to NF-κB) and an increase in antiviral gene expression (IRF-1). This suggests that KKM improved the immune system in terms of inflammation reduction and creating better defense against viruses. Transcript origin analysis (TOA) found that most of the observed gene expression changes stem from B lymphocytes and plasmacytoid dendritic cells.
Irwin and colleagues (
While CRP did not change after either of the interventions, IL-6 was marginally reduced and TNF was significantly reduced after Tai Chi, indicating that it can reduce cellular inflammatory responses. Similarly, gene expression analysis found a 9% reduction in expression of 19 pro-inflammatory genes and a 3.3% increase in expression of 34 genes involved in the production of proteins that regulate anti-viral response and tumor activity in the Tai Chi group relative to CBT-I. In total, 68 genes were downregulated and 19 upregulated after Tai Chi. The downregulated genes are involved in the generation of white blood cells and inflammation. Similar to previous studies, TELiS bioinformatics analysis found a significant reduction of activity of pro-inflammatory transcription factor NF-κB.
Bower et al. (
Instead of measuring cytokines directly, Bower and colleagues chose downstream markers of pro-inflammatory cytokine activity, which are easier to detect as they are produced in a greater amount. The downstream markers are also considered a more accurate and stable measure of inflammation than the cytokines that produce them. Downstream markers included were as follows: sTNF-RII (a marker of TNF activity), IL-1ra, and CRP (markers of IL activity). These markers were measured from blood, while cortisol was measured from saliva (samples collected by participants themselves) immediately after waking, 30 min and 8 h after waking, and before bedtime.
Genome-wide transcriptional profiling identified 282 genes that were upregulated and 153 downregulated genes after 3 months of yoga. A 15% gene expression change was considered statistically significant, unlike other studies that set 20% as a cutoff point. The majority of downregulated genes were related to type I interferon responses (i.e., cytokines that are released when a virus infects a cell), which has previously been associated with fatigue in cancer patients. Similarly, behavioral measures of fatigue were significantly reduced after months of yoga and remained reduced at a 3-month follow-up.
Transcription Element Listening System showed that yoga reduced the activity of NF-κB, which is suggestive of lower inflammation, as this is a key regulator of pro-inflammatory gene expression. CREB is another transcription factor whose activity was reduced with yoga, suggesting a downregulation of the SNS. Finally, TELiS found that yoga increased the activity of anti-inflammatory glucocorticoid receptor (GR), which indicates a change in HPA axis in terms of responding better to cortisol and stopping the stress response more quickly. However, such change in the HPA axis should lead to reduced levels of cortisol, which was not verified with the cortisol analysis from saliva. Regarding downstream markers of inflammation, sTNF-RII increased in the control group, but remained at the same level in the yoga group. There were no significant changes for IL-1ra and CRP.
Bower and colleagues (
Mindful awareness practices significantly reduced stress, fatigue, sleep disturbance, hot flashes, and marginally reduced depressive symptoms. Conversely, it significantly increased positive affect and peace and meaning. A set of 19 pro-inflammatory genes was significantly downregulated with MAP when compared to the control condition. TELiS analysis of significantly changed genes found that transcription factor NF-κB showed a significant decrease while anti-inflammatory GR and interferon regulatory factors (IRF) increased and CREB remained the same. IL-6 was not significantly changed in general, but those who practiced meditation more frequently had lower levels of IL-6, while other proteins were non-significant even after the adjustment for the practice frequency. Downregulated genes mostly originated from monocytes and dendritic cells, while upregulated genes mostly originated from B lymphocytes.
Duraimani and colleagues (
Both interventions equally increased the expression of telomerase-related genes. Telomeres themselves did not change with either intervention, though this rarely happens over the course of just a few months. Extensive health education proved to be better for hypertensive adults because it lowered diastolic blood pressure more than TM and led to healthier lifestyle behaviors.
Irwin and colleagues (
Behavioral outcomes regarding sleep are not reported in this paper. Four months after the intervention had finished, CRP was significantly reduced in the CBT-I group and remained at the same level after 16 months. In the Tai Chi group, CRP was only marginally reduced after 4 months and it became non-significant afterward. On the other hand, pro-inflammatory cytokines were reduced in both groups 2 months after the intervention, but they remained reduced for 16 months in the Tai Chi group alone. Gene expression profiling was carried out on a random subsample of 78 older adults at a 4-month follow-up. Relative to sleep education, CBT-I downregulated 347 genes and upregulated 191 genes, while Tai Chi downregulated 202 genes and upregulated 52 genes. The majority of downregulated genes after CBT-I and Tai Chi are involved in inflammation. On the other hand, the majority of upregulated genes after CBT-I are involved in interferon and antibody responses, while those upregulated after Tai Chi do not have a known common function. TELiS found that both CBT-I and Tai Chi reduced activity of NF-κB relative to sleep education, though the difference was only marginally significant in the Tai Chi group. Both interventions reduced activity of CREB as well, while Tai Chi also reduced activity of activator protein 1 (AP-1, controls cellular differentiation, proliferation, and cell death) and marginally increased GR activity. TOA found that the genes that are downregulated by CBT-I and Tai Chi originated mostly from monocytes and dendritic cells.
Kuo et al. (
Immediately after RR-MBI and at a short-term follow-up 3 weeks later, both IBS and IBD patients showed greater quality of life and a significant reduction of symptoms of their condition and of anxiety. They reported improved coping with pain, but no change in how pain interferes with their functioning. Regarding biological measures, there was no change in ESR and CRP. In the IBD group, a total of 1059 genes had changed. These were related to improvements in inflammatory response, cell growth, proliferation, and oxidative stress-related pathways—kinases, inflammation, cell cycle, and proliferation. In the IBD group, 119 genes that are related to cell cycle regulation and DNA damage changed expression. Bioinformatics analysis of genes that changed expression (by using Interactive network analysis) found that NF-κB is a key molecule for both IBS and IBD.
Ho and colleagues (
Based on the variability in the CSAQ score, researchers classified all 25 participants into three MBSR responder categories: poor responder, moderate responder, and good responder. This categorization was the basis for the gene expression analysis. Researchers identified 194 differentially expressed genes that can be used to predict to which responder category each caregiver belongs. These genes were related to inflammation, stress response, and depression, which suggest that psychological benefits of MBSR might be emerging due to reduction in these variables. Furthermore, researchers identified 91 genes that can be measured at baseline to predict with 94.7% accuracy the likelihood that a caregiver will get psychological benefits from MBSR. These genes were related to immune system functions, such as toll signaling and insulin, which suggests that the likelihood to benefit from MBSR depends on immunological status.
Ravnik-Glavač and colleagues (
Electroencephalography showed almost identical patterns in both meditators: increased theta and alpha frequency range. Genes that changed expression for 30% or more after entering into higher consciousness were considered significant. For one participant, 1,688 genes changed expression (1,559 downregulated and 109 upregulated) and 608 for the other (338 upregulated and 270 downregulated). Although the number of changed genes differed between meditators, they shared 118 genes. The genes that changed in both meditators suggest a downregulation of metabolism and cell cycle processes. Additionally, some of the genes involved in immune system, cell death, and the stress response were downregulated. However, the two gene expression profiles were too different and thus difficult to compare and make generalizable conclusions.
Qu et al. (
The RR has been defined as a physiological state that represents the opposite state of the stress response (
The results were validated in a separate independent analysis on a new set of samples derived from previous groups (five controls, five short-term practitioners, and six long-term practitioners). Validation results were similar to the original results from the full sample, which supports the assumption that these changes do not occur randomly.
Bhasin and colleagues (
Results showed that experts and short-term practitioners had different gene expression profiles at baseline. Following a RR session, experts showed more consistent and pronounced gene expression changes than short-term practitioners. Both experts and short-term practitioners presented changes that have been linked to energy metabolism, electron transport chain, biological oxidation, and insulin secretion—all these pathways are crucial for mitochondrial energy mechanics, oxidative phosphorylation, and cell aging. Using systems biology analysis, it was found that the most upregulated critical molecules were ATP synthase and insulin, which promote mitochondrial energy production and utilization (resilience), and the most downregulated NF-κB pathway genes. Changes were generally more pronounced in experts. Upregulated genes were related to energy metabolism, mitochondrial function, insulin secretion, and telomere maintenance. Downregulated genes were related to inflammatory response and stress pathways. Finally, FeNO was increased or showed a trend toward increase during RR in all practitioners regardless of experience.
Kaliman and colleagues (
Epel and colleagues (
The central biological outcome of this study was gene expression. There were 390 genes that changed expression in all three groups, most likely due to the relaxation component that was common to all groups. These gene expression changes referred primarily to lower expression of genes related to stress response, wound healing, and injury. In addition to these changes common across groups, regular meditators showed lower expression of genes involved in protein synthesis, viral expression, and viral infectious cycle, while the novice meditators had no distinctive gene expression changes.
They also assessed other biological outcomes, including telomerase (an enzyme that can stabilize or lengthen telomeres), TNF alpha, and amyloid beta (Aβ) metabolism. Greater ratio of proteins Aβ42/Aβ40 is associated with lower risk of dementia (
The 18 examined studies indicate that MBIs reverse skewing of the transcriptome that is related to adversity, which counteracts the effects of stress on the immune system. Although most genes showed small or moderate effect sizes individually, a general pattern emerges: pro-inflammatory genes and pathways get downregulated (see Table
A major shortcoming of the literature is the lack of active control groups that carefully mirror the MBIs (e.g., length of time, meaningfulness of the practice). This should be a mandatory procedure in studies of gene expression analysis with behavioral interventions to account for the many non-specific effects of MBIs, such as social support or teacher–student relationship. An active control group was included in six out of the nine randomized controlled studies, but control conditions ranged from relaxation—which produces similar effects to MBIs regarding stress reduction—to education. Black and colleagues (
One other problem to consider are the various environmental and lifestyle factors that may change gene expression in similar ways to MBIs. For example, similar differences can be observed when analyzing gene expression from peripheral blood mononuclear cells (PBMCs) after exercise. Although at first there is an increase in the expression of pro-inflammatory genes due to regeneration of muscles after exercise, the long-term effects show a decrease in the expression of pro-inflammatory genes (
Another limitation is inherent to gene expression data. By themselves these do not provide much useful information unless the relationship between gene expression and psychological variables is directly explored. Only two of the reviewed studies (
The studies presented considerable variation, both in their type of interventions and gene expression assessment. MBIs varied from seated meditation at home to movement in groups, with lengths ranging from 4 days to 4 months: half of them used healthy adults while the other half had clinical or highly stressed samples. One interesting hypothesis to test is that the effects of MBIs will be easier to detect on populations with high levels of inflammatory gene expression at baseline [such as older adults; (
Another source of heterogeneity in the reviewed studies is the cell type from which gene expression data are collected. In 72% of reviewed studies, data were obtained from peripheral blood mononuclear cells (PBMCs). As PBMCs consist of particular cell subtypes that have different gene expression patterns and functions, their variety could affect data interpretation. The results of studies that analyzed from which cell types the observed gene expression emerged (TOA) were mixed, thus all PBMCs will have to be included in future studies.
Another aspect to bear in mind is that the biological consequences of the observed gene expression changes were not found directly, because the studies that employed circulating proteins (e.g., CRP, interleukins, or cortisol) generally did not find significant results. In fact, 38% of the reviewed studies measured at least one inflammatory protein and the results were non-significant in 76% of cases and those that were significantly changed (usually TNF, CRP, and IL-6) are not consistently reduced across studies. Our systematic review indicates that circulating proteins rarely change after a few months of practice, which is how long the studies usually last (46% of studies in this review lasted between 6 and 12 weeks). This suggests that as long as the study interventions consist of only a few months of practice, it will be of limited value to measure proteins. Fortunately, gene expression is more sensitive to MBIs than circulating proteins. Gene expression changes are observed after a few weeks of meditation [e.g., Ref. (
One final methodological concern has to do with the assessment of inflammation. Throughout this review we encountered 11 different measures of inflammation. Thus, if a single inflammatory measure has decreased after an intervention, we cannot confidently conclude that the immune system is enhanced. Future studies should attempt to directly find functional consequences of observed gene expression changes. For instance, PMBC subtypes could be isolated before and after MBIs to verify if they show different
Before widely integrating MBIs in health care, more research must be done with the aim of constructing and validating a comprehensive theory of MBIs with a multi-level approach that draws connections between genetic and other data, particularly psychological and behavioral. This is the only way of advancing the literature on MBIs and responding to recent criticisms about the theoretical incongruence and lack of consistent evidence for the benefits of these techniques [e.g., Ref. (
The results of 18 studies that used gene expression analysis in research on meditation and related MBIs have overall found downregulation of NF-κB-targeted genes, which can be understood as the reversal of the molecular signature of the effects of chronic stress. Even though the study designs, the population, and the types of MBI used in the studies included in this review vary, it indicates that some of the psychological and physical benefits of MBIs are underpinned by biological changes in NF-κB genes. These results need to be replicated in larger samples and with stronger research designs that control for non-specific effects of these practices and for as confounding lifestyle factors, such as sleep, diet, and exercise. This research opens the doors to the development and testing of a multi-level theory of MBIs, which integrates the biological, psychological, and environmental levels.
IBu: database search, study design, data interpretation, drafting the paper, final approval, agreement to be accountable. MF and IBr: study design, data interpretation, critical revision, final approval, agreement to be accountable. JJ and CM: data interpretation, critical revision, final approval, agreement to be accountable.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Common abbreviations and their definitions.
BMI | Body mass index, calculated as the body weight divided by square of the body height |
CBT | Cognitive behavioral therapy, the most common approach in psychotherapy |
CREB | cAMP response element-binding protein, a transcription factor that regulates genes involved in neuroplasticity and memory |
CRP | C reactive protein, a protein produced by the liver that can be measured from the blood as an indicator of inflammation |
CTRA | Conserved transcriptional response to adversity, a molecular signature of stress |
FeNO | Fractional exhaled nitric oxide, a measure of airway inflammation |
GR | Glucocorticoid receptor, a transcription factor that affects inflammation and cellular proliferation |
GSEA | Gene Set Enrichment Analysis, a type of bioinformatics analysis of the genes that change expression |
HPA | Hypothalamus–pituitary–adrenal (axis), the key circuitry involved in the stress response |
IBD | Inflammatory bowel disease, a term that include Crohn’s disease and ulcerative colitis, which are chronic inflammatory disease of the colon and/or small intestine |
IBS | Irritable bowel syndrome, a chronic inflammatory condition that brings symptoms such as cramps, bloating, diarrhea, or constipation |
IL | Interleukin, a protein that regulates immune responses |
IPA | Ingenuity Pathway Analysis, a type of bioinformatics analysis of the genes that change expression |
IRF | Interferon regulatory factors, a family of transcription factors that regulate antiviral responses |
KKM | Kirtan Kirya Meditation, a form of meditation that includes singing a mantra and finger gestures (mudras) |
MAP | Mindful awareness practices, a standardized 6-week mindfulness intervention |
MBCT | Mindfulness based cognitive therapy, an approach that combines CBT and mindfulness |
MBI | Mind-body intervention, an umbrella term for meditation, yoga, mindfulness, Tai Chi, Qigong and relaxation response |
MBSR | Mindfulness Based Stress Reduction, a standardized 8-week mindfulness intervention |
miRNA | microRNA, a small non-coding RNA molecule that can interfere with the expression of a gene after it is transcribed |
mRNA | Messenger RNA, a large family of RNAs that transport genetic infomation from DNA to ribosomes |
NF-κB | Nuclear Factor Kappa B, a transcription factor regulating a large number of genes related to immune response, cell survival, differentiation, and proliferation |
PBMC | Peripheral blood mononuclear cells, blood cells that have a round nucleus: lymphocytes and monocytes |
RR | Relaxation response, it refers to any practice that can elicit a physiological response that is the opposite of the stress response |
RT qPCR | Real time quantitative polymerase chain reaction is a laboratory technique that detects gene expression |
SK&P | Sudarshan Kirya and related practices include yoga poses, breathing exercises and meditation |
SNS | Sympathetic nervous system, activates fight or flight response when stress is detected |
TELiS | Transcription Element Listening System, a type of bioinformatics analysis of the genes that change expression |
TLR | Toll-like receptor, protein that plays a role in the immune system |
TM | Transcendental meditation, a form of meditation based on the repetition of a mantra |
TNF | Tumor necrosis factor, a prototypical pro-inflammatory cytokine that plays a central role in inflammation, immune system development, and apoptosis |
TOA | Transcript origin analysis, a bioinformatics analysis that determines the cellular origin of detected gene expression changes |
TSST | Trier Social Stress Test, a behavioral test of stress reactivity that consists in giving a speech and doing arithmetic operations in front of judges |