Tag: gut microbiota

How Your Gut Microbiota is Linked to Both Positive and Negative Aspects of Mental Health

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Microbiota composition is linked to both positive and negative aspects of mental health

 

A large-scale study in Belgium and the Netherlands found links between the abundance of certain groups of gut bacteria species and mental health outcomes. Faecalibacterium and Coprococcus bacteria that produce a short-chain fatty acid called butyrate were consistently more abundant in individuals with higher quality of life. In contrast, Dialister, Coprococcus spp, tended to be depleted in individuals with depression. Social functioning tended to be better in individuals with many bacteria capable of producing 3,4-dihydroxyphenylacetic acid in their gut. 3,4-dihydroxyphenylacetic acid is a substance our body produces when processing dopamine, a neurotransmitter associated with experiencing good feelings (Valles-Colomer et al., 2019). The study was published in Nature Microbiology.

 

Social functioning was better in those with bacteria capable of producing a substance our body produces (3,4-dihydroxyphenylacetic acid) when processing dopamine 

 

Humans have known for centuries that there is a link between how our digestive system works and how we feel. Everyone senses from experience that our mental state also deteriorates when our digestive system doesn’t work well. However, in the past century, medical and biological science has advanced enough to allow scientists to examine the gut microbiota in our digestive system and study the interaction between them and the human body in detail.

 

A large-scale study found links between the abundance of certain gut bacteria species and mental health outcomes

 

What is gut microbiota?

The human gut microbiome, often called gut microbiota or gut flora, is a complex community of trillions of microorganisms that reside in the digestive tract, primarily in the colon. These microorganisms include bacteria, viruses, fungi, and other microbes. Gur microbiota is critical in digesting food, absorbing nutrients, and aiding our metabolic activity.

 

Humans have known for centuries there is a link between our digestive system and how we feel

 

Gut microbiota helps maintain a balanced and healthy immune system. The composition and diversity of gut microbiota can vary significantly among individuals and can be influenced by factors such as diet, genetics, and lifestyle. It is increasingly recognized as a crucial factor in overall health and well-being (Heiss et al., 2021; Zhu et al., 2023).

 

Microbiota-gut-brain-axis

A key pathway through which the link between gut microbiota and well-being is achieved is the microbiota-gut-brain axis (MGBA). The microbiota-gut-brain axis is a bidirectional communication system connecting the gut, microbiota, and brain. This axis regulates physiological and psychological processes (Carbia et al., 2023; Zhu et al., 2023).

 

Gut microbiota can vary among individuals and is recognized as a crucial factor in overall health and well-being (Heiss et al., 2021; Zhu et al., 2023)

 

The microbiota-gut-brain axis (MGBA) is based on small proteins called cytokines and several other biomolecules, including the hormone cortisol, short-chain fatty acids (SCFAs), tryptophan, neurotransmitters, and others (see Figure 1). 

 

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Figure 1. Some of the Biomolecules involved in MGBA

 

Emerging studies reveal that the gut microbiota produces substances that can influence the brain’s activity and its responses to stress and emotions. Additionally, the microbiota-gut-brain axis is closely tied to the immune system, influencing the body’s inflammatory responses and potentially contributing to neuroinflammation (Zhu et al., 2023).

 

Gut microbiota produces substances that influence the brain’s activity and its responses to stress and emotions

 

These scientific findings suggest that interventions targeting the gut microbiota, such as probiotics and dietary changes, may positively impact mental health and neurological disorders. This can open a new avenue of treatment for mental health issues and possibly other disorders.

 

The current study

Study author Mireia Valles-Colomer and her colleagues wanted to examine the association between gut microbiota composition and quality of life indicators in the general population. They also wanted to examine links between gut microbiota composition and depression (Valles-Colomer et al., 2019).

They note that recent advances in genetic sequencing technology allowed researchers to start studying the role of the gut microbiota in a broad range of neurological and psychiatric disorders and diseases. Advancements in the field of metagenomics are a particularly important part of this as it allows relatively easy and noninvasive exploration of human gut microbiota composition.

 

Recent advances in genetic sequencing technology allows researchers to study the role of microbiota in neurological and psychiatric disorders 

 

Metagenomics

Metagenomics is a field of genetics and microbiology that involves the study of genetic material collected directly from environmental samples, like soil, water, or the human gut, without the need for isolating and cultivating individual organisms. It employs advanced DNA sequencing techniques to analyze and characterize collective genomes of microorganisms in studied samples and their genetic diversity.

In the case of human gut microbiota studies, researchers typically collect stool samples for this purpose. They then use metagenomics techniques to determine the presence, absence, and abundance of different species of microorganisms in the gut microbiota (see Figure 2).

 

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Figure 2. Metagenomics

 

The procedure – the Belgian Flemish Gut Flora project data

The authors of this study analyzed data from two large-group longitudinal studies in Europe. The first set came from the Belgian Flemish Gut Flora Project (FGFP). It contained data from 1054 individuals on gut microbiota and depression as reported by general medical practitioners. The quality of life of these study participants was assessed using the RAND 36-Item Health Survey 1.0. This assessment covers eight health concepts – role limitations caused by emotional health problems, social functioning, emotional well-being, vitality, physical functioning, role limitations caused by physical health, body pain, and general health perception.  Participants who were using antidepressants but were not diagnosed with depression were excluded from the analysis.

From this group, study authors selected 80 participants with clinically diagnosed depression (40 were using antidepressants) and 70 healthy participants as controls, matched with them on age, sex, body mass index, and stool consistency for in-depth analysis using shotgun metagenomic sequencing. Shotgun metagenomic sequencing is a method that involves sequencing all the genetic material present in a microbial community sample, providing a comprehensive view of the genes and organisms within that community.

 

The Lifelines Cohort data and controls

Researchers used another sample to verify their findings – the Lifelines Cohort. The Lifelines Cohort is a large-scale, three-generation longitudinal study in the Netherlands. It contains a large amount of medical and psychological data from over 167,000 participants so far. The Lifelines cohort study was started in 2006 and aimed to include 10% of the northern population of the Netherlands of all ages. The authors of the Lifelines Cohort study hope to be able to follow these individuals for 30 years and collect follow-up data during this time.

In this study, the authors used data from 1063 individuals from the Lifeline Cohort. The quality of life of this group was assessed in the same way as in the Belgian sample. Participants self-reported depression. Researchers asked participants to indicate the disorders they have or have had, and depression was on the list. Participants also reported on their use of antidepressants in the last three months.

The study authors used gas chromatography-mass spectrometry (GC-MS) to determine butyrate levels in stool samples from this dataset. Butyrate is a short-chain fatty acid produced by certain species of bacteria in the gut during the fermentation of dietary fiber (see Figure 3). It is an important energy source for the cells lining the colon and helps maintain their integrity and function. Additionally, it has anti-inflammatory properties and has been associated with various health benefits. Butyrate potentially reduces the risk of inflammatory bowel diseases and promotes overall gut health.

 

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Figure 3. The Short-Chain Fatty Acid Butyrate

 

Additionally, study authors collected and sequenced seven stool samples from patients suffering from major depressive disorder resistant to treatment. Participants in this sample were diagnosed with moderate-to-severe depression and inadequate response to at least two therapies with antidepressants. Inadequate response means that symptoms of depression persist after treatment.

 

Gut microbiota composition was related to quality of life

Results revealed multiple associations between microbiome characteristics and all aspects of quality of life (see Figure 4). Study participants with better quality of life indicators tended to have more Faecalibacterium and Coprococcus bacteria in their guts. Those with better physical functioning tended to have fewer bacteria from the Flavonifractor group of species (genus). This group of bacterial species was also increased in individuals suffering from major depressive disorder (MDD).

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Figure 4. Associations between microbiome characteristics and all aspects of quality of life (as outlined earlier)

 

Study authors note that Faecalibacterium and Coprococcus bacteria produce the short-chain fatty acid butyrate. Butyrate levels in the gut are generally reduced in individuals with inflammatory bowel disease and those with depression. They examined the Lifelines cohort data to verify this finding, and the results showed that the abundance of these bacteria is indeed associated with butyrate concentrations in the stool.

 

Butyrate levels in the gut are reduced in those with inflammatory bowel disease and depression

 

Coprococcus and Dialister bacteria are depleted in the guts of individuals suffering from depression

Study authors identified 4 groups of bacterial species that were consistently depleted in individuals suffering from depression (depleted in this case, means that they are present in numbers significantly lower than those found in typical healthy individuals).

However, further analyses revealed that antidepressants can substantially affect the composition of gut bacteria. When study authors controlled for the use of antidepressants, only Coprococcus and Dialister groups of species remained associated with depression. There were significantly fewer bacteria from these groups in the guts of individuals suffering from depression than healthy individuals (see Figure 5). This finding was held in the Flemish Gut Flora and the Lifeline Cohort data.

 

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Figure 5. Microorganism abundances linked to Quality of Life and Depression

 

Bacteria producing 3,4-dihydroxyphenylacetic acid are more abundant in individuals with better social functioning

Next, the study authors examined the gut-brain modules, i.e., they looked for groups of bacteria that produce substances that could affect mental states and their links to quality-of-life indicators. These analyses showed that bacteria producing 3,4-dihydroxyphenylacetic acid (DOPAC) were more abundant in participants with better social functioning scores.

The potential for producing this substance was the most strongly associated with Coprococcus group of bacteria. DOPAC is produced from dopamine, an important neurotransmitter, and researchers believe it can reduce the proliferation of colon cancer cells. Reduced DOPAC levels are a potential biomarker of Parkinson’s disease (Valles-Colomer et al., 2019).

 

Bacteria involved in the degradation of glutamate and production of GABA tended to be depleted in participants with depression

Additionally, bacteria involved in glutamate degradation tended to be depleted in participants with depression. Glutamate is an amino acid that plays a role in various metabolic and signaling pathways in the body. However, it is also the primary excitatory neurotransmitter in the central nervous system. This means that it increases the likelihood of neurons generating a nerve impulse.

Microorganisms involved in synthesizing gamma-aminobutyric acid (GABA) also tended to be depleted in participants with depression. GABA is an important inhibitory neurotransmitter. It makes neurons less likely to fire a nerve impulse (see Figure 6).

 

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Figure 6. Link of microbial substance to the quality of life and depression

 

Conclusion

Overall, the analysis of two large sets of gut microbiome samples from two different (although neighboring) countries confirmed specific links between gut microbiota composition and mental health indicators. Individuals with better quality of life indicators tended to have more Faecalibacterium and Coprococcus bacteria in their gut. Those with better physical functioning tended to have fewer bacteria from the Flavonifractor species group. Bacteria from Coprococcus and Dialister groups of species tended to be much less present in the guts of individuals suffering from depression. 

Bacteria capable of producing 3,4-dihydroxyphenylacetic acid or DOPAC were more abundant in participants with better social functioning scores. DOPAC is produced from dopamine, an important neurotransmitter in the human body, and it plays various important roles in the body’s functioning. Bacteria involved in the degradation of glutamate and the production of GABA, two important neurotransmitters, tended to be depleted in individuals with depression (see Figure 7).

 

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Figure 7.  Summary

 

While these findings are only correlational and do not allow for cause-and-effect conclusions, future research can be expected to map causal pathways responsible for the observed associations. This could open a new avenue of mental health treatments to achieve improved mental outcomes by affecting the gut or adjusting gut microbiota composition. It is also not hard to imagine scientists in the future using genetic techniques to create microorganisms that could influence mental health or mental states when placed in the gut.

The paper “The neuroactive potential of the human gut microbiota in quality of life and depression” was authored by Mireia Valles-Colomer, Gwen Falony, Youssef Darzi, Ettje F. Tigchelaar, Jun Wang , Raul Y. Tito, Carmen Schiweck, Alexander Kurilshikov , Marie Joossens, Cisca Wijmenga, Stephan Claes, Lukas Van Oudenhove, Alexandra Zhernakova, Sara Vieira-Silva , and Jeroen Raes.

To learn more about this topic,, CNP has developed two university-level continuing education courses exploring the evidence based interconnections in the microbiota-gut-brain axis diet-mental health relationship (MGBA-DMHR). See our course pages here. 

References

Carbia, C., Bastiaanssen, T. F. S., Iannone, F., García-cabrerizo, R., Boscaini, S., Berding, K., Strain, C. R., Clarke, G., Stanton, C., Dinan, T. G., & Cryan, J. F. (2023). The Microbiome-Gut-Brain axis regulates social cognition & craving in young binge drinkers. EBioMedicine, (In press), 104442. https://doi.org/10.1016/j.ebiom.2023.104442

Heiss, C. N., Mannerås-Holm, L., Lee, Y. S., Serrano-Lobo, J., Håkansson Gladh, A., Seeley, R. J., Drucker, D. J., Bäckhed, F., & Olofsson, L. E. (2021). The gut microbiota regulates hypothalamic inflammation and leptin sensitivity in Western diet-fed mice via a GLP-1R-dependent mechanism. Cell Reports, 35(8). https://doi.org/10.1016/j.celrep.2021.109163

Valles-Colomer, M., Falony, G., Darzi, Y., Tigchelaar, E. F., Wang, J., Tito, R. Y., Schiweck, C., Kurilshikov, A., Joossens, M., Wijmenga, C., Claes, S., Van Oudenhove, L., Zhernakova, A., Vieira-Silva, S., & Raes, J. (2019). The neuroactive potential of the human gut microbiota in quality of life and depression. Nature Microbiology, 4(4), 623–632. https://doi.org/10.1038/s41564-018-0337-x

Zhu, X., Sakamoto, S., Ishii, C., Smith, M. D., Ito, K., Obayashi, M., Unger, L., Hasegawa, Y., Kurokawa, S., Kishimoto, T., Li, H., Hatano, S., Wang, T. H., Yoshikai, Y., Kano, S. ichi, Fukuda, S., Sanada, K., Calabresi, P. A., & Kamiya, A. (2023). Dectin-1 signaling on colonic γδ T cells promotes psychosocial stress responses. Nature Immunology. https://doi.org/10.1038/s41590-023-01447-8

 

 

Gut Microbiota Play Crucial Role in Mediating Effects of Western Diet

Posted on by CNP Super Admin

Introduction

The past several decades have seen the rise of an obesity pandemic that is ongoing worldwide. While obese individuals were quite rare just a century ago, 2015-2018 estimates for the U.S. state that more than two-thirds of the adult population is overweight or obese (Wong et al., 2022). Determining the causes of this increase in obesity rates has attracted much research attention. Studies have revealed a complex interplay between diet components, environmental factors, and previously unknown psychological and physiological mechanisms resulting in overeating and obesity in the long term. These novel studies on the intersection of nutrition and psychology are part of a developing field of science called nutritional psychology (The Center for Nutritional Psychology, 2023) (see Figure 1).

 

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Figure 1. Diet, environment, psychological, and physiological factors in nutritional psychology 

 

There is a complex interplay between diet, environmental factors, and psychological and physiological mechanisms resulting in overeating and obesity

 

Gut microbiota and the microbiota-gut-brain axis

The human gut microbiome consists of trillions of microorganisms that live in the human intestinal tract. These microorganisms play a key role in digesting the food we eat. However, their influence extends beyond the gut, encompassing crucial roles in metabolic regulation, body weight maintenance, and immune system modulation. 

This growing body of evidence suggests that these gut microorganisms also profoundly impact brain functions, mood, cognition, and emotional well-being  (Zhu et al., 2023). This topic is explored in continuing education curricula within nutritional psychology — particularly how the gut microbiota and the gut-brain axis interconnect with the diet-mental health relationship to influence psychological functioning and experience, shedding light on its potential therapeutic implications for mental health outcomes.

 

This growing body of evidence suggests that gut microorganisms profoundly impact brain functions, mood, cognition, and emotional well-being

 

Scientists have recently discovered a communication pathway connecting the gut microbiome and the brain. This pathway is called the microbiota-gut-brain axis. It is based on small proteins called cytokines and a number of other biomolecules, including the hormone cortisol, short-chain fatty acids (SCFAs), tryptophan, and others.

The Western diet

The Western diet is a modern dietary pattern prevalent in Western societies, characterized by a high intake of processed and hyperpalatable foods with increased contents of fat, sugary snacks, and refined grains. It typically includes low consumption of fruits, vegetables, unprocessed-high-quality proteins, nuts, and seeds. This diet’s excessive reliance on added sugars and unhealthy fats has been linked to an increased risk of obesity, metabolic syndrome, and various chronic diseases.

Studies have indicated that feeding mice a Western diet causes inflammation in the region of the brain called the hypothalamus (Heiss et al., 2021; Thaler et al., 2013). Inflammation of the hypothalamus damages the neurons and leads to the formation of scars made of glial cells. This is called gliosis. Inflammation of the hypothalamus often happens before a mouse starts gaining weight. Due to this, scientists believe it might cause weight gain by causing leptin resistance.

 

Studies have indicated that feeding mice a Western diet causes inflammation of the region of the brain called the hypothalamus

 

Leptin and leptin resistance

Leptin is a hormone produced by fat cells during eating. It regulates appetite and body weight and is produced in proportion to the amount of fat in the body. Leptin concentrations inform the brain of how much fat is stored. Increased leptin concentrations (normally caused by an abundance of body fat) “tell” the brain to decrease food intake and increase energy expenditure.

 

Leptin is a hormone produced by fat cells that regulate appetite and body weight

 

Factors such as chronic inflammation or eating high-fat diets (HFDs) may cause the body to be less receptive to leptin. This is called leptin resistance. Leptin resistance results in disrupted appetite and energy regulation, i.e., the brain does not reduce food intake in spite of the abundance of body fat. This can contribute to obesity and cause difficulty controlling body weight (Thaler et al., 2013) (see Figure 2).

 

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Figure 2. Normal leptin cycle versus leptin resistance.

 

Gliosis, leptin resistance, and gut microbiota

Microglia are a type of immune cell in the central nervous system that helps protect and maintain the brain and spinal cord by detecting and responding to potential threats or damage. Studies have shown that activation of microglia cells that happens during inflammation of the hypothalamus might be causing leptin resistance. Removing these microglia cells from the hypothalamus has improved sensitivity to leptin. Improved sensitivity to leptin allows the brain to recognize when enough fat is stored in the body and reduce food intake. 

 

Studies have shown that the activation of microglia cells that happens during inflammation of the hypothalamus might be causing leptin resistance

 

Intriguingly, according to the scientific evidence presented in our recent NP 120 course, it has been discovered that the gut microbiota plays a significant role in regulating the development and maturation of microglia cells and influencing their function. Although the mechanism of this action remains unknown, it has led scientists to believe there might be a link between hypothalamus inflammation and gut microbiota (Heiss et al., 2021) (see Figure 3).

 

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Figure 3. Link of Gut Microbiota in regulating development and maturation of microglia cells

 

There might be a link between hypothalamus inflammation and gut microbiota (Heiss et al., 2021)

 

The current study

Study author Christina N. Heiss and her colleagues wanted to know whether mice that lack gut microbiota are protected against diet-induced inflammation of the hypothalamus. They noted previous studies’ results showing mice with depleted gut microbiota and those treated with antibiotics to be protected from diet-induced obesity.

In other words, they noted that mice that consume a Western diet, a diet that normally leads to obesity in mice, do not become obese if microbiota are not present in their guts. This might be because the absence of microbiota prevents inflammation of the hypothalamus, which would, in turn, prevent leptin resistance from developing. If this is the case, the mechanism for preventing overeating based on leptin would remain intact, preventing mice from becoming obese. Alternatively, it could be that, without microbiota, the guts of mice could not digest complex nutrients from the food they eat, thus substantially reducing the amount of nutrition they can derive from food. In this case, obesity would be avoided because their bodies cannot use their food. But which of these is the case?

The procedure

The study authors used three groups of male mice, 10-13 weeks old – conventionally raised mice, germ-free mice, and antibiotic-fed mice. They used several genetic groups of mice, including a strain of genetically engineered mice that allow for controlled and regulated manipulation of specific genes in specific tissues (Tamoxifen-inducible Cre mice).

In the scope of the experiments, researchers fed mice either a chow diet or a Western diet. Western diet was given for either 2 days, 1 week, or 4 weeks, depending on the experiment conducted in the scope of the study.

The chow diet for mice is a nutritionally balanced and standardized diet formulated to provide essential nutrients required for the health and growth of laboratory mice. It typically consists of a combination of proteins, carbohydrates, fats, vitamins, and minerals in pellet or block form. The Western diet used in this study was high in fat and sucrose, with 40% of calories coming from fat.

All food for mice was sterilized, i.e., underwent procedures that killed all microorganisms in the food before mice ate it. The chow diet was sterilized in an autoclave, which uses high pressure and steam to kill microorganisms. The Western diet food was irradiated, i.e., radiation was used to kill microorganisms.

The mice

Conventionally raised mice were laboratory mice kept in regular conditions and fed a normal diet for laboratory mice. They have normal gut microbiota.

Germ-free mice are created through techniques that ensure they do not acquire gut microbiota from birth through their entire lifetimes. They are typically born using cesarean section deliveries of pregnant mice in a sterile environment. This is done to prevent the transfer of microbes during birth. After that, they are kept in specialized sterile isolation spaces called isolators or bubbles that maintain a controlled germ-free environment.

These isolators provide filtered air, sterile food, and autoclaved water to prevent microbial contamination. Researchers raising these mice take special care to maintain strict barrier measures, including specialized clothing and equipment, to prevent the unintentional introduction of microorganisms. They regularly monitor these mice’s bodily fluids and tissues through special techniques to ensure the absence of any detectable microorganisms. Germ-free mice are typically leaner than conventionally raised mice and, consequently, have lower leptin levels in circulation.

Antibiotic-fed mice in this study had 1g of ampicillin and 0.5g of neomycin added per liter of their drinking water. Ampicillin and neomycin are antibiotics. Researchers kept the drinking water with antibiotics added in bottles protected from light. They prepared a new solution every second day. Researchers started giving this water with antibiotics to mice three days before changing their regular diet to a Western diet.

 

Mice without gut microbiota are protected from diet-induced inflammation of the hypothalamus

 

Results showed that conventionally raised mice fed a Western diet for 1 week developed gliosis in the hypothalamus. Inflammation indicators were increased in these mice in the part of the hypothalamus called the arcuate nucleus compared to conventionally raised mice fed regular mice food (chow) (see Figure 4).

 

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Figure 4. Conventionally raised mice fed a Western diet developed gliosis in the hypothalamus

 

When researchers examined germ-free mice and mice whose gut microbiota were depleted using antibiotic treatment (antibiotic-fed mice), results showed that these mice also showed no increase in inflammation indicators or the proliferation of microglia cells after eating a Western diet for a week.

 

Gliosis in the hypothalamus leads to greater gain in body weight and fat mass

 

The study authors also wanted to know whether gliosis in the hypothalamus caused by a Western diet leads, in turn, to increased body weight and fat mass accumulation in mice. To test that, they fed conventionally raised mice and antibiotic-fed mice a Western diet for 4 weeks.

Results showed that conventionally raised mice fed a Western diet gained more body weight and fat mass than antibiotic-fed mice. Compared to antibiotic-fed mice, they also had increased hypothalamus inflammation indicators and increased numbers of a specific type of microglia cells (iba1-positive microglia).

There was no association between the number of microglia in the arcuate nucleus region of the hypothalamus and changes in body weight or fat mass at the end of the 4 weeks. However, fat mass and the relative increase in fat mass during the study were associated with the number of a specific type of glial cells called astrocytes.

Further analysis showed that germ-free and antibiotic-fed mice are more sensitive to leptin than conventionally raised mice. When researchers gave them leptin injections, the first two types of mice reduced their food intake more than conventionally raised mice did.

 

Glucagon-like-peptide 1 (GLP-1) seems to be crucial for protection against diet-induced inflammation of the hypothalamus

 

Germ-free and antibiotic-fed mice had higher levels of the hormone called glucagon-like peptide 1 (GLP-1) when they were fed a regular diet. This hormone secreted in the small intestine’s intestinal lining cells (L cells) is important in regulating blood sugar levels. It also helps reduce inflammation and protect neurons.

Study authors believed it might also be crucial for the protection from inflammation of the hypothalamus induced by the Western diet. After mice were fed a Western diet for a week, antibiotic-treated and germ-free mice had higher levels of GLP-1 than conventionally raised mice. These mice did not gain weight or develop hypothalamic inflammation after this diet. However, when researchers measured these same things in antibiotic-fed and germ-free mice whose GLP-1 signaling pathway was disabled, they also gained weight and developed inflammation, similar to conventionally raised mice. This indicated that the functional signaling path of GLP-1 is crucial for countering the inflammation of the hypothalamus induced by a Western diet.

 

Just a week on a Western diet led to inflammation of the hypothalamus that, in turn, disrupted the body’s mechanism for regulating food intake

 

Conclusion

These findings in mice show that gut microbiota changes how the organism, of mice in this case, reacts to a Western diet. When gut microbiota was intact, just a week on a Western diet led to inflammation of the hypothalamus that, in turn, disrupted the body’s mechanism for regulating food intake. However, when gut microbiota was depleted or absent, this inflammation did not happen, provided that the signaling pathway of one specific hormone (GLP-1) was intact.

While the study was done on mice, similar physiological mechanisms exist in humans. Due to this, these findings on mice help scientists better understand how and through which physiological mechanisms changes in the human diet that occurred in the last century disrupted food intake regulation in the human body leading to the current obesity pandemic.

The paper “The gut microbiota regulates hypothalamic inflammation and leptin sensitivity in Western diet-fed mice via a GLP-1R-dependent mechanism” was authored by Christina N. Heiss, Louise Manneras-Holm, Ying Shiuan Lee, Julia Serrano-Lobo, Anna Hakansson Gladh, Randy J. Seeley, Daniel J. Drucker, Fredrik Backhed, and Louise E. Olofsson.

References

Heiss, C. N., Mannerås-Holm, L., Lee, Y. S., Serrano-Lobo, J., Håkansson Gladh, A., Seeley, R. J., Drucker, D. J., Bäckhed, F., & Olofsson, L. E. (2021). The gut microbiota regulates hypothalamic inflammation and leptin sensitivity in Western diet-fed mice via a GLP-1R-dependent mechanism. Cell Reports, 35(8). https://doi.org/10.1016/j.celrep.2021.109163

Thaler, J. P., Guyenet, S. J., Dorfman, M. D., Wisse, B. E., & Schwartz, M. W. (2013). Hypothalamic inflammation: Marker or mechanism of obesity pathogenesis? Diabetes, 62(8), 2629–2634. https://doi.org/10.2337/DB12-1605

The Center for Nutritional Psychology. (2023). What is Nutritional Psychology? https://www.nutritional-psychology.org/what-is-nutritional-psychology/

Wong, M. C., Mccarthy, C., Fearnbach, N., Yang, S., Shepherd, J., & Heymsfield, S. B. (2022). Emergence of the obesity epidemic: 6-decade visualization with humanoid avatars. The American Journal of Clinical Nutrition, 115(4), 1189–1193. https://doi.org/10.1093/AJCN/NQAC005

Zhu, X., Sakamoto, S., Ishii, C., Smith, M. D., Ito, K., Obayashi, M., Unger, L., Hasegawa, Y., Kurokawa, S., Kishimoto, T., Li, H., Hatano, S., Wang, T. H., Yoshikai, Y., Kano, S. ichi, Fukuda, S., Sanada, K., Calabresi, P. A., & Kamiya, A. (2023). Dectin-1 signaling on colonic γδ T cells promotes psychosocial stress responses. Nature Immunology. https://doi.org/10.1038/s41590-023-01447-8

 

 

Researchers Discover Immune Mechanism Linking Changes in Gut Microorganisms and Behavior after Chronic Stress

Posted on by CNP Super Admin

Stress is inevitable, but it can disturb our body’s physiological signaling mechanisms when it becomes chronic. These mechanisms are interlinked with the Microbiota Gut-brain axis (MGBA) and influence the diet-mental health relationship (DMHR) in many ways. Being a major immune organ and highly colonized with the microbiome, our gut experiences certain immune inflammatory responses due to stress, which affect the gut microbiome composition and contribute to the onset of depression and anxiety. 

A new study led by researchers at Johns Hopkins has strengthened our understanding of the role of specific gut immune cells in microbiota composition and influencing the brain’s responsiveness to stress. This early-stage experiment on mice found that a specific type of white blood cells, gamma-delta T lymphocytes, play a key role in the cellular mechanism leading to adverse behavioral changes under chronic stress. After chronic stress, some mice in the experiment developed social avoidance behavior, i.e., they started avoiding contact with other mice. These mice had reduced diversity of microorganisms in their guts and increased concentrations of gamma-delta T lymphocytes in their intestines and in the membranes surrounding their brains. Under equal chronic stress conditions, mice without gamma-delta T lymphocytes did not develop social avoidance behavior (Zhu et al., 2023). The study was published in Nature Immunology.

 

After chronic stress, some mice in the experiment started avoiding contact with other mice. They had reduced microbial diversity and increased concentrations of gamma-delta T lymphocytes in their gut and surrounding their brain

 

Chronic stress

Chronic stress is a consistent sense of feeling pressured and overwhelmed over a long period of time. There are many possible sources of chronic stress in modern society. These include bad living conditions and homelessness, bad family and social relations, negative interactions between work and family, adverse work conditions, illness, and many others (Armon et al., 2014; Goodman et al., 1991; Tsukerman et al., 2020). Chronic stress slowly drains a person’s psychological energy and has damaging effects on both health and well-being.

Chronic stress and the gut microbiota

Physiologically, chronic stress induces immune changes and inflammation, leading to psychiatric disorders such as depression and anxiety (Hodes et al., 2014). These immune changes include changes to the gut microbiota – the trillions of microorganisms that live in the human intestinal tract (Figure 1). 

 

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Figure 1. Chronic stress leads to immune changes, inflammation, depression, and anxiety

 

Gut microorganisms play a key role in digesting food, but they are also incredibly important for various other processes, such as the differentiation of certain immune cells (Zhu et al., 2023). Differentiation is when immature and unspecialized cells transform into specialized, mature cells that perform specific bodily functions. It is one of the critical processes of life. When a person is under stress, the body reacts with inflammation, that in turn affects the composition of microorganisms in the gut but also creates physiological changes that reach the brain and affect cognition and behavior.

Due to this, studying physiological changes associated with chronic stress is very important for understanding the development of the most common psychiatric disorders and finding effective ways to treat them. However, research ethics and practical considerations impose very strict limits on what types of studies can be conducted on humans. That is why studies of the physiology and biochemistry of chronic stress are often done on animals, particularly mice, using specific research protocols. One research protocol used to induce chronic stress in mice for research purposes is the chronic social defeat stress protocol.

What is chronic social defeat stress?

Chronic social defeat stress is a protocol (procedure) in which a mouse is exposed to a larger aggressive mouse in an enclosed space. This is followed by a confrontation between the two mice in which the mouse undergoing this treatment is defeated and forced into a subordinate position (social defeat). Typically, this procedure is repeated daily over ten days (Figure 2). 

 

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Figure 2. Chronic Social Defeat Stress Protocol

 

The chronic social defeat stress protocol produces effects similar to depression in exposed mice. It also produces a number of other easily detectable effects such as increased weight of spleen of these mice, lower preference for sucrose, and others. That is why it is extensively used in research on mice (Golden et al., 2011).

 

The chronic social defeat stress protocol produces effects similar to depression in exposed mice. 

 

The current study

Study author Xiaolei Zhu and his colleagues wanted to explore the cellular mechanisms behind social avoidance behaviors caused by chronic stress. They were particularly interested in the role a specific type of white blood cell called the gamma-delta T lymphocyte has in these changes and in the changes in the composition of gut microorganisms caused by stress.

What are gamma-delta T lymphocytes?

Gamma-delta T lymphocytes (γδ T-cells) are a specific type of white blood cells in the body. Still, they are found in high concentrations in various mucosal tissues called meninges, including intestines and membranes surrounding the brain. Lymphocytes are involved in the body’s immune responses. Studies have shown that gamma-delta T lymphocytes located in the meninges regulate anxiety-like behaviors and memory. Furthermore, research indicated that gamma-delta T lymphocytes in the intestines could travel to the meninges under certain conditions. This has led scientists to assume that these gamma-delta T lymphocytes from the gut may be involved in brain function changes when inflammation occurs (Zhao et al., 2018; Zhu et al., 2023) (Figure 3).

 

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Figure 3. Gamma-delta T lymphocytes are in intestinal mucosal tissue and membranes around the meninges. 

 

The experiment

The study authors applied the chronic defeat stress protocol on a group of mice. Afterward, researchers examined the social behavior of these mice (towards other mice, using a social interaction test). They noticed that some of these mice started avoiding contact with other mice in a test situation, i.e., manifested social avoidance behavior, while others did not. They named the group of mice that showed social avoidance behavior the susceptible group. In contrast, the group of mice that did not show social avoidance behavior was named the resilient group. Researchers kept a third group of the same genetic strain of mice as controls and did not expose them to the chronic social defeat protocol (see Figure 4).

 

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Figure 4. Susceptible vs. resilient vs. no exposure

 

After the procedure, researchers collected stool samples from the mice and conducted their genetic analysis in order to identify the compositions of microorganisms present in the guts of these mice. This procedure is called the metagenomic sequencing of the gut microbiota. They also used a procedure called flow cytometry to determine the number and characteristics of gamma-delta T lymphocytes in the gut and in the meninges of these mice.

Comparison with humans

Parallel with this experiment, researchers investigated the differences in the composition of gut microbiota in humans diagnosed with major depressive disorder and healthy individuals by analyzing their stool samples. They found that a lower abundance of the Lactobacillus group of bacteria in the gut was associated with higher depression and anxiety symptoms. They confirmed this using three different assessments of depression and anxiety symptoms (the Montgomery-Asberg depression scale, the Hamilton Depression scale, and the Hamilton Anxiety Scale)(Zhu et al., 2023). Based on this, study authors assumed that concentrations of these bacteria in the gut might play a role in the vulnerability to stress in mice and humans. They decided to look for differences in the abundance of Lactobacillus bacteria in different groups of mice in their experiment.

Susceptible mice had a reduced abundance of Lactobacillus johnsonii bacteria in the gut! (See Figure 5).

 

%learn about nutrition mental health %The Center for Nutritional Psychology Figure 5. Humans + Mouse experiment showing a lower abundance of lactobacillus in gut bacteria = with higher depression and anxiety

 

A comparison of the gut microbiota of susceptible mice, resilient mice, and the control group showed that susceptible mice had less diverse microbial populations in the gut. The gut microbiota of susceptible mice differed from the gut microbiota of resilient mice and the control group on a number of bacterial species. As researchers expected, one of these species was Lactobacillus Johsonii. Their concentration was reduced in susceptible mice’s guts compared to resilient mice and the control group.

Susceptible mice had increased concentrations of gamma-delta T cells in both meninges and intestines

Given the previously described relationship between Lactobacillus bacteria and immune responses, researchers examined whether concentrations of gamma-delta T lymphocytes were increased in mice exposed to the chronic social defeat stress treatment. Results showed that susceptible mice had increased concentrations of gamma-delta T lymphocytes in their colons and meninges (membranes surrounding the brain) compared to resilient and healthy mice.

 

Susceptible mice had increased concentrations of gamma-delta T lymphocytes both in their colons and their meninges 

 

In susceptible mice, many of the gamma-delta T cells in brain membranes came from the gut!

Researchers then wanted to know whether the gamma-delta T cells found in the meninges of susceptible mice were cells that differentiated there or those cells that traveled from the gut. They identified differences between these two types of gamma-delta T cells and measured their concentrations. Results showed that, in resilient mice and the control group, gamma-delta T lymphocytes found in the meninges were indeed differentiated. However, in susceptible mice, there were fewer such cells, but many gamma-delta T lymphocytes came from the gut.

 

In susceptible mice, there were fewer such cells, but there were lots of gamma-delta T lymphocytes that came from the gut

 

Social avoidance after the chronic social defeat stress does not develop in mice without gamma-delta T lymphocytes.

Finally, researchers wanted to test whether the gamma-delta T lymphocytes were responsible for the social avoidance behavior after exposure to chronic social defeat. They repeated the procedure on a new group of special mice that did not have the gamma-delta T cells. As researchers expected, these mice did not develop social avoidance behavior after exposure to the chronic social defeat stress protocol.

Conclusion

The study showed that a certain type of white blood cells – gamma-delta T lymphocytes and their accumulation play a key role in changes to behavior induced by stress. In the context of MGBA-DMHR, it also demonstrates interactions between gut microbiota, the body’s immune responses, and the brain when an organism is stressed. Given that many of the physiological processes in mice are similar to those in humans, these findings contribute to the scientific understanding of physiological mechanisms of behavioral changes that chronic stress and related disorders in humans. These insights can help develop novel ways to treat and prevent major depressive disorder and other stress-related disorders. They can also open new approaches to diagnosing individual susceptibility to stress and increasing resilience.

The paper “Dectin-1 signaling on colonic gamma-delta T cells promotes psychosocial stress responses” was authored by Xiaolei Zhu, Shinji Sakamoto, Chiharu Ishii, Matthew D. Smith, Koki Ito, Mizuho Obayashi, Lisa Unger, Yuto Hasegawa, Shunya Kurokawa, Taishiro Kishimoto, Hui Li, Shinya Hatano, Tza-Huei Wang, Yasunobu Yoshikai, Shin-ichi Kano, Shinji Fukuda, Kenji Sanada, Peter A. Calabresi, and Atsushi Kamiya.

For more research in the Microbiota Gut-Brain Axis — Diet-Mental Health Relationship (MGBA-DMHR), visit CNP’s Nutritional Psychology Research Library (NPRL) Microbiota Gut-Brain Axis—Diet-Mental Health Relationship research category, or enroll in NP 120: Microbiota Gut-Brain Axis and the DMHR (available in May 2023).

References

Armon, G., Melamed, S., Toker, S., Berliner, S., & Shapira, I. (2014). Joint Effect of Chronic Medical Illness and Burnout on Depressive Symptoms Among Employed Adults. Health Psychology, 33(3), 264–272. https://doi.org/10.1037/a0033712

Golden, S. A., Covington, H. E., Berton, O., & Russo, S. J. (2011). A standardized protocol for repeated social defeat stress in mice. Nature Protocols, 6(8), 1183–1191. https://doi.org/10.1038/nprot.2011.361

Goodman, L., Saxe, L., & Harvey, M. (1991). Homelessness as psychological trauma. American Psychologist, 46(11), 1219.

Hodes, G. E., Pfau, M. L., Leboeuf, M., Golden, S. A., Christoffel, D. J., Bregman, D., Rebusi, N., Heshmati, M., Aleyasin, H., Warren, B. L., Lebonté, B., Horn, S., Lapidus, K. A., Stelzhammer, V., Wong, E. H. F., Bahn, S., Krishnan, V., Bolaños-Guzman, C. A., Murrough, J. W., … Russo, S. J. (2014). Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress. Proceedings of the National Academy of Sciences of the United States of America, 111(45), 16136–16141. https://doi.org/10.1073/pnas.1415191111

Tsukerman, D., Leger, K. A., & Charles, S. T. (2020). Work-family spillover stress predicts health outcomes across two decades. Social Science & Medicine, 265, 113516. https://doi.org/10.1016/j.socscimed.2020.113516

Zhao, Y., Niu, C., & Cui, J. (2018). Gamma-delta (γδ) T Cells: Friend or Foe in Cancer Development. Journal of Translational Medicine, 16(1), 1–13. https://doi.org/10.1186/s12967-017-1378-2 

Zhu, X., Sakamoto, S., Ishii, C., Smith, M. D., Ito, K., Obayashi, M., Unger, L., Hasegawa, Y., Kurokawa, S., Kishimoto, T., Li, H., Hatano, S., Wang, T. H., Yoshikai, Y., Kano, S. ichi, Fukuda, S., Sanada, K., Calabresi, P. A., & Kamiya, A. (2023). Dectin-1 signaling on colonic γδ T cells promotes psychosocial stress responses. Nature Immunology. https://doi.org/10.1038/s41590-023-01447-8

 

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