Microbial Reprogramming in Obsessive–Compulsive Disorders: History
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Contributor:
Ghizlane Bendriss
,
Ross MacDonald
,
Clare McVeigh

Obsessive–compulsive disorder (OCD) is a debilitating mental health disorder characterized by intrusive thoughts (obsessions) and repetitive behaviors (compulsions). Dysbiosis, an imbalance in the gut microbial composition, has been associated with various health conditions, including mental health disorders, autism, and inflammatory diseases. While the exact mechanisms underlying OCD remain unclear, researchers present a growing body of evidence suggesting a potential link between dysbiosis and the multifaceted etiology of OCD, interacting with genetic, neurobiological, immunological, and environmental factors.

  • OCD
  • obsessive–compulsive disorder
  • microbiota
  • gut
  • gut–brain axis
  • probiotics
  • fecal transplants

1. Introduction

Obsessive–compulsive Disorder (OCD) is a chronic mental health disorder characterized by the presence of intrusive and persistent thoughts that cause distress called obsessions; these are followed by compulsions, which are repetitive behaviors or mental acts that individuals feel driven to perform to calm their obsessions [1]. OCD affects approximately 2–3% of the global population and greatly interferes with quality of life, disturbing the daily functioning of an individual, from eating to bathing to walking or even breathing. For example, an individual with OCD can spend thirty minutes closing a door and verifying it is closed, with the hope that the anxiety might be calmed after a certain number of repetitions. The decision making of individuals with OCD is greatly affected, as every decision may be felt as a threat, leading to maximum indecisiveness [2][3][4]. It is a very debilitating disorder that often hides behind another disease or disorder. Indeed, although OCD is now recognized as an independent disorder category, it often occurs with other disorders such as autism, attention deficit hyperactivity disorder (ADHD), depression, general anxiety disorder, eating disorder, hoarding disorder, Tourette syndrome, panic disorder, or schizophrenia [5]. This category includes other disorders such as hoarding disorder, hair-pulling disorder, and skin-picking disorder [6].
The exact mechanisms underlying OCD are not yet fully understood. Research has highlighted several associations, leading to the conclusion that a combination of genetic, neurobiological, immunological, and environmental factors may contribute to its development. Indeed, studies have identified the heritability of OCD through multiple genes such as the serotonin transporter gene (SLC6A4) and the gene encoding the dopamine D2 receptor (DRD2) [7][8]. Also, OCD has been associated with neurobiological changes such as the dysregulation of the cortico-striato-thalamo-cortical (CSTC) circuit. Brain regions involved include the orbitofrontal cortex, the anterior cingulate cortex, and the basal ganglia, as well as dysregulation in neurotransmitters like serotonin, dopamine, and glutamate [6][9][10][11]. In addition, environmental factors, such as childhood trauma, including physical and/or sexual abuse, have been associated with an increased risk of developing OCD. Finally, stressful life events, such as significant life changes or trauma, have been found to precede the onset or exacerbation of OCD symptoms [6][12].
To date, cognitive behavioral therapy (CBT) and pharmacotherapy are the primary treatments for OCD [13][14]. CBT typically involves exposure and response prevention, where individuals are gradually encouraged to face their obsessions while refraining from engaging in their compulsive behaviors. This helps to reduce the anxiety associated with the obsessions and weaken the link between the obsession and compulsion. CBT has been shown to be effective in reducing OCD symptoms and improving overall functioning [14]. On the other hand, selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine, sertraline, and fluvoxamine, are the first-line medications for OCD treatment [13][15]. These medications increase serotonin levels in the brain and help alleviate symptoms. Additionally, combining SSRIs with antipsychotics or glutamate modulators is sometimes used for individuals who do not respond adequately to SSRIs alone [16]. Despite the availability of treatment options for OCD, there are significant limitations that warrant the exploration of novel therapeutic approaches. While these interventions can be effective for some individuals, many patients experience only partial responses to treatment, lingering symptoms, and high rates of relapse [16][17]. CBT is efficient, but each treatment plan is specific to an obsession and does not avoid the appearance of another obsession and compulsion later, which would require another course of CBT. Additionally, there are side effects associated with the use of medication, such as gastrointestinal disturbances and sexual dysfunction, which can further impact treatment adherence and quality of life [18].
The limitations of current treatment options emphasize the need for innovative and therapeutic approaches that target the etiology of OCD. To date, several factors have been proposed to contribute to the development of OCD, and it is difficult to point to one single cause. Nevertheless, there is one emerging avenue of investigation that presents itself as promising and key for the understanding and treatment of OCD: the gut microbiota. The gut microbiota comprises trillions of microorganisms residing in the gastrointestinal tract, from bacteria to fungi to viruses, archaea, and protozoa. These microbes outnumber human cells by a factor of 10, and the genes they express form the microbiome [19]. These are usually classified into three categories according to their interaction with their human hosts: beneficial, pathogens, and commensal microbes. Because they control each other’s growth, eubiosis (the undefined but balanced composition of the gut microbiota) is essential to prevent the overgrowth of pathogens or a lack of growth of certain beneficial microbes from lacking. In contrast, dysbiosis refers to an imbalance in the composition or function of the gut microbiome. It can occur when there are changes in the relative abundance of certain microbial species or alterations in the overall diversity, resulting in the alteration of the metabolites produced by the microbiota. Dysbiosis has been associated with various health conditions, including metabolic disorders, mental health disorders, autoimmune diseases, and inflammatory bowel diseases [20][21][22][23][24][25][26][27][28][29][30][31][32][33]. Interestingly, dysbiosis has been associated with all disorders where OCD has been found as a comorbidity such as autism, Tourette Syndrome, anxiety disorders, panic disorder, eating disorders, depression, and hoarding disorder but also gastrointestinal diseases such as ulcerative colitis and Crohn’s disease [34][35][36].

2. Mechanisms of the Microbiota–Gut–Brain Axis (MGBA)

The MGBA refers to the bidirectional communication between the gut microbiota, the gastrointestinal tract, and the central nervous system (CNS). From brain to gut, endocrine systems such as the hypothalamic–pituitary–adrenal and hypothalamic–pituitary–gonadal axes regulate the gut microbiota [37][38][39]. From gut to brain, the gut microbiome, consisting of microbes, their genomes, and their products, can influence brain function through a variety of mechanisms, summarized in Figure 1. Researchers will describe these below as (1) the endocrine pathway; (2) the nervous pathway; and (3) the immune pathway.
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Figure 1. Mechanisms of the MGBA. Gut microbes in the gut lumen produce SCFAs, neurotransmitters, precursors, and defensins but also toxins. Microbial products can thus modulate gut permeability and immune function, endocrine secretions, and the vagal function of the brain.

3. Microbial Reprogramming Strategies

3.1. Prebiotics, Probiotics, and Postbiotics

If dysbiosis is a central element in the development of OCD, then it would be expected that the manipulation of the gut microbiota might influence its occurrence and offer potential options for its treatment. This does in fact appear to be the case, researhers gather clinical evidence of the use of probiotics and fecal microbiota transplants in the treatment of OCD.
A probiotic is a live organism that, when ingested in adequate amounts, exerts a health benefit on the host [40]. Probiotics use dietary fibers or resistant starch as nutrient sources (or prebiotics) to produce beneficial metabolites (postbiotics). The term synbiotic is used to refer to the mixture of both prebiotics and probiotics [41]. Dietary fibers and resistant starch, therefore, play an essential role in fermentation and postbiotic production [42][43][44]. Westernized diets are characterized by a relatively low intake of dietary fiber, which could explain the presence of dysbiosis in most modern diseases and disorders. Dietary fibers also include plant-based carbohydrates, such as polyphenols, and non-carbohydrate compounds, such as lignin. Probiotics such as Lactobacillus, Bifidobacterium, and Akkermansia can use these compounds to produce SCFAs, which, in turn, promote various beneficial effects in the host [45][46][47][48][49][50][51].
Over the last decade, a number of studies have shown promising results for the use of probiotics in the treatment of OCD. However, while a growing number of studies have investigated the potential value of probiotics in treating autism and ADHD, investigations of probiotic interventions for OCD are still at their very early stages, with most studies being performed on animal models.
Kantak et al. (2014) found that two-week pretreatments with Lactobacillus rhamnosus GG had the ability to reduce obsessive–compulsive disorder in mice. The results were comparable to treatment with fluoxetine [51].
In 2018, Tabouy et al., using Shank3 KO mice (a model used to study neurodevelopmental disorders such as autism), found Lactobacillus reuteri to be in a decreased relative abundance in the Shank3 KO. The treatment of Shank3 KO mice with Lactobacillus reuteri induced a significant decrease in repetitive behaviors in both males and females [52].
In a study conducted by Szklany et al. (2020), male mice receiving (from the day of birth onwards) a prebiotic mixture composed of short-chain galactooligosaccharides (scGOS) and long-chain fructo-oligosaccharide (lcFOS) exhibited changes in the serotonergic system [53]. These neurological modulations were associated with behavioral changes, such as a reduction in anxiety and repetitive behavior during development and increased social interest in adulthood compared with mice fed a control diet. The brains of the treated group exhibited altered mRNA expression in astrocytic glial fibrillary acidic protein and microglial integrin alpha M. There was also enhanced mRNA expression in BDNF in the prefrontal cortex. Additionally, analysis of the cecal content of the treated animals revealed relatively increased levels of SCFA, such as butyric acid, and decreased levels of valeric, isobutyric, and isovaleric acid [53].
Another animal study conducted by Sanikhani et al. (2020) demonstrated the effectiveness of Lactobacillus casei Shirota in treating OCD in a rat model. After daily administrations of L. casei Shirota (109 CFU/mL for four weeks), the probiotic showed beneficial effects, possibly effected through the modulation of genes related to serotonin. Following concurrent treatment with L. casei Shirota and fluoxetine, the expression level of Bdnf significantly increased, while the expression of Htr2a (serotonin receptor 2A) decreased in the orbitofrontal cortex tissues of all rats involved in the study [54].
In 2021, Sunand et al. [55] found that selected probiotic strains and complex treatments with probiotics significantly ameliorated microbial diversity; repetitive behaviors; and the concentrations of NF-a, BDNF, and 5-HT.
In 2022, Alghamdi et al. [56], using an animal model of autism induced by propionic acid, found that subjects with cognitive dysfunction had altered levels of neurotransmitters in their brains. However, in the group of animals treated with probiotics, neurotransmitter levels were 1.2-fold higher compared with the control group. In the same study, the alpha-melanocyte-stimulating hormone (α-MSH) was monitored. α-MSH acts on melanocortin type 4 receptors (MC4R), a receptor that interacts with neurochemical systems that regulate socioemotional behaviors, including oxytocin and dopamine. Oxytocin can influence social cognition by modulating various neurochemical systems, including serotonin, glutamate, dopamine, and GABA neurotransmitters in specific brain regions, such as the hypothalamus, amygdala, and hippocampus. The study observed significantly lower levels of α-MSH in animals treated with propionic acid compared with the controls. However, this effect was reversed by the administration of bee pollen and a mixed probiotic bacteria preparation called ProtexinR, which contains beneficial bacteria such as Bifidobacterium infantis, Bifidobacterium breve, Lactobacillus acidophilus, Lactobacillus bulgaricus, Lactobacillus casei, Lactobacillus rhamnosus, and Streptococcus thermophiles. The concentration of the mixed probiotic bacteria in ProtexinR was 1 billion CFU per gram [56].
Pochakom (2022) investigated supplementation with Lacticaseibacillus rhamnosus HA-11 (Lr) and Ligilactobacillus salivarius HA-118 (Ls) in the BTBR T+ Itpr3tf/J (BTBR) mouse model of autism (109 CFU/mL in drinking water for 4 weeks) [57]. Supplementation with Lr, but not Ls, increased the microbial richness and diversity and increased the concentrations of beneficial neuroactive compounds, such as 5-aminovaleric acid and choline. Both the Lr and Ls treatments reduced behavioral deficits in social novelty preference, but no changes in hyperactivity or repetitive behaviors were observed [57]. This suggests that not all probiotic microbes result in the same outcomes, and a more complex mix of microbes might actually be required to target various behaviors.
Sen et al. 2022 [58] found that the daily oral administration of Blautia stercoris MRx0006 attenuated social and repetitive behaviors in a mouse model of autism. The study showed that MRx0006 increases the expression of oxytocin and its receptor in hypothalamic cells in vitro and hypothalamic oxytocin mRNA in mice while altering the metabolome profile. It was proposed that biotherapy using Blautia stercoris would be a viable treatment option for autism.
Studies on human subjects are rarer but encouraging. A double-blind randomized controlled trial focused on the effect of a synbiotic called Synbiotic 2000, composed of three anti-inflammatory lactic acid bacteria and four anti-inflammatory fibers, on patients with ADHD [40]. One of the measured outcomes was repetitive behavior. Synbiotic 2000 reduced both the total score of autism symptoms and restricted, repetitive, and stereotyped behaviors, as compared with a placebo [52]. Similarly, in a case report on a child with autism, Sacharomyces boulardii was shown to reduce OCD behavior [59].

3.2. Fecal Microbiota Transplants

Fecal microbiota transplantation (FMT), or the transfer of fecal matter from a healthy donor to a patient, has emerged as another promising therapeutic approach for restoring a healthy gut microbiome and achieving beneficial effects in various diseases [60]. Currently, there are no FMT studies that have been performed specifically to treat OCD. However, several studies have noted significant changes in microbial ecology, metabolism, and behavior observed in patients after FMT, most of them providing strong support for FMT as a therapeutic method to treat OCD [61][62][63][64][65][66].
Kang et al. (2017) published an important follow-up after the publication of the first clinical trial results using FMT on autistic children [67]. Spectacular improvements were observed in GI symptoms, autism-related symptoms, and gut microbiota diversity with a higher abundance of Bifidobacteria and Prevotella, and these were sustained after two years [61]. The autism-related symptoms even exhibited further improvement, suggesting that the fecal transplants might have initiated further changes during the two-year period. These findings underscore the long-term safety and effectiveness of FMT as a potential therapy for gut-dysbiosis-associated disorders. Although the focus of the study was not OCD behavior, it is particularly relevant considering the close relationship between gut dysbiosis and brain dysfunction. For example, Kilinçarslan et al. (2020) found that the severity of several factors, including obsession, decreased after FMT in patients with inflammatory bowel disease [68]. This suggests that the restoration of a healthy gut microbial community through FMT can have positive effects on psychological symptoms associated with certain diseases. Alghamdi et al. (2022) conducted a study in a rodent model of autism and included the use of FMT from healthy donor rats, which resulted in a significant increase in α-MSH levels by 2.7 fold (compared with 1.2 fold for probiotics) and an increase in the brain levels of neurotransmitters (1.6 fold) and substance P (2.2 fold) to above that of the controls [56]. These results suggest that FMT might be superior to probiotics in initiating metabolic changes; however, further clinical studies are needed to compare both the efficacy and safety of FMT and probiotics.
Although not focusing on OCD but on autism, a very interesting recent study by Wang et al. (2023) highlights important changes after fecal transplants [69]. Fecal microbiota samples from ASD children and healthy donors were transplanted into a mouse model of ASD. The researchers conducted 16S rRNA gene sequencing on fecal samples and untargeted metabolomic analysis on samples to identify differences in gut microbial communities and metabolic pathways related to ASD behaviors. mRNA sequencing analysis was also performed on colon and brain tissues after sacrificing the animals to identify enriched signaling pathways and potential molecular mechanisms. The study revealed metabolite changes related to serotonergic and glutamatergic synapse pathways. They also demonstrated that these were associated with behavioral changes in ASD: there was an increase in ASD-like behaviors in mice that received FMT from ASD donors but a decrease in such behaviors in mice that received FMT from healthy donors. Indeed, the colonization of certain bacterial genera, such as Bacteroides, Odoribacter, Turicibacter, and Alistipes, was correlated with an improvement in behavior after FMT, but this did not specifically point to OCD behavior. However, the changes in serotoninergic and glutamatergic pathways might also predict positive outcomes for future OCD studies.
The close link between gut dysbiosis and brain function underscores the importance of targeting the gut microbiota for therapeutic interventions. FMT offers a unique opportunity to restore a healthy gut microbial community and potentially alleviate symptoms associated with various disorders. These findings highlight the potential benefits of FMT in improving mental health conditions and support the further exploration of this therapeutic approach.

This entry is adapted from the peer-reviewed paper 10.3390/ijms241511978

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