A new study published in JAMA Psychiatry sheds light on the interplay between the gut microbiome and metabolic processes in individuals with depression. The research reveals associations between alterations 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 impairments, motor function problems, inflammation, disturbances in the immune system, and increased risk of cardiometabolic disorders and mortality.
Most antidepressant medications 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 utilize 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 alterations related to energy and lipid metabolism. In this study, the researchers focused on variations in lipids and metabolites associated with major depressive disorder (MDD).
“I am a molecular epidemiologist focusing on unravelling the molecular underpinnings of neuro-psychiatric disorders,” said lead author Najaf Amin, a senior research associate at Oxford Population Health at the University of Oxford.
“Given that major depression and anxiety show a very modest genetic background, I am more interested in molecular layers that are influenced by environmental/lifestyle exposures. Recently, I published the largest gut microbiome wide study of depression in Nature Communications, wherein we identified and replicated the association of 13 microbial taxa associated with depressive symptoms. Most of these were involved in the metabolism of short chain fatty acids and other neurotransmitters relevant for depression.”
“Further our analysis showed that there may be causal association with one of the taxa. We are now interested in identifying the mechanisms through which the gut microbiome may influence depression. We and others have shown that gut microbiome strongly influence the levels of circulating metabolites.”
“We are therefore interested in identifying the connection between gut microbiome and metabolome that influences the risk of depression,” Amin told PsyPost. “And since the gut microbiome is mainly determined by lifestyle factors, e.g., diet, we are also interested in identifying the dietary 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.
The 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.
The researchers conducted a large-scale study using data from the UK Biobank, which includes over more than 500,000 individuals, including those with lifetime and recurrent MDD. The participants were between the ages of 37 and 73 when they were recruited from 2006 to 2010, and blood samples were collected from them.
The study focused on two types of MDD phenotypes: lifetime MDD and recurrent MDD. These phenotypes were identified using specific diagnostic codes and information on antidepressant therapy. 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 beginning of the study.
The final sample included 58,257 individuals, including 6,811 individuals with lifetime MD Dand 4,370 with recurrent MDD.
The researchers found that individuals with MDD showed alterations in the levels of various substances involved in lipid and energy metabolism. They identified 124 different metabolites, including some that were previously unknown, that were associated with MDD.
The study revealed that the metabolic shifts observed in depression were connected to specific types of gut bacteria. The presence of certain bacterial groups, such as those belonging to the order Clostridiales and the phyla Proteobacteria/Pseudomonadota and Bacteroidetes/Bacteroidota, was associated with changes in the levels of high-density lipoproteins (HDL) and very-low-density lipoproteins (VLDL) in the blood.
Moreover, the researchers observed that different bacterial families within these groups were linked to either increased or decreased levels of HDL and VLDL. This suggests that the composition of gut bacteria may influence the way our body handles lipids and energy. The findings also supported previous studies that had reported similar associations between depression and changes in lipid profiles.
“There is a very strong connection between gut microbiome composition and circulating levels of metabolites that associate with major depression,” Amin told PsyPost. “Although we cannot at this point claim causality, poorer gut health will certainly exacerbate any existing symptoms of depression, leading a person into a vicious cycle.”
“It is therefore important to maintain a good gut health, which can be achieved through eating a very balanced/healthy diet and avoiding processed foods/western diets that lead to dysbiosis.”
Additionally, the study highlighted the potential impact of the gut microbiome on mitochondrial metabolism, specifically the tricarboxylic acid (TCA) cycle. Individuals with depression exhibited 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 of some of the microbial taxa are remarkable,” Amin said. “Some of these are so highly correlated as if these were the same traits.”
To validate 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 Treatments (PREDICT). These replication studies involved participants with depression and control individuals who were characterized using a similar metabolomics platform. The sample included 5,283 individuals with depression 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 the most of the VLDLs, IDLs and fatty acids change as a result of the disease process, it was inconclusive about the metabolites in energy metabolism pathway and most of the HDLs. Secondly, all our findings point towards the role of Acetyl Coenzyme A, but we could not test this as we do not have this measured.”
The study, “Interplay of Metabolome and Gut Microbiome in Individuals With Major Depressive Disorder vs Control Individuals“, was authored by Najaf Amin, Jun Liu, Bruno Bonnechere, Siamak MahmoudianDehkordi, Matthias Arnold, Richa Batra, Yu-Jie Chiou, Marco Fernandes, M. Arfan Ikram, Robert Kraaij, Jan Krumsiek, Danielle Newby, Kwangsik Nho, Djawad Radjabzadeh, Andrew J. Saykin, Liu Shi, William Sproviero, Laura Winchester, Yang Yang, Alejo J. Nevado-Holgado, Gabi Kastenmüller, Rima Kaddurah-Daouk, Cornelia M. van Duijn.
