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An Update on the Relationship Between the Gut Microbiome and Obsessive-Compulsive Disorder

Jasmine Turna, BSc, PhD(C); Beth Patterson, BScN, MSc; and Michael Van Ameringen, MD, FRCPC

ABSTRACTThe gut microbiome, the collection of

microbes and their genetic material in the human gastrointestinal tract, has recently become a topic of interest in psychiatry. To date, animal studies have repeatedly shown behavior to be affected by alterations in the gut microbiota. Furthermore, studies in clinical psychiatric populations have also illustrated that microbial dysbiosis may play a role in these conditions, but results have been inconsistent. Given the exist-ing animal and human literature provid-ing evidence for a role of the microbiome in anxiety and depressive disorders, this review explores and develops similar lines of evidence in obsessive-compulsive disor-der. Theoretical treatment options target-ing the gut microbiome are also discussed. [Psychiatr Ann. 2017;47(11):542-551.]

Obsessive-compulsive disorder (OCD) is a psychiatric condition marked by recurrent intrusive

thoughts and ritualistic behaviors aimed at reducing the associated distress. The etiology of OCD is complex and involves multiple pathways, with imbalances in central serotonin, glutamate, and dopa-mine systems thought to play a causative role. This etiological basis remains large-ly theoretical and has received mixed scientific support. The current theories are premised on the observed benefit of pharmacological interventions such as serotonin reuptake inhibitors (SRIs). Given that 40% to 60% of patients with OCD do not respond to first-line treat-ments such as SRIs or cognitive-behav-ioral therapy (CBT),1 it is important that

Jasmine Turna, BSc, PhD(C), is a Research Assistant, MacAnxiety Research Centre, McMaster

University; and a Graduate Student, MiNDS Neuroscience Graduate Program, McMaster Univer-

sity. Beth Patterson, BScN, MSc, is a Research Nurse, Department of Psychiatry and Behavioural

Neurosciences, McMaster University; and a Research Research Manager, MacAnxiety Research

Centre, McMaster University. Michael Van Ameringen, MD, FRCPC, is a Professor, Department of

Psychiatry and Behavioural Neurosciences, McMaster University; the Director, MacAnxiety Re-

search Centre, McMaster University; and a Psychiatrist, Hamilton Health Sciences.

Address correspondence to Jasmine Turna, BSc, PhD(C), MacAnxiety Research Centre, McMas-

ter University, 1057 Main Street W, L02, Hamilton, ON, L8S 1B7; email: turnaj@mcmaster.ca.

Grant: M. V. A. has received grants from the Hamilton Academic Health Sciences Organization

and the Canadian Foundation for Innovation.

Disclosure: Beth Patterson reports that her spouse is on the speakers bureau for Lundbeck,

Purdue, and Allergen; her spouse is a consultant for Purdue and Allergen; and her spouse has

performed contracted research for Shire, Janssen-Ortho, and Pfizer. Michael Van Ameringen is

on the speakers bureau for Lundbeck, Purdue, and Allergen; is a consultant for Purdue and Aller-

gen; and has performed contracted research for Shire, Janssen-Ortho, and Pfizer. The remaining

author reports no relevant financial relationships.

doi: 10.3928/00485713-20171013-01

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researchers examine alternative putative pathophysiological mechanisms that may be involved in OCD. The connection between the gut microbiome and brain is a novel pathway, and its role in mental health is currently being explored. There is some evidence to suggest that it may play a role in the neurobiological under-pinnings of OCD.

WHAT IS THE GUT MICROBIOME?The human gut microbiome refers

to the collection of microbes and their genetic material in the human gastroin-testinal (GI) tract.2 These microorgan-isms populate the human distal gut and outnumber all remaining human cells by more than 10-fold.3 They serve numer-ous structural, metabolic, and protective functions, and it is believed that a deli-cate balance of these bacteria may con-tribute to overall health.

The composition of the core bacteria is established in early life and begins to resemble the fully formed adult gut microbiome by age 3 years.4 The adult gut microbiome is predominantly stable and dominated by the Firmicutes (spe-cies such as Lactobacillus, Clostridium, and Enterococcus) and Bacteroidetes (species like Bacteroides) phyla.4 Other phyla such as Actinobacteria (Bifidobac-teria), Proteobacteria (Escherichia coli), Fusobacteria, Verrucomicrobia, and Cyanobacteria are also present.5 Many factors affect the relative proportions of the bacteria comprising the microbi-ome. For instance, whether a person was born vaginally or via cesarean delivery, whether they were breast-fed or bottle-fed, his or her diet, medications, and stress have all been shown to alter the presenting gut microbial profile.4

HOW DOES THE GUT MICROBIOME RELATE TO MENTAL HEALTH?

Research has shown that the gut and brain are connected through a system termed the “gut-brain axis,” and the mi-crobiota are thought to modulate this

bi-directional pathway.5-8 Because of the ability of the gut microbiota to alter behavior,5-8 researchers have begun ex-ploring its involvement in neuropsychi-atric conditions. The existing scientific literature strongly supports the theory

that the behavioral influence of the gut microbiota may be regulated by the im-mune system via cytokine release, lead-ing to an inflammatory response.9 Other proposed mechanisms of action include release of gut hormones activating the enteric nervous system and signaling the brain via ascending neural pathways (ie, vagus nerve).10 The final proposed mech-anism involves the inherent ability of these bacteria to produce neurotransmit-ters such serotonin, dopamine, gamma- aminobutyric acid, norepinephrine, and acetylcholine,11 as dysregulation of many of these neurotransmitter systems has been implicated in numerous psy-chiatric conditions.

Animal StudiesTo date, animal studies have repeat-

edly shown that rodent behavioral re-sponses change when the gut microbi-ome is modified. For example, germ-free (GF) mice (those with no commensal in-testinal bacteria) exhibit altered anxiety behaviors compared to conventionally reared mice.5-8 This theory has been fur-thered by exploiting the inherent behav-ioral differences in BALB/c (generally more anxious) and National Institutes of Health (NIH) Swiss mice (gener-ally more exploratory). When GF mice of both breeds are colonized with the

microbiomes of each respective breed, the recipient’s exploratory behaviors become representative of the donor.12 Furthermore, re-establishment of the gut microbiota in GF mice during the early part of life also alters their behavior such that they begin to act similarly to non-GF mice.6,7 This normalization, howev-er, does not apply if the microbiota are reconstituted in adulthood, suggesting that the anxiety response may be pro-grammed during a critical period early in life. Studies using probiotic treatments have also shown reduced anxiety13,14 and depression-like14,15 symptoms in healthy mice, effects that are lost when part of the vagus nerve is removed, suggesting a role for vagal response in the gut-brain axis. Similarly, top-down modulation of the gut-brain axis has also been observed with external stressors (eg, maternal separation, prolonged stressors) affect-ing the composition of the gut micro-biome.16-18 This indicates a role for the hypothalamic-pituitary-adrenal (HPA) axis in the gut microbiome, which is enhanced in GF mice.19 Taken together, these findings suggest a role of the gut microbiome in mental health.

Human Studies The existing dogma surrounding mi-

crobiome research suggests that “dys-biosis” is associated with a diseased state. The extant literature has linked al-terations in the gut microbiota to several physical conditions, including celiac disease,20 obesity,21 inflammatory bowel disease (IBD; ie, ulcerative colitis and Crohn’s disease),22 and irritable bowel syndrome (IBS).23 Interestingly, high levels of comorbid psychiatric symp-toms, particularly depression and anxi-ety, have also been documented in these populations.24 As such, the attention of microbiome research has shifted to psy-chiatric populations.

Presently, the gut microbiome has only been evaluated in clinical popula-tions of patients with autism spectrum

Animal studies have repeatedly shown that rodent behavioral

responses change when the gut microbiome is modified.

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disorder (ASD), major depressive disor-der (MDD), and bipolar disorder (BD). Typically, these studies use 16s ribo-somal RNA pyrosequencing to analyze fecal samples and determine micro-bial profiles, with differences reported in terms of species diversity, alpha- diversity (richness), beta-diversity (dis-similarity measure), and relative abun-dance of operational taxonomic units (OTUs; groups of microorganisms clustered by DNA sequence similar-ity). Compared to healthy children, children with autism have been found to have 10 times more Clostridium type microbes,25-28 in addition to a va-riety of other microbial compositional differences (Figure 1).

Case-control studies have consistent-ly observed microbiota compositional changes in patients with MDD com-pared to healthy controls (HC), notwith-standing the fact that these differences have varied across studies (Table 1).35-38

A recent study also evaluated the gut microbiome in people with BD (n = 116, most taking more than one psychotropic medication) and HCs (n = 64).39 The OTU analysis revealed significantly decreased levels of Fae-calibacterium (phylum Firmicutes, family Ruminoccocae), independent of age, sex, body mass index, and false discovery rate.39

WHY OBSESSIVE-COMPULSIVE DISORDER?

Although no longer classified as an anxiety disorder, anxiety remains a pre-dominant feature of OCD. As a result, much of the aforementioned animal literature regarding anxiety and the gut microbiome may also be applicable to OCD. For instance, our early neurobio-logical understanding of OCD posited that balancing certain neurotransmitters (ie, serotonin, dopamine, and glutamate) accounts for the treatment effects of traditional therapies (ie, SRIs and aug-mentative antipsychotic agents).40 The

gut bacteria may be able to alter levels of neurotransmitters, as they are known to produce them. There is also extensive evidence linking the HPA axis and gut microbiome.2 Interestingly, elevated basal activity of the HPA axis has also been noted in OCD, as demonstrated by increased urinary free cortisol,41 and ce-rebrospinal fluid levels of corticotropin-releasing hormone and adrenocortico-tropic hormone,42,43 suggesting a role in OCD. Although preclinical data suggest a role for the gut microbiome in anxiety disorders, the literature specific to OCD is limited. One study revealed that 2 and 4 weeks of pretreatment with a probiotic (Lactobacillus rahmnosus GG) attenu-ated OCD symptoms to the same degree as fluoxetine in an RU24969 (also known as 5-HT1A/1B receptor agonist) mouse model of OCD.44 In healthy people (n = 66), 30 days of daily intake of a probiotic formulation containing Lacto-bacillus helveticus and Bifidobacterium longum has been shown reduce a variety of subscores on the Hopkins Symptom Checklist (HSCL-90), including “obses-sive-compulsive” (P < .05) and global Hospital Anxiety and Depression Scale score (P < .05) compared to placebo.45 Additional lines of evidence that have typically been used to link anxiety and mood disorders and the gut microbiome may also be relevant to OCD. This in-cludes comorbidity with GI conditions and inflammation.

Overlap with Gastrointestinal Illness

As mentioned previously, gut micro-bial dysregulation has been demonstrat-ed in numerous GI conditions. These illnesses are also often paired with high rates of comorbid anxiety and mood dis-orders. However, the prevalence of OCD in these populations may also be signifi-cant.46,47 Whereas one study reported the lifetime prevalence of OCD was no different in their IBS proband versus controls or in relatives of these people,48

another indicated that 74.2% of their IBS sample had an anxiety or depressive dis-order, including OCD.49 A more recent study examining psychiatric disorders in patients with functional bowel dis-orders reported that 85% of the sample was diagnosed with a psychiatric dis-order, the most prevalent being dysthy-mia (25%) and OCD (20%).50 Some lit-erature also suggests that IBS and other functional bowel disorders may also be more prevalent in OCD populations. For instance, one study reported increased prevalence of IBS in their OCD sample (n = 37) (35.1%) compared to age- and sex-matched nonpsychiatric controls (n = 40, 2.5%, P = .00002).51 Similar rates have also been reported in a sample from India in which 26.2% of patients with OCD and 3.5% of the control group had IBS;52 however, rates of IBS in OCD populations may be similar to that of community samples.53 In a sample of children with ASD, children with mixed bowel issues (constipation and diarrhea) were more likely to have parent reports of repetitive or compulsive behaviors and a previous OCD diagnosis as per parental report.54

There may also be overlap between symptoms of OCD and GI conditions, further promoting the involvement of the gut-brain axis in OCD. Patients with IBD have been frequently de-scribed as obsessive, rigid, and com-pulsive.55 “Bowel obsession syndrome” (BOS) has also been used to describe people with an overwhelming fear of bowel incontinence when in public, paired with ritualistic behaviors sur-rounding prevention of such occur-rences. Although not considered a functional gastrointestinal disorder, the clinical characteristics of BOS sig-nificantly overlap with the diagnostic criteria of OCD. Interestingly, these symptoms have also been successfully treated with imipramine or doxepin,56 clomipramine,57 and psychotherapy58-60 in a number of case reports. A single

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Figure 1. Microbial differences observed in people with autism spectrum disorder per varying taxonomic levels.

case report also revealed abrupt onset of OCD in a child with Crohn’s disease without a familial or personal history of OCD.55 No previous exposure to group A beta-hemolytic streptococcal infec-tion was noted, reducing the probability of pediatric autoimmune neuropsychi-atric disorder associated with strep-tococcal (PANDAS) infection. The only determined temporal association to the onset of OCD symptoms was a change in medication from infliximab to adalimumab (two immunomodulat-ing medications) after exacerbation of IBD symptoms. Although the OCD symptoms resolved after 10 days with-out any intervention,55 this highlights the overlap between OCD and GI ill-ness while furthering the suggestion of OCD potentially being immunomodu-lated. Overall, the data suggest that there may be a more substantial link between OCD and GI conditions than

previously thought, promoting the link between OCD and the gut microbiome.

Immune Dysregulation There is much support for the role

of inflammation in neuropsychiatric conditions, including OCD. Some evi-dence draws from PANDAS, a condi-tion where antibodies produced against the streptococcal proteins find targets in the brain leading to inflammation of the basal ganglia and bilateral lentiform nuclei.61 Given the sudden onset, it is thought that the repetitive behaviors may be a result of this neuroinflamma-tion. Increased levels of systemic pro-inflammatory markers (tumor necro-sis factor [TNF]-alpha and eotaxin-3, P < .05) and decreased anti-inflam-matory (interleukin [IL]-8, interferon gamma-induced protein-10, IL-17a, interferon-gamma, IL-10, and IL-12; P < .05) markers have been reported

in patients with PANDAS when com-pared to children who experienced a group A streptococcal infection but did not subsequently develop PANDAS.62 Human leukocyte antigen analysis has also revealed positive association in patients with a diagnosis of pediatric acute-onset neuropsychiatric syndrome (PANS) versus controls, and prevalence rates for arthritis and autoimmune dis-ease (ie, Hashimoto’s thyroiditis, celiac disease, and psoriasis) were 25% and 18%, respectively.63 The average length of PANS flare-up is significantly shorter when treated with nonsteroidal anti-in-flammatory drugs (NSAIDs) or predni-sone.63 Past infection has also been re-lated to future onset of OCD in adults. For example, a large prospective cohort study revealed that intestinal infection (odds ratio [OR] = 1.34, P < .01) was associated with subsequent onset of an anxiety disorder (including OCD).64

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Toxoplasma gondii infection has also been associated with OCD (OR = 3.4, P = .0004).65

Numerous studies have also re-ported an altered inflammatory cy-tokine profile in adult patients with OCD.66,67 The only study evalu-ating primary pediatric OCD re-ported increased levels of IL-17A (P = .03), TNF-alpha (P = .01), and IL-2 (P = 0.02) in patients with OCD than in controls; symptom severity

and illness duration were not signifi-cantly correlated with cytokine lev-els.68 This may be further supported by the finding in patients with early-onset OCD revealing increased pro-duction of inflammatory cytokines by monocytes when stimulated with lipo-polysaccharide (LPS) or dexametha-sone and LPS.69 As such, patients with OCD may possess an intrinsic vulner-ability to monocyte activation, which may generate an increased inflam-

matory response.69 In adult popula-tions, results of studies investigating cytokines are inconsistent; however, many believe that this may be con-sequent to the confounding effects of medications and comorbid conditions (specifically mood disorders, which have been associated with low-grade inflammation) in study populations. For example, a meta-analysis revealed decreased levels of IL-1 beta while showing no differences in levels of

TABLE 1.

Summary of Microbial Differences Observed in Major Depressive Disorder Case-Control Studies

Study Bacterial Difference Significance of Bacterial Changes

Naseribafrouei et al.35

MDD (n = 37)

HC (n = 18)

General underrepresentation of Bacteroidetes phylum

(decreased Bacteroidales [order] associated with MDD)

(P = .05)

Congruent to obese microbiota that, like MDD, have been

associated with low-grade inflammation (no difference in

MDD and HC BMI)

Increased Alistipes (P = .007) and Oscillibacter (P = .03)

(genus)

Alistipes increased in CFS and IBS; associated with inflam-

mation and indole-positive so may influence tryptophan

availability

Oscillibacter produces valeric as final metabolic product,

which structurally resembles GABA and binds GABA

receptors

Jiang et al.36

MDD (n = 46)

A-MDD (n = 29)

R-MDD (n = 17)

HC (n = 30)

A-MDD vs. HC: species diversity increased in A-MDD

(Shannon index)

Increased RA Bacteroidetes (primarily Parabacteroides

and Alistipes), Fusobacteria, and Proteobacteria (P < .05)

Decreased RA Firmicutes and Actinobacteria (P < .05).

Increased diversity usually associated with nondiseased

state, finding unclear

Bacteroidetes: Alistipes (refer to Naseribafrouei et al.35)

Proteobacteria: Increased gut permeability allows for such

invasive gram-negative bacteria into systemic circulation

and presence of these bacteria in gut have been linked to

behavioral changes in mice previously

Firmicutes (Lachnospiraceae family): decreases SCFA pro-

duction, causing intestinal barrier dysfunction

R-MDD vs. HC: Increased RA Firmicutes, Fusobacteria, and

Actinobacteria (P < .05)

Increased RA Bacteroidetes and Proteobacteria (P < .05)

Negative correlation between RA Faecalibacterium and

MDD symptoms (P < .05)

Atypical antipsychotic use was widespread among patients;

a previous animal study demonstrated similar results where

chronic antipsychotic administration increased Firmicutes

and decreased Bacteroidetes (Davey et al.95)

Zheng et al.37

MDD (n = 58)

HC (n = 63)

Increased RA Actinobacteria and decreased Bacteroidetes

(P < .01)

Findings conflict with Jiang et al.,36 and appear to be driven

by disturbances of microbial genes and host metabolites

involved in carbohydrate and amino acid metabolism;

however, FMT of MDD samples into GF-mice revealed onset

of depression-like behaviors 2 weeks post-FMT

Aizawa et al.38

MDD (n = 43)

HC (n = 57)

Significantly increased Bifidobacterium counts

(P < .012) and decreased Lactobacillus counts (P < .067)

than controls

Bifidobacterium and Lactobacillus thought to have benefi-

cial effect on stress response and MDD

Abbreviations: A-MDD, active MDD; BMI, body mass index; CFS, chronic fatigue syndrome; FMT, fecal microbiota transplant; GABA, gamma-aminobutyric acid; GR, germ free; HC, healthy controls; IBS, irritable bowel syndrome; MDD, major depressive disorder; RA, relative abundance; R-MDD, responding MDD; SCFA, short chain fatty acid.

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IL-6 and TNF-alpha between cases and controls, suggesting a noninflam-matory profile.70 However, a stratified subgroup analysis revealed moder-ating effects of age and inclusion of patients on pharmacological treatment and with comorbid mood disorders.70 A recent study in drug-naïve, comor-bidity-free patients with OCD revealed increased plasma levels of IL-2, IL-4, IL-6, IL-10, and TNF-alpha compared to age- and sex-matched controls, suggesting immune dysregulation as increased levels of the anti-inflam-matory cytokine IL-10 may have been in response to an overall proinflam-matory cytokine profile.71 A positive association between some autoim-mune conditions (systemic lupus ery-thematosus, thyroid dysfunction, and multiple sclerosis) and OCD has also been suggested.72 Although circulat-ing cytokines do not provide a clear picture of increased inflammation in OCD, these bodies of evidence further the role of immune dysregulation, and as an extension, the inflammatory re-sponse in OCD.

Beyond this, the role of inflam-mation in OCD may also be support-ed by treatment response observed in trials using immunomodulating compounds. In a 28-week crossover, randomized controlled trial (RCT), intake of Trichuris suis ova (stud-ied in autoimmune disorders) in pa-tients with ASD was shown to reduce scores on the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) compul-sion subscale (d = 0.52).73 Adjuvant celecoxib (200 mg twice daily), a NSAID, has also been shown as su-perior to fluvoxamine monotherapy (200 mg/day) after 10 weeks of treatment while also having an ear-lier response.74 Similarly, an ear-lier study had shown adjunctive ce-lecoxib (200 mg twice daily) was superior to 8 weeks of fluoxetine (20 mg/day) monotherapy.75

WHAT DOES THIS MEAN FOR TREATMENT?

At the present time, there are no published studies evaluating the gut microbiome in OCD. As such, we can only consider theoretical treatments that either alter the gut microbiota or have shown promise in conditions in which microbial disruption has

occurred. Potential therapies include antibiotics, probiotics, and fecal bio-therapy.

Antibiotics With the ability to eliminate micro-

bial pathogens, antibiotic treatment can dramatically alter the gut microbi-al landscape both in the short and long term, in part by reducing bacterial den-sities.76 Given that microbiome dysbio-sis does not preclude the overgrowth of certain microbial components at the root of any observed dysbiosis, antibi-otics targeting a given class of bacte-ria could theoretically offer benefit by “normalizing” the microbial profile.

The extant literature supports the use of antibiotics in ASD, MDD, and BD, conditions in which microbial dysregulation has been identified. In one study, 8 weeks of open-label treat-ment with vancomycin (500 mg/d) in children with regressive-onset autism (n = 11) revealed short-term improve-ments in communication and behavior.34 Like imipramine, the tetracycline anti-biotic doxycycline was shown to reverse

LPS-induced behavioral effects (ie, depressive behavior) in mice.77 Similar-ly, minocycline is known to alter gluta-mate transmission and has a regulatory effect on proinflammatory cytokines. It has also been evaluated in psychiatric conditions revealing antidepressant ef-fects when used as a monotherapy in patients with HIV with mild-to-mod-erate depression,78 as an adjunctive therapy in patients with unipolar psy-chotic depression,79 and in rats based on the forced swim test.80 Eight weeks of open-label adjunctive treatment with minocycline also revealed significant changes in the Montgomery-Asberg Depression Rating Scale in bipolar I or II disorder patients in the midst a major depressive episode.81

When considering antibiotics as a treatment for OCD, much support stems from PANDAS, where system-atic evidence alludes to their ben-efit in acute episodes.82 However, open-label83 and RCT84 data suggest that the therapeutic benefits of mi-nocycline may also translate to non-PANDAS OCD. In a 10-week RCT, minocycline adjunctive to fluvox-amine in moderate-to-severe OCD (n = 51) revealed significant-ly higher rates of remission, par-tial (≥25% reduction in Y-BOCS score) and complete response (≥35% reduction in Y-BOCS score) (P < .001) than placebo (n = 51).84 With antibiotics eliciting anti-inflammatory effects and symptomatic relief achieved in psychiatric conditions in which mi-crobial dysbiosis has been suggested, it is possible that these effects may be regulated by the microbiome.

ProbioticsProbiotics are live microorganisms

that, when administered in adequate amounts, confer a health benefit on the host.85 To date, they have been an ef-fective treatment for a wide range of GI conditions, including IBS and IBD.85

Probiotics are live microorganisms that, when administered in adequate amounts, confer a health

benefit on the host.

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There is much animal data illus-trating the behavioral effects of probiot-ics,13-15,19,86 and some evidence suggest-ing probiotics may ameliorate anxiety and depressive symptoms in primarily healthy populations.87 A 3-week RCT (n = 124) involving daily intake of a pro-biotic milk (containing Lactobacillus casei) or placebo did not demonstrate an overall change in mood or cogni-tion.88 However, lower baseline mood, as per the profile of mood states, revealed greater improvements in the group re-ceiving the probiotic drink than the pla-cebo group (P < .025).88 In addition to improved “obsessive-compulsive” subscores on the HSCL-90, Messaoudi et al.45 also noted improvements in de-pression, anxiety, and paranoid-ideation subscores and urinary free cortisol lev-els in healthy adults randomized to a probiotic formulation containing Lacto-bacillus helveticus and Bifidobacterium longum or placebo. Steenbergen et al.89 had 20 healthy participants consume ei-ther a multispecies probiotic or placebo for 4 weeks and found that the probiotic group had reduced cognitive reactivity to sad mood. Significant pre- to post reduc-tions in anxiety and depressive symp-toms were also reported in a sample of petrochemical workers after intake of a probiotic capsule or yogurt; however, no significant between-group differences were seen post-intervention, as all three groups had reductions in the mean scores on the General Health Questionnaire and the Depression Anxiety Stress Scale.90

Presently there is only one RCT show-ing benefit of a probiotic in patients with MDD.91 In this study, 40 patients with MDD (who met Diagnostic and Statisti-cal Manual of Mental Disorders, fourth edition criteria,92 and had a 17-item Ham-ilton Depression Rating Scale score ≥15) and were randomized to receive a pro-biotic capsule (Lactobacillus acidophi-lus, L. casei, and B. bifidum) or placebo (n = 20) for 8 weeks. At endpoint, those receiving probiotics reported signifi-

cantly lower scores on the Beck Depres-sion Inventory total scores (-5.7 ± 6.4 vs -1.5 ± 4.8, P = .001) compared to place-bo. Significant decreases in serum insu-lin levels (-2.3 ± 4.1 vs 2.6 ± 9.3 μIU/mL, P = .03) and serum high-sensitivity

C-reactive protein concentra-tions (-1138.7 ± 2274.9 vs 188.4 ± 1455.5 ng/mL, P = 0.03) were noted, in addition to an increase in total plas-ma glutathione levels (1.8 ± 83.1 vs -106.8 ± 190.7 μmol/L, P = 0.02).

There are a variety of mechanisms by which probiotics may elicit these ef-fects, many which involve the gut mi-crobiota. Although the exact mechanism of action remains unknown, strains of lactobacilli and bifidobacterium have been shown to produce gamma- aminobutyric acid,24 the primary inhibito-ry neurotransmitter in the central nervous system, and oral administration of Bifi-dobacterium infantis has been shown to increase levels of tryptophan, a precursor to serotonin.15 Based on such evidence, probiotics may act as a direct delivery vehicle for neuroactive compounds. They may also inhibit proinflammatory cyto-kines such TNF-alpha and IL-6, some of which have been implicated in psychiat-ric conditions, including OCD.

Fecal Microbiota TransplantFecal microbiota transplant (FMT),

also known as bacteriotherapy, involves the transfer of fecal microbes from a healthy person to an ailing person.93

Although many patients view this treat-ment negatively, it is has proven to be a reliable an inexpensive option with a low side-effect profile.93 It has been used to mainly treat recurrent Clostridium difficile infections.93 Although there are no existing clinical trials evaluating the effects of FMT in neuropsychiatric con-ditions, this may change as the body of microbiome research in psychiatric con-ditions continues to grow. This notion is supported by the wealth of rodent data suggesting significant changes in im-mune response and behavior after FMT. More interestingly, FMT of pooled fecal samples from five nonmedicated patients with MDD and five healthy controls into GF-mice revealed behavioral differenc-es 2 weeks post-FMT.37,94 Recipients of the MDD fecal samples illustrated more depression-like symptoms compared to recipients of “healthy” microbiota, and the initially observed microbial differ-ences in the stool samples were main-tained.37 This finding promotes the pos-sible involvement of the gut microbiome in neuropsychiatric illness and suggests FMT as a viable treatment option as the relationship between psychiatry and the gut microbiome continues to develop.

CONCLUSIONThe interest in the gut-brain axis and

potential role of the gut microbiome in psychiatry has gained much traction in recent years, as evidenced by the grow-ing scientific literature suggesting dys-biosis in conditions such as ASD, MDD, and BD. Although promising, it should be noted that many of these studies (in particular those for MDD and BD) are accompanied by several limitations. In addition to small sample sizes, much of the existing literature fails to evaluate many factors known to alter the gut mi-crobiome, such as diet and medications, leaving the results muddled with con-founding effects of such variables.

Although the state of the gut microbi-ome in OCD has not yet been evaluated,

The interest in the gut-brain axis and potential role of the gut microbiome in psychiatry has gained much traction in

recent years.

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the substantial preclinical and clinical evidence outlined here suggests that there may be a role for this theoretical relationship. Similar to mood and anxi-ety disorders, rates of comorbid OCD in patients with GI disorders may also be significant. Immune dysregulation has also been demonstrated in OCD and may serve as a potential route of com-munication between the gut microbiota and the brain, as it has also been noted in many illnesses in which microbial alterations have been observed. Over-all, the multifactorial nature of OCD pathophysiology and a lack of putative mechanisms beyond those involving neurotransmitters highlights the dearth of knowledge available to guide new therapeutic advances. As such, there is a need to explore mechanisms beyond these current theories. Although treat-ments targeting the gut microbiome are currently available, the existing state of the literature does not support their use in treating OCD, anxiety, or mood disor-ders. It does, however, shed light on the need to explore the potential role of the gut microbiome in OCD, as this could shape the future of novel therapies for a condition that is highly refractory in nature.

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