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 (10
9 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 (10
9 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.