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The Microbiota-Inflammasome Hypothesis of Major Depression.
We propose the "microbiota-inflammasome" hypothesis of major depressive disorder (MDD, a mental illness affecting the way a person feels and thinks, characterized by long-lasting feelings of sadness). We hypothesize that pathological shifts in gut microbiota composition (dysbiosis) caused by stress and gut conditions result in the upregulation of pro-inflammatory pathways mediated by the Nod-like receptors family pyrin domain containing 3 (NLRP3) inflammasome (an intracellular platform involved in the activation of inflammatory processes). This upregulation exacerbates depressive symptomatology and further compounds gut dysbiosis. In this review we describe MDD/chronic stress-induced changes in: 1) NLRP3 inflammasome; 2) gut microbiota; and 3) metabolic pathways; and how inflammasome signaling may affect depressive-like behavior and gut microbiota composition. The implication is that novel therapeutic strategies could emerge for MDD and co-morbid conditions. A number of testable predictions surface from this microbiota-gut-inflammasome-brain hypothesis of MDD, using approaches that modulate gut microbiota composition via inflammasome modulation, fecal microbiota transplantation, psychobiotics supplementation, or dietary change.
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The gut microbiome regulates the increases in depressive-type behaviors and in inflammatory processes in the ventral hippocampus of stress vulnerable rats.
Chronic exposure to stress is associated with increased incidence of depression, generalized anxiety, and PTSD. However, stress induces vulnerability to such disorders only in a sub-population of individuals, as others remain resilient. Inflammation has emerged as a putative mechanism for promoting stress vulnerability. Using a rodent model of social defeat, we have previously shown that rats with short-defeat latencies (SL/vulnerable rats) show increased anxiety- and depression-like behaviors, and these behaviors are mediated by inflammation in the ventral hippocampus. The other half of socially defeated rats show long-latencies to defeat (LL/resilient) and are similar to controls. Because gut microbiota are important activators of inflammatory substances, we assessed the role of the gut microbiome in mediating vulnerability to repeated social defeat stress. We analyzed the fecal microbiome of control, SL/vulnerable, and LL/resilient rats using shotgun metagenome sequencing and observed increased expression of immune-modulating microbiota, such as Clostridia, in SL/vulnerable rats. We then tested the importance of gut microbiota to the SL/vulnerable phenotype. In otherwise naive rats treated with microbiota from SL/vulnerable rats, there was higher microglial density and IL-1β expression in the vHPC, and higher depression-like behaviors relative to rats that received microbiota from LL/resilient rats, non-stressed control rats, or vehicle-treated rats. However, anxiety-like behavior during social interaction was not altered by transplant of the microbiome of SL/vulnerable rats into non-stressed rats. Taken together, the results suggest the gut microbiome contributes to the depression-like behavior and inflammatory processes in the vHPC of stress vulnerable individuals.
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Nutrition-based interventions for mood disorders.
Introduction: 'Nutritional Psychiatry' is an emerging area of research that has great potential as an adjunctive tool for the prevention and treatment of diverse neuropsychiatric disorders. Several nutrition-related aspects, such as obesity, dietary patterns, gut microbiome composition and gut permeability, bioactive food compounds, and nutrients can influence pathways implicated in the pathophysiology of mood disorders.Areas covered: Here, the authors review the current evidence on nutrition-mood interaction and nutrition-based treatments for the two main mood disorders, i.e., major depressive disorder and bipolar disorder.Expert opinion: Consistent evidence from observational studies has pointed out the association between a 'healthy' diet, generally characterized by a higher intake of fruits, vegetables, legumes, nuts, whole grains, and good quality sources of protein (i.e. fish and/or seafood), and decreased risk of mood disorders and the parallel association between a 'Western' diet pattern and increased risk. However, only a few clinical trials have evaluated the effect of nutritional interventions on the treatment of these conditions. The bidirectional interaction between the brain and the gut, named 'brain-gut-microbiome axis' or 'gut-brain axis', plays a key role in the link between nutrition and mood disorders. Therefore, nutrition-based strategies for gut microbiota modulation are promising fields in mood disorders.
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Advances in Gut Microbiome and Metabolomics Research in the Comorbidity of Inflammatory Bowel Disease and Depressive Disorder.
Inflammatory bowel disease (IBD) is a chronic autoimmune disorder characterized by persistent inflammation of the gastrointestinal tract, with a substantial proportion of patients experiencing comorbid depressive disorders. This comorbidity profoundly affects patients' long-term prognosis and quality of life. Emerging evidence suggests that the interplay between IBD and depression may be mediated by disruptions in the gut microbiome and metabolome. Notably, alterations in gut microbial composition and metabolic profiles observed in both IBD and depression indicate potential shared pathophysiological mechanisms, which could inform novel therapeutic strategies. This review aims to summarize recent advances in gut microbiome and metabolomics research related to IBD comorbid with depression, highlighting their implications for disease management and treatment. First, we provide an overview of the epidemiological features of IBD comorbid with depressive disorder, as well as the underlying pathophysiological mechanisms that may contribute to their bidirectional relationship. Subsequently, we highlight key microbiome and metabolite alterations observed in comorbid patients, which may contribute to disease onset and progression. At last, we also discuss emerging microbiota- and metabolite-based therapeutic approaches that hold promise for improving both gastrointestinal and psychological outcomes. In conclusion, integrating microbiome and metabolomics perspectives provides novel insights into the shared pathophysiology of IBD and depressive disorders and may inform the development of more effective and personalized interventions.
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Obesity and Depression: Common Link and Possible Targets.
Depression is among the main causes of disability, and its protracted manifestations could make it even harder to treat metabolic diseases. Obesity is linked to episodes of depression, which is closely correlated to abdominal adiposity and impaired food quality. The present review is aimed at studying possible links between obesity and depression along with targets to disrupt it. Research output in Pubmed and Scopus were referred for writing this manuscript. Obesity and depression are related, with the greater propensity of depressed people to gain weight, resulting in poor dietary decisions and a sedentary lifestyle. Adipokines, which include adiponectin, resistin, and leptin are secretory products of the adipose tissue. These adipokines are now being studied to learn more about the connection underlying obesity and depression. Ghrelin, a gut hormone, controls both obesity and depression. Additionally, elevated ghrelin levels result in anxiolytic and antidepressant-like effects. The gut microbiota influences the metabolic functionalities of a person, like caloric processing from indigestible nutritional compounds and storage in fatty tissue, that exposes an individual to obesity, and gut microorganisms might connect to the CNS through interconnecting pathways, including neurological, endocrine, and immunological signalling systems. The alteration of brain activity caused by gut bacteria has been related to depressive episodes. Monoamines, including dopamine, serotonin, and norepinephrine, have been widely believed to have a function in emotions and appetite control. Emotional signals stimulate arcuate neurons in the hypothalamus that are directly implicated in mood regulation and eating. The peptide hormone GLP-1(glucagon-like peptide- 1) seems to have a beneficial role as a medical regulator of defective neuroinflammation, neurogenesis, synaptic dysfunction, and neurotransmitter secretion discrepancy in the depressive brain. The gut microbiota might have its action in mood and cognition regulation, in addition to its traditional involvement in GI function regulation. This review addressed the concept that obesity-related low-grade mild inflammation in the brain contributes to chronic depression and cognitive impairments.
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Depressive hypertension: A proposed human endotype of brain/gut microbiome dysbiosis.
BACKGROUND: Hypertension (HTN) is frequently linked with depression (DEP) in adults with cardiovascular disease (CVD), yet the underlying mechanism and successful management remain elusive. We approached this knowledge gap through the lens that humans are eukaryote-prokaryote "meta-organisms," such that cardiovascular disease dysregulation is a mosaic disorder involving dysbiosis of the gut. We hypothesized that patients diagnosed with hypertension plus depression harbor a unique gut microbial ecology with attending functional genomics engaged with their hosts' gut/brain axis physiology. METHODS: Stool microbiome DNA was analyzed by whole metagenome shotgun sequencing in 54 subjects parsed into cohorts diagnosed with HTN only (N = 18), DEP only (N = 7), DEP plus HTN (DEP-HTN) (N = 8), or reference subjects with neither HTN nor DEP (N = 21). A novel battery of machine-learning multivariate analyses of de-noised data yielded effect sizes and permutational covariance-based dissimilarities that significantly differentiated the cohorts (false discovery rate (FDR)-adjusted P ≤ .05); data clustering within 95% confidence interval). RESULTS: Metagenomic significant differences extricated the four cohorts. Data of the cohort exhibiting DEP-HTN were germane to the interplay of central control of blood pressure concomitant with the neuropathology of depressive disorders. DEP-HTN gut bacterial community ecology was defined by co-occurrence of Eubacterium siraeum, Alistipes obesi, Holdemania filiformis, and Lachnospiraceae bacterium 1.1.57FAA with Streptococcus salivariu. The corresponding microbial functional genomics of DEP-HTN engaged pathways degrading GABA and beneficial short chain fatty acids (SCFA), and are associated with enhanced sodium absorption and inflammasome induction. CONCLUSIONS: These data suggest a new putative endotype of hypertension, which we denote "depressive-hypertension" (DEP-HTN), for which we posit a model that is distinctive from either HTN alone or DEP alone. An "endotype" is a subtype of a heterogeneous pathophysiological mechanism. The DEP-HTN model incorporates a unique signature of microbial taxa and functional genomics with crosstalk that putatively intertwines host pathophysiology involving the gastrointestinal tract with disruptions in central control of blood pressure and mood. The DEP-HTN endotype model engages cardiology with gastroenterology and psychiatry, providing a proof-of-concept foundation to explore future treatments, diagnosis, and prevention of HTN-coupled mood disorders.
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Alterations in short-chain fatty acid-associated gut microbiota and tight junction integrity in adolescent major depressive disorder.
Major depressive disorder (MDD) often begins during adolescence, a critical developmental period during which nearly 50% of lifetime cases emerge. Despite its high prevalence and impact, objective diagnostic biomarkers for adolescent MDD remain limited, particularly those related to gut microbiota. Our study examined potential co-diagnostic biomarkers from peripheral blood and fecal samples in adolescents with MDD. We enrolled drug-naïve adolescents with first-episode MDD (n = 46, aged ≤18 years, 71.74% female) and age-/sex-matched healthy controls (HCs, n = 44). The levels of tight junction proteins (Claudin-5, Zonulin, FABP) and inflammatory biomarkers (IL-6, IL-8, TNF-α, and CRP) were markedly elevated in the plasma of adolescents with MDD, indicating gut barrier dysfunction and systemic inflammation. The microbiome in MDD patients exhibited a lower Firmicutes-to-Bacteroidetes ratio. At the genus level, Intestinimonas and Barnesiella were significantly enriched, while Dialister and Collinsella were considerably reduced. Integrating Collinsella abundance with tight junction proteins and inflammatory markers significantly improved diagnostic performance, achieving an area under the curve (AUC) of 0.964. Moreover, Collinsella negatively correlated with sex, Claudin-5, and TNF-α. Claudin-5 was strongly associated with short-chain fatty acids (SCFAs)-related pathways, including alanine, aspartate, glutamate metabolism, D-glutamine and D-glutamate metabolism, and autophagy regulation. Treatment of Caco-2 cells with propionate and butyrate confirmed the regulatory effects of SCFAs on tight junction biomarkers. These findings suggest the interplay between gut dysbiosis, barrier dysfunction, and inflammation in adolescent MDD and support microbiota-host biomarkers as a promising strategy for improving MDD diagnostic precision.
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Recognizing depression as an inflammatory disease: the search for endotypes.
Major depressive disorder (MDD) affects millions of individuals worldwide, leading to considerable social and economic costs. Despite advancements in pharmacological treatments, achieving remission remains a key challenge, with a substantial number of patients showing resistance to existing therapies. This resistance is often associated with elevated levels of proinflammatory cytokines, suggesting a connection between inflammation, MDD pathophysiology, and treatment efficacy. The observation of increased immune activation in about a quarter of patients with MDD resulted in the distinction between inflammatory and noninflammatory endotypes. Although anti-inflammatory treatments show promise in alleviating depression-like symptoms, responses are heterogeneous, thus highlighting the importance of identifying distinct inflammatory endotypes to tailor effective therapeutic strategies. The intestinal microbiome emerges as a crucial modulator of mental health, mediating its effects partially through different immune pathways. Microbiota-derived short-chain fatty acids (SCFAs) significantly impact innate and adaptive immune cells, regulating their differentiation, function, and cellular response. Furthermore, gut-educated immune cells reach the border regions of the central nervous system (CNS), regulating glial cell functions. Although the CNS modulates immune responses via efferent parts of the vagus nerve, afferent tracts concurrently transport information on peripheral inflammation back to the brain. This bidirectional communication is particularly relevant in depression, allowing for therapeutic stimulation of the vagus nerve in the context of inflammatory depression endotypes. In this review, we explore the intricate relationship between inflammation and depression, discuss how inflammatory signals are translated into depressive-like symptoms, and highlight immune-modulating therapeutic avenues.
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Exploring the Correlation between Changes in Gut Microbial Community Diversity and Depression in Human Populations.
Depression, also known as depressive disorder, is a group of psychosomatic affective disorders characterized by persistent and significantly depressed mood, delayed thinking, and cognitive impairment. The aim of this study was to explore the correlation between changes in gut microbial community diversity and depression to provide data on new strategies for the prevention and treatment of depression. In this study, we separated participants into a group of depressed patients and a healthy comparison group. We analyzed the gut microbial community structure of depressed patients and healthy comparisons using second-generation sequencing of the bacterial 16S RNA gene. There were significant differences in the gut microflora structure between patients with depression and healthy individuals. The gut flora alpha diversity index was significantly reduced in patients with depression compared to that in the healthy population. At the species level, the relative abundance of Coprococcus catus and Bacteroides barnesiae was significantly lower in the depressed group than that in the control group. The development of depression may be associated with a decrease in beneficial gut bacteria.
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Association Between Gut Microbiome and Frailty in the Older Adult Population in Korea.
Frailty is a common geriatric syndrome associated with the risk of adverse health outcomes. Recently, 2 key pathophysiological characteristics of frailty, altered energy metabolism and dysregulated immunity, have been reported to be associated with gut microbiome dysbiosis, indicating that the gut microbiome plays a role in frailty. However, few studies have directly examined the relationship between the gut microbiome and frailty. Here, we investigated the association of frailty measures with the gut microbiome using 16S rRNA gene sequencing data obtained from the fecal samples of 176 Korean older adults. Overall frailty was scored using the Korean Frailty Index (FI). Grip strength and Geriatric Depression Scale (GDS) scores were used as physical and mental frailty measures, respectively. In contrast to age, metabolic, and inflammatory biomarkers, the frailty measures were associated with interindividual variations in microbial composition (false discovery rate [FDR] < 0.2). Both FI and GDS scores were negatively associated with microbial diversity (FDR < 0.2). Frailty measures showed distinct associations with specific microbial taxa and metabolic functions. Particularly, the Bacteroides enterotype was found only in subjects categorized in the frail group. Moreover, we observed that the abundance of beneficial taxa, such as Prevotella copri and Coprococcus eutactus, was reduced in frailer individuals, whereas that of detrimental taxa, such as Bacteroides fragilis and Clostridium hathewayi, was increased (FDR < 0.2). Our findings suggest that the gut microbiome can be used an indicator of an increased risk of frailty or a target for improving health in frail older adults.