Gastric Microbiota and Their Impact on Mental Health

RELEASE DATE

May 1, 2022

EXPIRATION DATE

May 31, 2024

FACULTY

Donna M. Lisi, PharmD, BCPS, BCPP, BCGP, BCACP, BCMTMS
Clinical Pharmacist
Somerset, New Jersey

FACULTY DISCLOSURE STATEMENTS

Dr. Lisi has no actual or potential conflicts of interest in relation to this activity.

Postgraduate Healthcare Education, LLC does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced, objective, and scientifically rigorous. Occasionally, authors may express opinions that represent their own viewpoint. Conclusions drawn by participants should be derived from objective analysis of scientific data.

ACCREDITATION STATEMENT

acpePharmacy
Postgraduate Healthcare Education, LLC is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

UAN: 0430-0000-22-050-H01-P
Credits: 2.0 hours (0.20 ceu)
Type of Activity: Knowledge

TARGET AUDIENCE

This accredited activity is targeted to pharmacists. Estimated time to complete this activity is 120 minutes.

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DISCLAIMER

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients’ conditions and possible contraindications or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

GOAL

To educate pharmacists about the potential role of the gastric microbiota in mental health, in particular as an etiological or contributory cause of psychiatric disorders.

OBJECTIVES

After completing this activity, the participant should be able to:

  1. Describe the proposed mechanism of how the microbiota-gut-brain axis affects mental health.
  2. Identify the differences between alpha- and beta-diversity of the gastric microbiota.
  3. Discuss the potential antibacterial properties of psychotropics.
  4. Summarize the potential role of psychotropics in the development of antibiotic resistance.

ABSTRACT: One in five Americans suffers from mental illness, with up to 60% of patients experiencing treatment resistance. As a result, efforts have been made to search for a more holistic approach to the treatment of psychiatric disorders. Although data are preliminary, one novel intervention focuses on the microbiota-gut-brain axis, a complex bidirectional interaction between the gut and the brain that may affect the development of psychiatric disorders and the response to drug therapy. Additionally, psychotropics may affect the gastric microbiota, altering metabolism and affecting bacterial growth. Conversely, the gastric microbiota can alter a drug’s effects or adverse effects and directly participate in chemical transformation of medications. Pharmacists should be familiar with the emerging science of pharmacomicrobiomics, which describes the influence of the microbiome compositional and functional variations on drug response and disposition, and how this new discipline may impact the management of mental health disorders.

According to statistics from 2020 by the Substance Abuse and Mental Health Services Administration, nearly one in five Americans, or 52.9 million, have a mental health disorder.1 Of these patients with psychiatric disorders, about 20% to 60% are considered treatment resistant.

Treatment resistance can increase healthcare costs up to 10-fold compared with care for persons without a mental health disorder.2 These numbers appear to be even higher due to the adverse effects of the COVID-19 pandemic lockdown on mental health.3

Attempts have been made to take a more holistic approach to the management of mental illness. Recent evidence has pointed to the gastric microbiota (GM) and its role in mental health.

MICROBIOTA-GUT-BRAIN AXIS

The human GM consists of over 40,000 species of microorganisms, which number in the 1013 to 1014, with the predominant phyla being Firmicutes and Bacteroidetes and, to a lesser extent, Proteobacteria, Actinobacteria, Fusobacteria, and Verrucomicrobia phyla. The GM is also made up of viruses, protozoa, archae, and fungi. These microbes contain 150-fold more genes than in the human genome.4,5

Although research in this field is still preliminary, it is thought that the GM may mediate a complex bidirectional interaction between the gut and the brain called the gut-microbiota-brain axis (GMBA).6 The GMBA is involved in bidirectional communication between the nervous system and the gastrointestinal (GI) tract. This interaction includes the CNS, autonomic nervous system, enteric nervous system, hypothalamic-pituitary-adrenal axis, neural, endocrine and immune systems, and bacterial metabolites and by-products.6-8

During dysbiosis, which is an alteration in the GM, pathways between the GI tract and brain become dysregulated. Changes in the GM can result in abnormal absorption from the gut into the circulation, a process called leaky gut syndrome. This can lead to inflammation and secondary damage to the brain and CNS due to altered permeability of the blood-brain barrier and neuroinflammation, which can trigger psychiatric and neurologic diseases.6,7 Dysbiosis can change the structure and function of the intestinal barrier, which may allow for the translocation of bacterial antigens to escape into the systemic circulation. When gram-negative organisms are involved, bacterial lipopolysaccharides can enter the systemic circulation and trigger an inflammatory response. Bacterial lipopolysaccharides also exacerbate hepatic steatosis and insulin resistance.9 It is thought that inflammation plays a role in psychiatric disorders and that the GM can modulate low-grade inflammation, contributing to the pathogenesis of psychiatric illnesses.10 The gut microbiome may also be involved in programming the hypothalamic-pituitary-adrenal axis early in life, which can affect response to stress throughout the life span.11

DIVERSITY OF THE GUT MICROBIOTA

Studies examining the GM often report on alphaand beta-diversity and relative abundance of various organisms. Whereas alpha-diversity is used to compare microbial communities across groups of individuals to evaluate the role of a particular factor such as a psychiatric diagnosis on the number of species (richness) and how well each species is represented (evenness), beta-diversity measures the interindividual diversity between samples looking for similarities of communities compared with other samples analyzed.12

Alpha-diversity is assessed by the Chao1, Shannon-Weaver, Simpson, phylogenic diversity (PD) whole tree, and Abundance-based Coverage Estimators (ACE) indices.13 The Chao1 is an ACE of species richness, while the Shannon-Weaver and Simpson indices estimate species’ richness and evenness.14 PD whole tree is defined as the minimum total length of all the phylogenetic branches required to span a given set of taxa on the phylogenetic tree.15 Similar to Chao1, ACE is an estimator of species richness. Another term associated with alpha-diversity is Operational Taxonomic Unit (OTU), which is used to define different levels such as phylum, class, order, family, genus, and species. Whereas Chao1 and ACE measure relative bacterial richness, OTU measures richness actually observed in the samples.14 Betadiversity is measured by UniFrac and Bray-Curtis dissimilarity.13 UniFrac is a beta-diversity measure that uses phylogenetic information to compare environmental samples.16 Whereas the Bray-Curtis is used to quantify the compositional dissimilarity between two samples, the UniFrac is used to estimate the differences between samples or groups based on phylogenetic distance.17

Low alpha-diversity is thought to be associated with the occurrence and, in some cases, the severity of chronic diseases (e.g., schizophrenia).18

In psychiatric illnesses such as depression, bipolar disorder, schizophrenia, and anxiety, GM perturbations have been found to be associated with depletion of certain anti-inflammatory, butyrate-producing bacteria and the enrichment of proinflammatory bacteria. An overlap between psychosis and schizophrenia, bipolar disorder, anxiety, and major depressive disorder (MDD) altered taxa was also observed. This may imply overlapping pathophysiology between these conditions.12

In a recent review and meta-analysis published in psychiatric disorders, investigators observed that the genus Eggerthella was found to be increased in MDD, bipolar disorder, psychosis, and schizophrenia, but the genera Faecalibacterium and Coprococcus were decreased. Eggerthella is associated with GI inflammation, while Faecalibacterium has antiinflammatory properties. Both Faecalibacterium and Coprococcus are involved in short-chain fatty acid butyrate production, whereas Eggerthella is involved in this compound’s depletion. Short-chain fatty acid (SCFA) butyrate is associated with anti-inflammatory properties. Concentrations of Faecalibacterium, which are decreased in MDD and bipolar disorder, have been found to be adversely associated with depression severity.12

Recent data from the multicenter, cross-sectional study CARDIA found that the GM is related to cognitive function in midlife. Cognitive function assessment was introduced into the CARDIA in 2010-2011, which was Year 25 of the study. Follow-up assessment of cognitive status occurred in 2015-2016 (Year 30) and involved the use of six cognitive tests. The mean study participants’ age was 55.2 years and ranged from 48 to 60 years. Beta-diversity was significantly associated with all cognitive measures, except for letter fluency. Levels of Barnesiella, Lachnospiraceae, and Sutterella were either positively (in the case of the first two organisms) or negatively (third organism) correlated with different domain-specific and global measures of cognitive status.19

Although preliminary, in patients with psychiatric disorders, the richness of the GM may be compromised, but diversity appears to be preserved. While alpha-diversity was not discriminatory between different types of psychiatric conditions, beta-diversity demonstrated a different clustering in patients with MDD, psychosis, and schizophrenia compared with healthy controls.12

Data from multiomics approaches are helping to determine the specific mechanism of the effect of the gut microbiota on host metabolism, immunity, and the brain.20

POTENTIAL EFFECTS OF MEDICATIONS ON THE GM

In patients with mental health issues, the effect of medications on the GM is an area of fervent research, although it is also fraught with limitations and confounders such as diet, age, environmental factors, hormones, sex, concomitant medications, seasonal variations, comorbidities, etc.21

Medications may affect the GM by altering metabolism and impacting bacterial growth, which results in changes in the microbiota’s composition and function. Conversely, the GM can affect a drug’s effects (or adverse effects) and thereby directly participate in the chemical transformation of medications.22-24

Pharmacomicrobiomics describes the influence of the microbiome compositional and functional variations on drug response and disposition.22 When considering the pharmacokinetic properties of medications, very little is known about the role of the GM in drug absorption. The GM may play a role in drug metabolism via hydrolytic and reductive reactions. Hepatic enzymes, on the other hand, are primarily involved in oxidative and conjugative metabolic reactions. Medications that undergo biliary excretion may once again undergo bacterial metabolism (e.g., deconjugation) and absorption or reabsorption. Further, the GM can alter the pharmacokinetics of medications by directly transforming the drug or by altering the host’s metabolism or immune system.22

PSYCHOTROPICS AND EFFECT ON GM

Antidepressants

It is thought that psychotropic medications such as antidepressants, antipsychotics, and mood stabilizers can influence the GM through antimicrobial activity.25 Although it is yet to be definitively demonstrated to be of clinical significance in humans, selective serotonin reuptake inhibitors (SSRIs) such as sertraline, fluoxetine, and paroxetine act as inhibitors of efflux pumps and/or amino acid transporters in bacteria cell walls. They have also been shown to inhibit gram-positive bacteria such as Enterococcus and Staphylococcus in vitro.26,27 They may interfere with the production of the slime layer biosynthesis.25

Medications may affect the GM by altering metabolism and impacting bacterial growth, which results in changes in the microbiota’s composition and function. Conversely, the GM can affect a drug’s effects (or adverse effects).

Of these SSRIs, sertraline is thought to have the most potent antimicrobial effect and can enhance the effects of antibiotics.25 Agents in this class (i.e., fluoxetine, sertraline, paroxetine) may also have antifungal effects against Aspergillus spp, Candida parapsilosis, and Candida albicans. The effects of SSRIs may be dose-dependent, with several SSRIs reporting antimicrobial properties only at high concentrations and antimicrobial enhancer properties at lower concentrations.25

Ketamine has been shown to have antimicrobial effects against several gram-positive and gram-negative bacteria and C albicans, while tricyclic antidepressant (TCA) use is associated with antiplasmid effects and decreased activity of DNA gyrase as well as the inhibition of gram-negative organisms and parasitic protozoan growth. Desipramine, a TCA, was noted to have potent antibacterial activity in vitro, causing significant growth reduction of Akkermansia muciniphila and Escherichia coli. Monoamine oxidase inhibitors can cause cell–wall synthesis inhibition.25,26

It has also been shown that both depression itself and antidepressant treatment alters the GM. It appears that high baseline levels of Firmicute and low levels of Bosea and Tetraspaera can predict response to antidepressant therapy in patients with MDD. Elevated levels of tryptophan were observed in nonresponders, indicating that there may have been impaired serotonin metabolism in the gut since increased metabolism of tryptophan by bacteria would have decreased tryptophan availability.28 However, others have reported that while the gut microbiota is altered in MDD, antidepressant therapy does not affect the GM.29

In a study involving 30 patients with MDD compared with 30 healthy controls, investigators observed a significant difference between in the GM of drug-naïve, first-episode MDD patients and controls. However, the composition and structure of the GM tended to be similar among patients with MDD with increased amounts of Firmicutes and decreased amounts of Bacteroidetes. Escitalopram in a maximum dose of 20 mg/ day appeared to normalize the GM in patients with MDD relative to healthy controls. The authors caution that this study had a small sample size and diet was not adequately controlled for.30

A recent in vitro antibacterial activity study found that desipramine and aripiprazole had the most inhibitory effect against all tested strains, which included Bacteroidetes, Firmicutes, Actinobacteria, Proteobacteria, and Verrucomicrobia, the most common organisms in the human GM. Phenelzine and (s)-citalopram showed moderate antibacterial activity against some intestinal strains. Bupropion caused minimal microbial inhibition, and venlafaxine appeared to be devoid of anti-infective effects. A muciniphila and Clostridium leptum were the most sensitive strains tested against antidepressants, while Lactobacillus rhamnosus was the most resistant.26 As levels of A muciniphila decreased in the GI tract, inflammation, insulin resistance, altered adipose metabolism, and atherosclerosis increased.31

A difference in the GM of patients taking antipsychotics has also been found. Drug-naïve, first-episode patients with schizophrenia had lower alpha-diversity and significant differences in beta-diversity compared with healthy controls prior to the initiation of antipsychotics. Following 24 weeks of risperidone therapy, there was normalization of the GM to that of healthy controls as evidenced by decreased abundance of Lachnoclostridium, increased abundance of Ramboutsia, and an increase in alpha-diversity. Further, treatment response was associated with baseline levels of Lachnoclostridium and Ramboutsia, indicating that these can possibly serve as biomarkers for efficacy. Lachnoclostridium and Ramboutsia both belong to Firmicutes phylum. Ramboutsia is involved in the production of SCFAs; low levels of this bacteria are thought to be associated with disturbances in the glutamate-gammaaminobutyric acid (GABA)-glutamate cycle and with the astrocyte-neuron metabolism system. Additionally, Lachnoclostridium appears to be involved in tryptophan metabolism.18

Another study found that normal-weight, drug-naïve patients with schizophrenia experiencing their first acute episode had significantly lower numbers of fecal Bifidobacterium spp, E coli, and Lactobacillus spp and higher numbers of fecal Clostridium coccoides compared with healthy controls. After 24 weeks of risperidone therapy, there was a significant increase in the numbers of fecal Bifidobacterium spp and E coli and a significant decrease in C coccoides and Lactobacillus spp. Of these GM alterations, only fecal Bifidobacterium spp changes were associated with increases in weight and BMI. Bifidobacterium spp have anti-inflammatory properties and may improve excessive weight gain by reducing proinflammatory cytokines.32 This metabolic effect has also been shown in children and adolescents. Chronic use of risperidone was associated with an inverse relationship with the Bacterioidetes/Firmicutes ratio and children’s weight. Further investigation revealed that the GM in children treated with risperidone was enriched for pathways that increase SCFA production, which has been implicated in weight gain.33

As in schizophrenia, differences have also been observed in the GM of patients with bipolar disorder. An abundance of the genera Lachnospiraceae, Akkermansia, and Sutterella was found in patients with bipolar disorder treated with antipsychotics compared with antipsychotic-naïve patients.31

In a study in which stool samples were collected from 40 patients with MDD and anxiety, a negative correlation was found between the dose of antipsychotics and gut diversity. This relationship was confirmed even when BMI and anxiety severity scores were accounted for. Investigators also found that there was a significant difference in both the alpha-diversity change in patients taking antipsychotics between baseline and the endpoint of the study, and there was a significant difference in betadiversity between patients taking antipsychotics and those not receiving the psychotropic agents.34

A naturalistic study of 40 patients with depression and anxiety found that there was a significant difference in alpha-diversity change only among those taking antipsychotics when comparing baseline to the end of the study; that beta-diversity also differed between antipsychotic users and nonusers; and that the dose of antipsychotics had a negative relationship with alpha-diversity in patients with depression and anxiety. Alterations in neurotransmitters were also observed with antidepressant use, including changes in GABA synthesis and degradation. Use of antipsychotics was associated with alterations in tryptophan synthesis and degradation, and anxiolytics were associated with increased GABA synthesis and decreased tryptophan synthesis.30,34

Others had previously shown that antipsychotic usage for at least 6 months decreased gut microbial diversity in female patients with bipolar disorder or schizophrenia.35

Researchers have found that the family Lactobacillaceae was significantly increased only in patients with psychosis and schizophrenia who were treated with antipsychotics. This increase may be associated with disease exacerbation.12 The GM may play a role in antipsychotic refractory psychosis in patients with schizophrenia.36

Researchers have found that the family Lactobacillaceae was significantly increased only in patients with psychosis and schizophrenia who were treated with antipsychotics. This increase may be associated with disease.

Other Psychotropics

Information on the antimicrobial effects of other classes of psychotropics is even more limited than for antidepressants and antipsychotics. Lithium appears to have antimicrobial and immunostimulating properties. Lamotrigine has been found to inhibit gram-positive organisms in vitro.25

The antimicrobial effects of psychotropic agents may be dose-related, with higher doses having an adverse effect on the GM. In the case of antipsychotics, these effects appear to occur at doses higher than what are used clinically.25

PSYCHOTROPICS AND ANTIBIOTIC RESISTANCE

The use of psychotropics may potentiate antibiotic resistance. It has been found in vitro that fluoxetine can promote resistance of E coli to antibiotics. It is thought to do this via reactive oxygen species (ROS) mutagenesis that triggers multiple efflux pumps to export antibiotics out of the cell.37 Increased potential for antidepressant-induced resistance in vitro was seen in another study in which the combined exposure of duloxetine and chloramphenicol synergistically promoted the development of multiantibiotic resistance (i.e., tetracycline, cefazolin, cefoxitin, ampicillin, chloramphenicol) to E coli in vitro. This resistance was thought to be mediated also via ROS-induced mutagenesis and by enhanced expression of efflux pumps. The mutagenesis of marR, the multiple antibiotic resistance locus on E coli, results in the multiple antibiotic resistance phenotype. The duloxetine and chloramphenicol combination resulted in a two-fold increase in the ROS content.38

Duloxetine has been associated with bioaccumulation, i.e., the process whereby bacteria store the drug intracellularly without chemically modifying it. However, duloxetine has been found to bind to metabolic enzymes and change the metabolic secretions of bacteria. It has also been associated with marked alteration of the composition of the microbial community through metabolic cross-feeding, a process whereby metabolites produced from dietary prebiotics by one bacterial species may act as a substrate to support the growth of other microbial populations.39,40

Another concern is that although antidepressants may possess antibacterial properties, which may result in levels below the minimum inhibitory concentration for a particular organism, they may lead to subinhibitory concentrations that only delay growth. This may lead to resistance. Further, antidepressants may inadvertently suppress beneficial bacteria such as Bifidobacterium, which protect the gut, boost the immune system, and help control inflammation.26

PSYCHOTROPIC-INDUCED METABOLIC ADVERSE EVENTS AND EFFECTS ON THE GM

Involvement of the GM may contribute to antipsychotic-induced weight gain since the GMBA can regulate metabolism, homeostasis, and energy balance.33,41 Antipsychotics may do this by interacting and changing the abundance of the GM.42 The administration of second-generation antipsychotics is associated with an increase in Firmicutes abundance relative to Bacteroidetes, and this may contribute to antipsychotic-induced metabolic alterations, such as adiposity, lipogenesis, and increases in plasma-free fatty superoxide dismutase and homeostasis model assessment of insulin resistence levels. These findings are indicative of the presence of low-level inflammation and decreased energy expenditure secondary to resting metabolic rate suppression.9 However, although antipsychotics such as olanzapine are associated with alterations in the GM, clinical data supporting this hypothesis are scarce.43 Extrapolating in vitro data to clinical effects is difficult because it is unclear if a drug reaches sufficient concentrations in the GI tract needed to replicate the laboratory findings. Additionally, factors such as exposure time, dose, solubility, distribution in fluids, volume of drug, transit time, ability of drug-metabolizing enzymes in the GI tract, effects of the presence of other medications, and uptake and metabolism of the drug by both human cells and by bacteria can affect results.44

Preliminary evidence indicates that psychotropic-induced weight gain may be associated with gastric dysbiosis that is related to Bacteroidetes depletion. As a result of this dysbiosis, propionate and indole production, which are generated by Bacteroidetes, are affected. This in turn affects lipid production as propionate and indole control lipid homeostasis. By depleting this microorganism, altered drug, lipid, and iron metabolism may occur, which can result in weight gain. Psychotropic agents lower the absorption of iron via gut microbes, which decreases total body iron stores. The upregulation of intracellular iron leads to the generation of excessive ROS and subsequent weight gain. It is postulated that restoring Bacteroidetes may help mitigate psychotropicinduced weight gain. However, clinical trials are lacking.45

Metformin has been found to ameliorate antipsychotic-induced metabolic dysfunction in part due to its effects on the GMBA. Metformin may reverse the reductions in Akkermansia that is induced by second-generation antipsychotics.44 Akkermansia may have anti-inflammatory properties, may protect and improve gut membrane integrity, may prevent the accumulation of fat, and may have a positive effect on cognition.19,26

GM changes induced by second-generation antipsychotics may lead to changes in SCFA production. Additionally, psychotropic agents regulate neuropeptides that may contribute to adverse metabolic effects; metformin blunts these deleterious effects.44

GAPS IN KNOWLEDGE

There are few human clinical trials exploring the role that the GM has on medication therapy and vice versa. Much of the research is based on nonhuman species or in vitro data. Studies that have been done are fraught with methodological limitations. This has resulted in gaps in knowledge. Among these areas of deficiency are a lack of understanding of the immunological effects of the human GM and its role in psychiatric and neurological disorders; lack of mapping of human GM–regulated neurotransmitters to determine their role in mental health; uncertainty about how microbial by-products generated in the GM influence brain function; lack of information on the effects of specific microbes throughout the life span; need for a standardized approach to conducting human clinical research; and inability to identify clinically relevant behavioral phenotypes in order to determine which interventions are most successful and which have limited utility.

ROLE OF THE PHARMACIST

As science continues to investigate the role that the GM has on the etiology, course, and response to treatment of psychiatric conditions, others are investigating ways to therapeutically manipulate the GM to help manage these conditions. These interventions include the use of probiotics, in particular psychobiotics (i.e., probiotics that confer mental health benefits to the host when ingested in a particular quantity through interaction with commensal gut bacteria), prebiotics, dietary, and/or fecal microbiota transplantation as well as microbiota transfer therapy.43,46-48 Although beyond the scope of this paper, pharmacists should be aware of the potential effects that these modalities may have on the management of psychiatric illnesses. At this point though, it is still too early to draw conclusions about the role of these strategies in the management of psychiatric conditions as highquality, human-derived data are lacking.

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