Invited ReviewEffects of obesity on depression: A role for inflammation and the gut microbiota
Introduction
The prevalence of obesity has increased worldwide in recent decades, mainly due to high-calorie diets and sedentary lifestyles (Drewnowski, 2000). The World Health Organization estimates that 39% of the human adult population is overweight and 13% is obese (WHO, 2016). Obesity is not only associated with significant diseases such as type 2 diabetes mellitus, cardiovascular disease, chronic kidney disease and cancer, but also reduces longevity and quality of life (Scully, 2014).
Global surveys indicate that ∼5% of the world population (approximately 300 million people) suffers from mood disorders (WHO, 2017). Depression is a leading cause of disability worldwide and can lead to suicide, which represents the second leading cause of death in people aged between 15 and 29 years (WHO, 2017). Epidemiological data indicate that individuals with obesity have an increased risk of developing mood disorders such as major depressive disorder (MDD), which represents the most prevalent type of depression (Mansur et al., 2015). The relationship between obesity and depression is bi-directional: individuals with depression have a 50% higher risk of developing obesity and, conversely, people with obesity have an increased risk of developing depressive symptoms and manic episodes. Despite the introduction of new antidepressant drugs, many obese patients treated for depression respond poorly to therapy, suggesting that obesity may reduce the efficacy of anti-depression treatment (Woo et al., 2016).
While depression is a multifactorial disease associated with factors such as stress, genetic predisposition and traumatic life events, recent studies indicate that chronic inflammation caused by a high-fat diet (HFD) may play a major role in inducing neuro-inflammation and depression. Notably, the gut microbiota mediates several of the effects of HFD on human physiology, and influences the mood and behavior of the host. We review here recent studies that suggest an association between obesity, the gut microbiota and depression. While the role played by neurological and hormonal systems has been described in previous reviews (Sarkar et al., 2016, Wang and Kasper, 2014), we focus here on the mechanisms underlying the effects of HFD on the immune system and brain physiology.
Section snippets
Obesity and inflammation
Obesity is associated with chronic, low-grade inflammation in peripheral tissues and blood circulation (Gregor and Hotamisligil, 2011). This association was first reported over two decades ago when the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-α) was found to be elevated in the blood and adipose tissues of obese individuals (Hotamisligil et al., 1995). Reduction of body weight in these subjects improved insulin sensitivity and reduced TNF-α expression in adipose tissues (
Inflammation and depression
Mood disorders are usually classified as depressed or elevated moods (mania), which may occur alone or together, as in bipolar disorder (Angst et al., 2015). Mood disorders such as depression and bipolar disorder are often accompanied by chronic anxiety and stress. While the cause of mood disorders is multifactorial, alterations in specific regions of the brain have been detected in some individuals, including the prefrontal cortex (PFC), amygdala (AMG), hypothalamus (HYP) and hippocampus (HPC)
HFD, brain inflammation and depression
Long-term HFD feeding is known to produce systemic, chronic inflammation in animals and humans (Buckman et al., 2014, Gregor and Hotamisligil, 2011). Rats fed a HFD for 16 weeks show an increased expression of IL-1β, IL-6 and TNF-α in the HYP compared with animals fed a normal diet (De Souza et al., 2005). Notably, HFD feeding reduces expression of tight junction proteins in the choroid plexus and BBB in rats, and may affect brain function by disrupting BBB integrity (Kanoski et al., 2010).
A role for the gut microbiota in obesity-induced depression
The human gastrointestinal tract is inhabited by trillions of microorganisms (Lin et al., 2014). More than 1500 species of bacteria have been identified so far in the human gut, with Bacteroidetes and Firmicutes representing the two predominant phylotypes (Gill et al., 2006). Different studies indicate consistently that the composition of the gut microbiota is different in lean and obese animals (Ley et al., 2005). HFD affects gut microbiota composition, increasing the Firmicutes/Bacteroidetes
Prebiotics and probiotics
Probiotics are living microorganisms that exert beneficial effects on the host (Delzenne et al., 2011). A large body of animal and clinical studies indicate that probiotics reduce body weight gain and inflammation in HFD-induced obesity (Kobyliak et al., 2016). Most of these studies were conducted using bacteria belonging to the genus Lactobacillus and Bifidobacterium.
In 2005, Logan and Katzman proposed the use of probiotics as adjunct therapy in the treatment of depression (Logan and Katzman,
Perspectives and concluding remarks
The studies presented here suggest that reducing obesity-induced neuro-inflammation may lead to beneficial effects on depression (see Fig. 1 for a summary of the pathways linking HFD, the gut microbiota, neuro-inflammation and depression). Modulation of the gut microbiota may thus represent a novel strategy for treating neuro-inflammation and depression. Probiotics, prebiotics, nutraceuticals and other plant and mushroom extracts may be used for the prevention and treatment of obesity and
Conflict of interest statement
YFK is President of Chang Gung Biotechnology Corporation. JDY is Chairman of the Board of Chang Gung Biotechnology Corporation. The authors (except for JS) have applied for patents related to the use of medicinal mushrooms and probiotics to treat human disease.
Acknowledgments
The author’s work is supported by Primordia Institute of New Sciences and Medicine, by grants MOST103-2320-B-182-027-MY3 and MOST103-2321-B-182-014-MY3 from the Ministry of Science and Technology of Taiwan, and grants CMRPD1B0053, CMRPD1C0781-3, CMRPD1E0071-3, CORPD1F0011 and QZRPD132 from Chang Gung Memorial Hospital.
References (105)
- et al.
Probiotic treatment reduces depressive-like behaviour in rats independently of diet
Psychoneuroendocrinology
(2017) The blood-brain barrier in neuroimmunology: tales of separation and assimilation
Brain Behav. Immun.
(2015)- et al.
Targeting of scavenger receptor class B type I by synthetic amphipathic alpha-helical-containing peptides blocks lipopolysaccharide (LPS) uptake and LPS-induced pro-inflammatory cytokine responses in THP-1 monocyte cells
J. Biol. Chem.
(2004) - et al.
Obese-type gut microbiota induce neurobehavioral changes in the absence of obesity
Biol. Psychiatry
(2015) - et al.
Obesity induced by a high-fat diet is associated with increased immune cell entry into the central nervous system
Brain Behav. Immun.
(2014) - et al.
Interferon-alpha-induced modulation of glucocorticoid and serotonin receptors as a mechanism of depression
J Hepatol
(2005) - et al.
Microbiota-generated metabolites promote metabolic benefits via gut-brain neural circuits
Cell
(2014) - et al.
Psychobiotics: a novel class of psychotropic
Biol. Psychiatry
(2013) Nutrition transition and global dietary trends
Nutrition
(2000)- et al.
A high-fat meal induces low-grade endotoxemia: evidence of a novel mechanism of postprandial inflammation
Am. J. Clin. Nutr.
(2007)
Examining the role of neuroinflammation in major depression
Psychiatry Res.
Chylomicrons promote intestinal absorption of lipopolysaccharides
J. Lipid Res.
Campylobacter jejuni infection increases anxiety-like behavior in the holeboard: possible anatomical substrates for viscerosensory modulation of exploratory behavior
Brain Behav. Immun.
Pathophysiology of irritable bowel syndrome
Lancet Gastroenterol. Hepatol.
Altered fecal microbiota composition in patients with major depressive disorder
Brain Behav. Immun.
Major depressive disorder: probiotics may be an adjuvant therapy
Med. Hypotheses
Increased IgA and IgM responses against gut commensals in chronic depression: further evidence for increased bacterial translocation or leaky gut
J. Affect Disord.
Is there a “metabolic-mood syndrome”? A review of the relationship between obesity and mood disorders
Neurosci. Biobehav. Rev.
Exercise reverses the harmful effects of consumption of a high-fat diet on synaptic and behavioral plasticity associated to the action of brain-derived neurotrophic factor
Neuroscience
Role of anti-inflammatory adipokines in obesity-related diseases
Trends Endocrinol. Metab.
Effects of Lactobacillus helveticus on murine behavior are dependent on diet and genotype and correlate with alterations in the gut microbiome
Psychoneuroendocrinology
Cognitive impairment following high fat diet consumption is associated with brain inflammation
J. Neuroimmunol.
Inflamed moods: a review of the interactions between inflammation and mood disorders
Prog. Neuropsychopharmacol. Biol. Psychiatry
Psychobiotics and the manipulation of bacteria-gut-brain signals
Trends Neurosci.
Scavenger receptor class B, type I-mediated uptake of various lipids into cells. Influence of the nature of the donor particle interaction with the receptor
J. Biol. Chem.
Neuromodulatory properties of inflammatory cytokines and their impact on neuronal excitability
Neuropharmacology
The role of microbiome in central nervous system disorders
Brain Behav. Immun.
Re-establishment of anxiety in stress-sensitized mice is caused by monocyte trafficking from the spleen to the brain
Biol. Psychiatry
Probiotic treatment protects against the pro-depressant-like effect of high-fat diet in Flinders Sensitive Line rats
Brain Behav. Immun.
Neuropsychiatric manifestations of human leukocyte interferon therapy in patients with cancer
JAMA
Factors controlling permeability of the blood-brain barrier
Cell. Mol. Life Sci.
Classification of mood disorders
Psychiatr. Pol.
Critical role of gut microbiota in the production of biologically active, free catecholamines in the gut lumen of mice
Am. J. Physiol. Gastrointest. Liver Physiol.
The effect of high-fat diet on rat's mood, feeding behavior and response to stress
Transl. Psychiatry
Bone marrow-derived microglia infiltrate into the paraventricular nucleus of chronic psychological stress-loaded mice
PLoS One
Pharmacotherapy of depression: a historical analysis
J. Neural Transm. (Vienna)
Trafficking of Shigella lipopolysaccharide in polarized intestinal epithelial cells
J. Cell Biol.
Serum and plasma BDNF levels in major depression: a replication study and meta-analyses
World J. Biol. Psychiatry
Purinergic signalling and immune cells
Purinergic Signal
Targeting the microbiota-gut-brain axis: prebiotics have anxiolytic and antidepressant-like effects and reverse the impact of chronic stress in mice.
Biol. Psychiatry
Hypothalamic inflammation: a double-edged sword to nutritional diseases
Ann. NY Acad. Sci.
Metabolic endotoxemia initiates obesity and insulin resistance
Diabetes
Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice
Diabetes
Association between decreased serum tryptophan concentrations and depressive symptoms in cancer patients undergoing cytokine therapy
Mol. Psychiatry
Ganoderma lucidum reduces obesity in mice by modulating the composition of the gut microbiota
Nat. Commun.
Antrodia cinnamomea reduces obesity and modulates the gut microbiota in high-fat diet-fed mice
Int. J. Obes.
The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner
Mol. Psychiatry
From inflammation to sickness and depression: when the immune system subjugates the brain
Nat. Rev. Neurosci.
Transplantation of fecal microbiota from patients with irritable bowel syndrome alters gut function and behavior in recipient mice
Sci. Transl. Med.
Consumption of a fat-rich diet activates a proinflammatory response and induces insulin resistance in the hypothalamus
Endocrinology
Cited by (149)
Association of macronutrient consumption quality, food source and timing with depression among US adults: A cross-sectional study
2024, Journal of Affective DisordersUnlocking the power of Lactoferrin: Exploring its role in early life and its preventive potential for adult chronic diseases
2024, Food Research InternationalLifestyle interventions to delay senescence
2024, Biomedical JournalFatty acid intake and prevalence of depression among Brazilian graduates and postgraduates (CUME Study)
2024, Journal of Affective DisordersClinical value and mechanistic analysis of HIIT on modulating risk and symptoms of depression: A systematic review
2024, International Journal of Clinical and Health PsychologyPriming of microglia with dysfunctional gut microbiota impairs hippocampal neurogenesis and fosters stress vulnerability of mice
2024, Brain, Behavior, and Immunity
- 1
These authors contributed equally.