A new study published in JAMA Psychiatry sheds light on the interaction between the gut microbiome and metabolic processes in depressed individuals. The study revealed links between changes in lipid and energy metabolism, specific types of gut bacteria and the presence of depressive symptoms, shedding light on the potential role of the gut-brain axis in depression.
Depression is a widespread mental health condition that significantly affects population health. Major depression is known to cause a range of debilitating symptoms beyond emotional distress, including cognitive impairment, motor function problems, inflammation, immune system disturbances, and increased risk of cardiometabolic disorders and mortality.
Most antidepressants work by modulating the levels of certain neurotransmitters in the brain that are part of the monoamine system. The monoamine pathway refers to a network of neurons in the brain that use neurotransmitters such as serotonin, norepinephrine, and dopamine. These neurotransmitters are involved in regulating mood, emotions and other cognitive functions.
But evidence suggests that there is a more complex interplay of multiple pathways involved in depression, including metabolic changes related to energy and lipid metabolism. In this study, researchers focused on variations in lipids and metabolites associated with major depressive disorder (MDD).
“I am a molecular epidemiologist who focuses on uncovering the molecular basis of neuropsychiatric disorders,” said the lead author Najaf AminSenior Research Fellow in Oxford Population Health at the University of Oxford.
“Given that major depression and anxiety show a very modest genetic basis, I’m more interested in the molecular layers that are influenced by environmental/lifestyle exposures. I recently published the largest gut microbiome study of depression in Nature Communications, where we identified and replicated the association of 13 microbial taxa associated with depressive symptoms. Most of them are involved in the metabolism of short-chain fatty acids and other neurotransmitters associated with depression.
“Our further analysis showed that there may be a causal relationship with one of the taxa. We are now interested in identifying the mechanisms by which the gut microbiome may influence depression. We and others have shown that the gut microbiome strongly influences circulating metabolite levels.
“Therefore, we are interested in identifying the relationship between the gut microbiome and the metabolome that influences depression risk,” Amin told PsyPost. “And since the gut microbiome is mainly determined by lifestyle factors, such as diet, we are also interested in identifying the nutritional factors that modulate these gut microbial taxa.”
The gut microbiome refers to the collection of microorganisms, including bacteria, fungi, viruses, and other microbes that inhabit the gastrointestinal tract. These microbes play a crucial role in maintaining various aspects of human health.
Metabolome, on the other hand, refers to the complete set of small molecules or metabolites present in a biological sample. These metabolites are the end products of various metabolic processes occurring in the body.
Researchers conducted a large-scale study using data from UK Biobank, which included more than 500,000 individuals, including those with lifelong and recurrent MDD. Participants were between the ages of 37 and 73 when they were recruited from 2006 to 2010, and blood samples were taken.
The study focused on two types of MDD phenotypes: lifetime MDD and recurrent MDD. These phenotypes were identified using specific diagnosis codes and antidepressant therapy information. Individuals with other mental illnesses such as bipolar disorder, schizophrenia, and psychosis were excluded from the study. The control group included individuals who did not report depression at the start of the study.
The final sample included 58,257 individuals, including 6,811 individuals with lifetime MD and 4,370 with relapsing MDD.
The researchers found that individuals with MDD showed changes in the levels of various substances involved in lipid and energy metabolism. They identified 124 different metabolites, including some that were previously unknown to be associated with MDD.
The study revealed that the metabolic changes seen in depression are associated with specific types of gut bacteria. The presence of certain bacterial groups, such as those belonging to the order Clostridiales and the type Proteobacteria/Pseudomonadota and Bacteroidetes/Bacteroidetais associated with changes in high-density lipoprotein (HDL) and very-low-density lipoprotein (VLDL) levels in the blood.
The researchers also noted that different bacterial families within these groups were associated with either increased or decreased levels of HDL and VLDL. This suggests that the composition of gut bacteria may affect the way our body deals with lipids and energy. The findings also support previous studies that have reported similar associations between depression and lipid profile changes.
“There is a very strong relationship between the composition of the gut microbiome and circulating levels of metabolites that are associated with major depression,” Amin told PsyPost. “While we can’t claim cause and effect at this stage, poorer gut health will certainly exacerbate any existing symptoms of depression, leading a person into a vicious cycle.”
“It is therefore important to maintain good gut health, which can be achieved by eating a very balanced/healthy diet and avoiding processed foods/Western diets that lead to dysbiosis.”
Additionally, the study highlights the potential impact of the gut microbiome on mitochondrial metabolism, specifically the tricarboxylic acid (TCA) cycle. Depressed individuals show increased levels of pyruvate and decreased levels of citrate, which are metabolites involved in the TCA cycle.
“The correlation patterns of the metabolic signatures of major depression and some of the microbial taxa are remarkable,” Amin said. “Some of them are so strongly related that they are the same traits.”
To confirm the findings, the results were compared with a previous study conducted in Dutch cohorts and another study called Predictors of Remission in Depression to Individual and Combined Treatment (PREDICT). These replication studies included depressed participants and control subjects who were characterized using a similar metabolomic platform. The sample included 5,283 depressed individuals and 10,145 control individuals
“The big question, of course, is ‘are these relationships causal?'” Amin noted. “We used Mendelian randomization to test this, and although it showed that most VLDL, IDL and fatty acids changed as a result of the disease process, it was inconclusive for metabolites in the energy metabolism pathway and most HDL.” Second, all of our findings point to a role for acetyl coenzyme A, but we couldn’t test that because we didn’t have that measured.
Learning, “Metabolome and gut microbiome interaction in individuals with major depressive disorder versus control individuals“, is by Najaf Amin, Jun Liu, Bruno Bonnechere, Siamak Mahmoudian Dehkordi, Matthias Arnold, Richa Batra, Yu-Jie Chiou, Marco Fernandes, M. Arfan Ikram, Robert Kraaij, Jan Krumsiek, Danielle Newby, Kwangsik Nho, Djawad Rajabzadeh, Andrew J. Saiqin, Liu Shi, William Sproviero, Laura Winchester, Yang Yang, Alejo J. Nevado-Holgado, Gabi Kastenmuller, Rima Cadura-Dauk, Cornelia M. van Duyn.