A Closer Look at the Importance of Gut Mechanisms in Depression

ntestinal microbiome, bacteria colonizing different parts of digestive system
Increasing evidence suggests that modulation of the gut microbiota could provide a novel intervention for depression and anxiety.

More than 1 kg of bacteria normally resides in the gut, an equivalent in weight to the whole brain, and represents more organisms than there are cells in the human body.1,2 The variety of genes in gut bacteria is greater than 100 times the quantity of the human genome.1,2 Thus, it is not surprising that a range of physiologic conditions in the body and the brain are increasingly linked to the status of the gut microbiome.1,2

The gut-brain axis encompasses 3 main systems in the human body: the central nervous system, the enteric nervous system, and the digestive system. It is involved in gut motility, secretion of hormones, and production of acid, bicarbonates, and mucus.3 The gut-brain-microbiota axis is a bidirectional communication system allowing gut microbes to communicate with the brain and for the brain to then send signals to the gut.1

Recent studies have pointed to the specific pathway via the vagus nerve and mechanisms of communication between the gut and brain that contribute to the expression of depression.1 In a 2018 review,3 Kim and Shin reported, “There is a high correlation between stress-related mental symptoms (such as anxiety) and irritable bowel syndrome (IBS). This correlation has provided a stimulus to study the importance of the gut-brain axis. More than 50% of IBS patients have comorbid depression or anxiety.” These findings suggest that the gut-brain axis might provide essential new targets for the prevention and treatment of depression and other neuropsychiatric disorders.1-3

Evolution of the Gut Microbiome

The gut is sterile prior to birth; its first encounter with bacteria is when the newborn passes through the birth canal where it is colonized via the mouth, skin, conjunctiva, and gastrointestinal tract. Various microbiotic bacteria are acquired through transmission from the mother, including primarily Bifidobacterium, Lactobacillus, and Prevotella through vaginal delivery, and Staphylococcus and Corynebacterium from cesarean section.3

The microbiome of each individual is unique. In a 2020 commentary published in the Canadian Journal of Psychiatry,4 Jane Foster, PhD, wrote, “An individual’s microbiome is their own, and the colonization of all surfaces of our body that begins at birth continues through early life. The diversity, composition, and function of an individual’s microbiome are influenced early in life by mode of delivery, breast milk versus formula, exposure to antibiotics and nonantibiotic drugs, sex, diet, stress, housing conditions, and geography. Our own genetics influence our microbiome, and gene–environment interactions over life influence the microbe–host interactions that impact host physiological processes.”

Role of Gut Microbiome in Depression

Depression is associated with an imbalance of the hypothalamic–pituitary–adrenal (HPA) axis whereby activation by cytokines (interleukins 1 and 6) trigger the release of cortisol, a potent stress hormone. Several observational studies show a bidirectional link between depression and the gut microbiome, which has been linked to dysregulation of the HPA axis.2,3,5 Conversely, improvements in symptoms of depression have correlated with restored stability to HPA activity.2

Homeostasis of the gut, determined by its unique bacterial community, may therefore be central to maintaining mood stability, according to a 2017 review of the impact of feeding systems on psychiatric conditions by Brittany L. Mason, PhD.5 “Shifts in the populations of bacteria that move the community away from its homeostasis result in dysbiosis and may cause [gastrointestinal] (GI) distress; however, more subtle shifts in bacterial populations will likely affect the system without causing major symptoms of GI dysfunction,” she wrote. Dr Mason pointed to increased immunoglobulin (Ig)A- and IgM-mediated immune responses to specific bacterial lipopolysaccharides in the blood of depressed patients as “supporting the hypothesis that increased intestinal permeability is a factor in depressive illness.”

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Improving Diet to Target Depression

“Unfortunately, we do not know conclusively what the structure of a normal microbiota is,” Ted Dinan, MD, PhD, Professor of Psychiatry at University College Cork, Ireland and former Chair of Clinical Neurosciences and Professor of Psychological Medicine at St. Bartholomew’s Hospital, London, United Kingdom told Psychiatry Advisor. “The consensus is that the greater the diversity the better.”

However, achieving the proper diversity of microbiota is still something of a mystery. Breastfed infants have a lower diversity but more stable composition of gut microflora than formula-fed babies. Over time, with the introduction of solid foods, the diversity of the gut microbiota increases, and throughout life, long-term dietary habits strongly influence gut microbiome compositions, as well as physical, psychological, and environmental stressors.

Increasing evidence suggests that modulation of the gut microbiota could provide novel interventions for depression and anxiety. Probiotics containing Bifidobacteria species have been shown to reduce cortisol responses involved in anxiety and it is believed they can also reduce symptoms of depression.5

Dr Dinan pointed to the Mediterranean diet as having benefits for mood disorders. “There is no doubt that a Mediterranean diet including fermented foods positively impacts mental health in those who suffer from depression,” he said, adding that “Exercise also has potent antidepressant activity and promotes greater diversity in the microbiota. It should be encouraged in all patients with depression.”


1. Dinan TG, Cryan JF. The microbiome-gut-brain axis in health and disease. Gastroenterol Clin North Am. 2017;46(1):77-89.

2. Bastiaanssen TFS, Cussotto S, Claesson MJ, Clarke G, Dinan TG, Cryan JF. Gutted! Unraveling the role of the microbiome in major depressive disorder. Harv Rev Psychiatry. 2020;28(1):26-39.

3. Kim YK, Shin C. The microbiota-gut-brain axis in neuropsychiatric disorders: pathophysiological mechanisms and novel treatments. Curr Neuropharmacol. 2018;16(5):559-573.

4. Foster JA. Decoding microbiome research for clinical psychiatry. Can J Psychiatry. 2020;65(1):19-20.

5. Mason BL. Feeding systems and the gut microbiome: gut-brain interactions with relevance to psychiatric conditions. Psychosomatics. 2017;58(6):574-580.