Oral Methods of Microbiota Manipulation for Depression Symptoms: A Systematic Review: Méthodes orales de manipulation du microbiote pour traiter les symptômes de dépression : Une revue systématique

Abstract

French

Objective

The effectiveness of current treatment options for depressive symptoms has been widely investigated with acknowledgment that some patients were either not adequately responding to treatment, finding the existing treatment intolerable, or otherwise prefer alternative options. There is increasing interest in microbiota modulation as an alternate form of depression treatment, with a growing number of trials and reviews on the subject published in the last five years. This systematic review aimed to analyze all completed randomized control trials (RCTs) that assessed depression symptoms in adults not using antidepressants, before and after oral methods of microbiota manipulation.

Method

All completed parallel-arm RCTs that assessed depression symptoms in adult participants before and after oral methods of microbiota manipulation were retrieved from four databases, MEDLINE, Embase, PsycINFO, and Cochrane Central Register of Controlled Trials. Data on study and intervention characteristics as well as RCT conclusions were collected independently and in duplicate, and each study's findings were summarized individually. Risk of bias was completed.

Results

We included 66 RCTs in our review, 34 of which concluded significant differences between the intervention and control group in depressive symptom using different interventions and measures. Of the 66 trials, 54 used probiotic interventions, seven used prebiotic, eight used synbiotic and two used oral fecal microbiota transplantation. Wide variation was observed in studies’ design, intervention composition and consumption methods across all 66 RCTs. No statistical synthesis or meta-analyses were possible due to the wide variety of interventions, measures and outcomes.

Conclusions

The heterogeneity of the existing RCTs did not allow for concrete conclusions on whether oral microbiota manipulation interventions are viable alternative treatment options for adults experiencing depression symptoms. We encourage the development of standardized guidelines for the design and reporting of microbiota studies in depression for the possibility of future intervention efficacy testing.

Graphical abstract

This is a visual representation of the abstract.

Keywords

depressive disorders systematic reviews randomized controlled trial microbiota

Introduction

Depressive symptoms are commonly treated with effective interventions,¹ however tolerability challenges and patients’ preferences for alternatives to pharmacotherapies have been seen. Such alternatives included microbiota manipulation² in depression.^3,4

The gut microbiota, the microorganism population within the human gastrointestinal tract, is a dynamic, individually unique and complex system that has been found to affect nearly every aspect of the body and development.² Various factors affect gut microbiota makeup including infant delivery and feeding, age, diet, medications, stress, and geographical location.⁵ An individual's microbiome is involved in overall health, metabolism, digestion, immune system function and protection, as well as central nervous system development.⁶ The health and composition of the gut microbiome is crucial for the maintenance of the other body systems. Significant differences in microbial composition have been found when comparing patients with healthy controls in a variety of illnesses including inflammatory bowel disease, cancer, obesity, as well as depression^4,7 Dysregulated gut microbiota has been linked to the development of gastrointestinal inflammation, cardiovascular and respiratory illnesses, and neuropsychiatric disorders, like depression and anxiety.^8,9

Microbiota manipulation is a process that aims to alter one's microbiota population, composition, and metabolic output,¹⁰ the most common methods included dietary changes (e.g., anti-inflammatory diet, ingestion of fermented foods), fecal microbiota transplantations (FMTs), and probiotic, prebiotic or synbiotic consumption.^8,11 The terminology for the varying methods of oral microbiota manipulation is often inconsistently described and not clearly defined, though there are a few notable differences between them. FMT consists of the replacement or integration of one individual microbiota into another individual, transferring fecal microbiomes of healthy individuals into ill individuals in hopes of repairing the assumed imbalanced native microbial composition.¹² There are several methods to introduce FMT in humans including oral capsules to be ingested by the individual, gastric tube, colonoscopy insertion or endoscopy through oesophagogastroduodenoscopy.¹³ The focus of this review is on the oral capsules.

Other oral microbiota manipulation methods include probiotics, prebiotics and synbiotics. Probiotics can fall under the classification of a dietary supplement and are defined as microecologics, strictly selected live strains of microorganisms that are used to help with whole-body immunity, intestinal flora structure and inhibit harmful microorganism overgrowth.¹⁴ While similar to FMT capsules, probiotics are made up of a small and limited number of bacterial cultures, stemming from a variety of locations throughout the human intestinal tract, as well as animal- and plant-based sources as opposed to direct sampling from a donor stool.¹⁵ Prebiotics consist of fibre sourced from non-digestible carbohydrates and oligosaccharides and have been reported to selectively stimulate and modulate the growth and activity of colon microbial species and reduce the severity of gastrointestinal symptoms such as diarrhea and inflammation.¹⁶ Synbiotics^14,16 are a combination of prebiotics and probiotics, mixed in a synergistic manner with the aim of improving the beneficial qualities and survival of both substances. The prebiotic compounds selectively favour the growth and increase the metabolism of probiotic organisms, assisting in their passage through the upper intestinal tract and implantation within the colon.

The relationship between the gut microbiome and the central nervous system, the gut–brain axis, has been studied in great depth¹⁷ suggesting bidirectional communication. This bidirectional communication network extends from the gastrointestinal tract to the central, autonomic and enteric nervous systems as well as the hypothalamic pituitary adrenal axis, linking gut function to the cognitive and emotional centres of the brain.¹⁸ Impacting one another, gastrointestinal symptoms such as indigestion, bloating, constipation and heartburn have been seen to arise with emotional or psychosocial events and disturbances in gut microbiome composition. Decreased microbiota diversity has been linked to the development and worsening of several psychiatric conditions including depression and anxiety.^19,20 With evidence of such a dynamic relationship, there has been an uptake of research examining microbiome manipulation on psychological pathologies and behaviour.^21,22

There has been an increasing interest in microbiota modulation as an alternate form of depression symptom treatment, with a growing number of trials and reviews on the subject published in the last few years.^23–25 These studies included various forms of microbiota including pre, pro and synbiotics, food supplements, and a limited number of trials. The most recent review published in 2023 included only seven trials²⁶ and the review that included FMT was conducted in 2021²³ and identified only one trial thus providing limited data to understand the role of FMT in depressive symptoms. The objective of this systematic review is to identify completed randomized control trials (RCTs) that assessed oral microbiota manipulation intervention in adults with depression symptoms not using antidepressants.

Methods

This review was not pre-registered. We conducted a systematic review following the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA).²⁷ This review included all completed RCTs that investigated methods of oral microbiota manipulation on the depressive symptoms measured using validated depression symptoms scale in adult participants. No Language restrictions were placed on the search strategy (see Supplemental e-Tables 1 and 2 for the inclusion criteria and search strategy). We excluded studies that were not an RCT design; followed a cross-over design; did not exclude participants who were receiving antidepressant treatment; used interventions combined with vitamins or supplements; or used diet manipulation as the primary intervention. We searched MEDLINE (1946 to 08 March 2023), Embase (1974 to 08 March 2023), PsycINFO (1987 to 2023 February) and Cochrane Central Register of Controlled Trials (2023 February) from inception to 9 March 2023. We re-run the search on 22 February 2024, to identify any additional trials. Title and abstract, full-text screening, and data extraction were completed independently and in duplicate by eight reviewers (AO, AM, JS, OS, GH, MB, JA, MH) in Covidence²⁸ following the Cochrane guidelines for systematic reviews.²⁹ Data extraction included study inclusion/exclusion criteria, participants’ baseline characteristics, the measure of depressive symptoms, the type of intervention, the duration, statistical analyses used, limitations and conclusions (see Supplemental e-Table 6: Systematic Review Data Extraction Variables). Each study's results were entered separately in Excel with the aim of synthesizing the data for meta analyses however no meta-analyses were possible due to the diversity of the studies identified. Risk of bias (RoB) was assessed independently and in duplicate by five reviewers (AO, OS, GH, MB, and JA) using the Cochrane RoB Tool. Screening, data extraction and assessment disagreements were resolved through discussion. The reporting of this review follows the PRISMA recommendations. We reported probiotic strain by genus, species, subspecies and alphanumeric designation as directed by the World Gastroenterology Organisation³⁰ and reported study limitations using standardized methods for RCTs.³¹

Results

Study Selection

The search strategy identified 4,979 studies, of which 2,876 were duplicates and were removed by Covidence²⁸ and 31 duplicates were identified manually. The remaining 2,072 articles were screened through title and abstracts, 1,781 irrelevant articles were excluded, leaving 291 articles eligible for full-text screening. Of the 291 articles eligible for full-test screening, 225 studies were excluded, 132 of which were published protocols or ongoing trials with no published results and only one study was published in Farsi that met the inclusion criteria³² focused on patients with hypothyroidism and fatigue and was excluded as it was unclear how depression symptoms were measured including the validation of the scale used. The second most common reason for excluding articles was the presence of a co-existing treatment within the trial or study population (k = 35). We included 66 studies in our systematic review. The study selection flow diagram is presented in Figure 1.

Figure 1.

PRISMA flow diagram.

RoB Assessment

The RoB for studies included in our study is summarized in Supplemental eTable 12 (RoB and eFigure 2: RoB – Robvis Traffic-light Plot, eFigure 3: RoB Robvis Summary Plot). Of the 66 included studies in our review, 16 (24%) were assessed to be at high overall RoB and 23 (35%) were assessed to have some concerns. Randomization was generally deemed to be low for RoB, with only two (3%) studies reported with a high RoB. Assignment to intervention RoB showed 20 (30%) studies with some concerns and three (5%) with high RoB, and adherence to intervention was generally deemed low for RoB (k = 58 low). Missing outcome data had two (3%) studies deemed high for RoB and 19 (29%) with some concerns, and selection of reported result was generally deemed low for RoB (k = 56 low).

Study Characteristics

Each of the 66 studies was found to have unique characteristics, outlined in Supplemental eTable 7. We found that the included studies originated from various countries, the most common countries of studies were Iran (n = 12) and China (n = 6). The sample size of the studies also varied greatly from as low as n = 18 to as high as n = 400 (median n = 59.5). The reporting of participants’ demographics varied across the studies. The lowest mean age reported was 19.4 years, while the highest mean age reported was 77.2 years. Most studies (k = 46) reported a mean or median age less than 50 years old. The percentage of female participants also varied greatly. We found three studies that did not report sex proportion, one study included exclusively male participants, and nine studies included exclusively female participants. Most of the included studies reported a majority (more than 50%) female population (k = 50). The most common population type included in the studies was healthy adults (k = 13), followed by patients with gastrointestinal disorders (k = 9), healthy adults with subclinical depression, anxiety or stress symptoms (k = 8) and psychiatric patients diagnosed with major depressive disorder (MDD) or bipolar disorder (k = 6).

Intervention Characteristics

Of the 66 trials included, 54 used probiotic interventions, seven used prebiotics, eight used synbiotics, and two studies used oral FMTs. All data pertaining to study intervention characteristics are summarized in Supplemental eTables 8 (eTable 8. Probiotic Study Intervention Characteristics), 9 (eTable 9. Prebiotic Study Intervention Characteristics, 10 (eTable 10. Synbiotic Study Intervention Characteristics), and 11 (eTable 11. Oral FMT Study Intervention Characteristics).

For the 54 studies that used a probiotic intervention, the most common method of consumption was a capsule (k = 34), followed by a powder (k = 19). One study used a beverage probiotic intervention. The probiotic studies varied in length; the shortest duration study reported a seven-day time frame, and the longest duration study a six-month time frame. The most common intervention length found amongst the probiotic trials was eight weeks (k = 14), followed by 12 weeks (k = 13). The most common intervention consumption dosing schedule was one dose daily (k = 35), with instructions varying with regards to the time of day to consume the intervention, with or without food, and the amount and/or type of liquid to consume the intervention with. Intervention compositions were also of wide variety with 36 different strains identified, distinctions made by genus, species and subspecies. Many of the trials (k = 32) used multi-strain probiotics, the number of bacterial strains used in an intervention varied from 1 to 14, most trials using a single strain intervention (k = 22) or a combination of two to four strains in their intervention (k = 23). We found that the most common bacterial species used was Lactobacillus acidophilus (k = 23), followed by Bifidobacterium bifidum (k = 18) and Bifidobacterium longum (k = 19). Dosing with regards to colony-forming units was also varied.

For the seven studies that used a prebiotic intervention, the most common method of consumption was a powder (k = 4), followed by delivery through a capsule (k = 1), a gummy (k = 1) and a jelly (k = 1). The prebiotic studies varied in duration; the shortest study reported a three-week duration (k = 1), the majority reported a four-week duration (k = 4), and the longest studies reported an eight-week time frame (k = 2). The intervention composition and consumption schedules also varied greatly across included trials, with each intervention using a unique recipe of dietary fibres and unique dosing instructions.

For the eight studies that used a synbiotic intervention, the most common methods of consumption were a capsule (k = 3) and a powder (k = 5), one study intervention with an unclear delivery format. The synbiotic studies also varied in length; the shortest study reported a six-week time frame, and the longest study a 24-week time frame. The most common intervention length found amongst the synbiotic trials was eight-weeks (k = 3). Intervention compositions varied, each presenting with a unique combination of bacterial strains and dietary fibres. The intervention consumption schedules for the synbiotic trials were for the majority one dose daily (k = 5), instructions varying with regards to time of day, with or without food, and amount or type of liquid to consume the intervention with.

For the two studies that used an oral FMT intervention, both used capsules as their delivery method. The oral FMT studies also varied in length, with one study reporting a three-week time frame and the other a 12-week time frame. The intervention compositions were unique to each study, and the intervention consumption schedules differed in number of capsules per dose and timing of dosage.

Depression Symptoms Outcomes

Table 1 provides the depression outcomes from each study. Thirty four out of 66 trials (total sample size for the 34 trials, n = 2,957) concluded the intervention showed a significant improvement in depression symptom. The baseline depression severity across the studies varied from “healthy” to severe symptoms based on the various measurement scales. Measurement of depression symptoms also varied including up to four scales used in the same study. Most studies used one scale to measure depressive symptoms (k = 37). A total of 34 different scales were used across the 66 studies, the most common depression assessment tool was Beck Depression Inventory II (BDI-II) (k = 16), followed by Hospital Anxiety and Depression Scale (HADS) (k = 11), and BDI (k = 8). The reporting of results was also inconsistent across the studies, with results presented as mean scores at baseline and checkpoints, mean score changes, proportion of participants improved, as well as only visually. The most common study limitations reported were related to outcome measures (k = 54), underpowered studies (k = 30) and study duration limitations (k = 18).

Table 1.

Depression Outcome.

Study	Intervention	Depression severity at baseline	Depression assessment tool	Effective for depression
Ascone 2022	Probiotic	Healthy	BDI-II; BSI	No
Azpiroz 2015	Prebiotic	Healthy	HADS	No
Bai 2022	Probiotic	Healthy; mild	HAM-D	No
Baiao 2022	Probiotic	Mild; moderate	PANAS; PHQ-9	Yes
Barthow 2022	Probiotic	Healthy	DASS-21; SF-36	No
Boehme 2023	Probiotic	Healthy	HADS; PANAS	Yes
Browne 2019	Probiotic	Mild; moderate; severe	EPDS; LEIDS-R	No
Camacho-Diaz 2023	Prebiotic	Moderate; severe	HADS	No
Chahwan 2019	Probiotic	Mild; moderate; severe	BDI-II; DASS-21; LEIDS-R; M.I.N.I	No
Cheng 2023	FMT	Mild	GDS-15; PHQ-9	No
Çİn Aslan 2023<	Probiotic and Prebiotic	Not reported	BDI; SF-36	Yes
Dapoigny 2012	Probiotic	Healthy; mild	HADS	No
Davoodabadi 2021	Probiotic	Mild	BDI	Yes
Dawe 2020	Probiotic	Not reported	EPDS; SF-12-v2	No
Dey 2023	Prebiotic	Healthy; mild; moderate	BDI-II	Yes
Freijy 2023	Probiotic	Healthy; mild	BDI-II; POMS-2-SF; SF-36; WHO-5	No
Guo 2021	FMT	Moderate	HAM-D	Yes
Hadi 2019	Synbiotic	Not reported	DASS-21	Yes
Haghighat 2021a	Probiotic & Synbiotic	Mild	BDI-II; SF-36	Yes
Haghighat 2021b	Probiotic & Synbiotic	Not reported	HADS	Yes
Han 2023	Probiotic	Not reported	CES-D	Yes
Ho 2021	Probiotic	Healthy; mild	BDI-II	Yes
Hulkkonen 2021	Probiotic	Not reported	EPDS	Yes
Inoue 2018	Probiotic	Healthy	PHQ-9	No
Jackson 2023	Prebiotic	Mild; moderate	BDI; PANAS-SF	Yes
Kim 2021	Probiotic	Healthy	GDS-K; PANAS	No
Kouchaki 2017	Probiotic	Not reported	BDI; DASS-21; GHQ-28	Yes
Lee 2021a	Probiotic	Moderate; severe	BDI-II	Yes
Lee 2021b	Probiotic	Healthy	CES-D-K	No
Louzada 2018	Synbiotic	Healthy	GDS-15	No
Lyra 2016	Probiotic	Healthy	HADS	Yes
Majeed 2018	Probiotic	Not reported	CES-D; HAM-D; MADRS	Yes
Marotta 2019	Probiotic	Healthy	BDI-II; LEIDS-R; POMS	No
Matsuura 2022	Probiotic	Healthy	GHQ-28; POMS-2-TMD	Yes
Messaoudi 2011	Probiotic	Healthy	HADS; HSCL-90	Yes
Molavi 2022	Probiotic	Not reported	BDI	Yes
Moludi 2019	Probiotic	Healthy; mild; moderate; severe	BDI-II	Yes
Moludi 2021	Probiotic	Not reported	BDI-II	Yes
Moludi 2022	Probiotic & Synbiotic	Not reported	BDI-II	Yes
Morales-Torres 2023	Probiotic	Healthy	PANAS; RYFF; SF-36; SWLS	No
Mullish 2024	Probiotic	Healthy; mild	HADS	Yes
Murata 2018	Probiotic	Not reported	POMS-2	No
Obermoser 2023	Probiotic	Healthy; mild; moderate; severe	BDI-II; SF-36	Yes
Önning 2023	Probiotic	Healthy; mild	POMS-SF	Yes
Östlund-Lagerström 2015	Probiotic	Not reported	EQ-5D-5L; HADS	No
Papalini 2019	Probiotic	Healthy	BDI; LEIDS-R	No
Patterson 2020	Probiotic	Healthy	DASS-42	No
Pinto-Sanchez 2017	Probiotic	Mild; moderate	HADS; SF-36	Yes
Rahimlou 2022	Probiotic	Healthy	BDI-II; GHQ-28	Yes
Ramezani 2023	Synbiotic	Not reported	BDI-II; SF-36	No
Rao 2009	Probiotic	Healthy	BDI	No
Roman 2018	Probiotic	Healthy	BDI; SF-36	No
Romijn 2017	Probiotic	Mild; moderate; severe	DASS-42; MADRS; QIDS-SRI16	No
Salleh 2021	Probiotic	Healthy	BRUMS	No
Shahrbabaki 2020	Probiotic	Not reported	HAM-D	No
Siegel 2020	Probiotic	Healthy	CES-D	No
Slykerman 2022	Probiotic	Not reported	WHO-5	No
Smith-Ryan 2019	Synbiotic	Healthy	HADS	No
Steels 2023	Prebiotic	Healthy; mild; moderate; severe	DASS-21	No
Steenbergen 2015	Probiotic	Healthy; mild	BDI-II; LEIDS-R	Yes
Vidot 2019	Synbiotic	Not reported	DASS-21	No
Walden 2023	Probiotic	Moderate	BDI-II; LEIDS-R	Yes
Wang 2022	Probiotic	Not reported	HAM-D	Yes
Wang 2023	Probiotic	Mild; moderate; severe	HAM-D	Yes
Watanabe 2022	Probiotic	Healthy	POMS-2	Yes
Zhu 2023	Probiotic	Mild; moderate	HAM-D	Yes

Note. BDI-II = Beck Depression Inventory II; BSI = BritishStandards Institution HADS = Hamilton Anxiety Depression Scale; HAM-D =Hamilton Depression Rating Scale; PANAS = Positive and Negative Affect Schedule;PHQ-9 = Patient Health Questionnaire-9; DASS = Depression Anxiety Scale; SF-36= Short Form Health Survey; EPDS = Edinburgh Postnatal Depression Scale;LEIDS-R = Leiden Index of Depression Sensitivity-Revised; MINI = MiniInternational Neuropsychiatric Interview; GDS = Geriatric Depression Scale;POMS-2 = Profile of Mood States Second Edition; WHO-5 = World HealthOrganization (self- report instrument); CES-D = Center for EpidemiologicStudies Depression Scale; GHQ-28 = General Health Questionnaire; CES D = Centerfor Epidemiologic Studies Depression; MADRS = Montgomery-Asberg DepressionRating Scale; TMD = Temporomandibular Disorders; HSCL-90 = Hopkins SymptomChecklist; RYFF = Ryff Scales of Psychological Wellbeing; SWLS = Satisfactionwith Life Scale; QIDS-SR116 = Quick Inventory of Depressive Symptomatology;BRUMS = Brunel Mood Scale.

Studies With a Diagnosis of MDD

Five trials with sample size varied from n = 40 to n = 79 (total n = 305) investigated microbiota in individuals with MDD.^33–37 Three of these studies^33,35,36 (n = 155) used probiotic intervention and concluded reduction in depressive symptoms while two studies (n = 150) also used probiotic intervention^34,37 did not find a significant difference in depressive symptoms between intervention and control groups. Two studies that showed an improvement in depressive symptoms included individuals with comorbid irritable bowel syndrome.^35,36

Discussion

We identified 66 completed parallel-arm RCTs that assessed depressive symptoms in adults before and after oral methods of microbiota manipulation. Among the 66 studies, we found 54 probiotic intervention trials, seven prebiotic, eight synbiotic and two oral FMT intervention trials. The trial durations varied from two weeks to six months, and the total participant sample size varied from 18 to 400 participants. Although 34 of the studies reported finding significant differences in depression symptom outcomes between the intervention and the control groups, the wide variety in interventions, populations, duration, measurements and outcomes preclude drawing a firm conclusion regarding the efficacy of microbiota for relieving depressive symptoms.

When comparing the studies that concluded significant reduction in depressive symptoms in the intervention group, no obvious differences were seen in demographic details, duration of intervention (except for the two studies of FMT) or total sample size.

However, the symptoms severity at baseline as measured by depressive symptoms scales varied among the included trials. For example, 29 studies reported “healthy” when describing baseline depression symptoms scores, (nine of which reported mixed baseline scores of healthy, mild, moderate and severe), 19 out of 29 of those studies reported no significant effects of the microbiota manipulation on depressive symptoms. Studies that included “mild” and “moderate” depressive symptoms at baseline (k = 14) reported no significant differences between intervention and control in 10 out of 14 studies. Many trials (k = 18) did not report the baseline depressive symptoms severity, 11 of which concluded a significant difference between intervention and control groups.

These findings highlight the need to assess whether initial depressive symptom severity impacts the effectiveness of microbiota manipulation interventions on depressive symptoms.

When looking at the trials’ reporting of significant findings by intervention type, we identified 29/54 (54%) of the probiotic intervention studies, 2/7 (29%) of the prebiotic intervention studies, 4/8 (50%) synbiotic intervention studies, and 1/2 (50%) of the oral FMT intervention studies concluded significant differences in depressive symptoms between the intervention and control groups. The two trials that investigated oral FMT,^38,39 one trial reported a significant effect and the other did not. The main differences between these two studies are the duration of the intervention was longer in the positive trial (12 weeks compared to three weeks) and none were conducted in a primary population of MDD.

It is important to note the common limitations amongst the included trials. The most common limitation across the included studies was the lack of participants’ microbiome analysis before and after intervention. The inclusion of these data in microbiota manipulation trials has many benefits, including more accurate adherence, confirmation of intervention saturation, and the possibility for identification of the most beneficial bacterial strains in composite interventions. While most trials used probiotics, the significance of multi-strain probiotic interventions components remains largely unknown despite the availability of multiple approaches and best practice guidance to analyze the microbiome.⁴⁰

Although the ability of probiotics to modify the gut microbiota and relieve various disease symptoms has been reported, there is evidence of ideal probiotic intervention compositions for condition-specific symptom relief.⁴¹ Therefore, isolated microorganism trials that investigate changes in depressive symptoms must identify specific strains for the effective treatment of depressive symptoms, as well as specific dosing standards. We should highlight that our review did not include RCTs that solely focused on depression patients, and while 47/66 studies reported analyzing the effects of the intervention on depression as a primary outcome, only five trials included MDD participants. This subgroup of trials (k = 5) had modest sample size (minimum n = 40 to maximum n = 79) used PHQ-9, HADS, BDI, MADRS, and HAM-D and two trials included comorbid IBS. Despite having participants with MDD, all used probiotic as the intervention for various durations, these studies provided inconsistent results precluding any recommendations to be made on the use of probiotics in MDD.

The use of prebiotic, synbiotic and oral FMT as microbiota manipulation interventions for depressive symptoms is less common than probiotic interventions.²⁴ while trials have been conducted, there is a need for standardization and more precise analyses of these types of interventions using best practice approach informed by multi-omics for example.⁴⁰ In this review, we identified inconsistency in the composition of the intervention, dosing and consumption schedules, making it difficult to compare the studies and identify whether microbiota manipulation has a promise as a potential intervention for depression symptoms.

The heterogeneity in study methods, including varied intervention composition and dosing, depression symptom measurement tools, and reporting methods, did not allow a quantitative synthesis or meta-analysis to be conducted. The variety in study design also indicates a need for standardized study protocols. Amongst the 66 trials we included in our review, we found the use of 34 different depression symptom rating scales and different methods used to report study findings. While significant differences in sensitivity or specificity have not been established between the various depression rating scales,⁴² the inconsistency in assessment of outcomes and the reporting of the trials makes synthesis of results unfeasible. To allow for meaningful quantitative synthesis and meta-analysis, future studies should follow consensus guidelines when planning, conducting and reporting the results of studies, as well as standardizing intervention duration and increasing trial sample sizes.

The current literature shows a growing interest in testing microbiota manipulations in depression symptoms.^26,43,44 However, like our findings, the published reviews commented on the heterogeneity of the findings and the inability to make conclusive recommendations on the effectiveness of the interventions, urging for the standardization of microbiota manipulation interventions specifically for depression and mood disorders. Our review differs from a recent review²⁴ in several aspects including the focus on depression and depressive symptoms as the outcome, while the previous review included all psychiatric disorders with a confirmed diagnosis. The included studies were not all RCTs, and the included depression studies also included co-interventions such as vitamin B7 and antidepressants, e.g., escitalopram and fluoxetine. Our review excluded co-interventions to distinguish the effects of the microbiota as a stand-alone intervention. While there have been reviews concluding significant effects of probiotic interventions on depressive symptoms,^25,45 the published reviews exclusion criteria did not outline concurrent anti-depressant use, which may have impacted the study findings. Our exclusion of trials that allowed for concurrent antidepressant use and/or vitamin supplementation during the intervention timeline aimed to ensure the effects of microbiota manipulation are independently investigated.

The current study has limitations including potential known or unknown confounding factors such as receiving concurrent psychotherapy or other interventions that were not reported. The lack of trials’ data synthesis and meta-analysis precludes the current study from making firm conclusions on the use of microbiota manipulation in depression. Another limitation of the current review is the lack of pre-registration of the systematic review protocol.

Conclusion

While the topic of this review is accelerating in interest, it is evident that there is a need for further investigations on the effectiveness of oral microbiota manipulation as potential alternatives or additional options for depression symptom treatment. We identified 66 trials, 34 of which reported a significant effect of the intervention on depression symptoms. While these reports seem promising, there are many inconsistencies in studies’ methods, interventions used, reporting and analysis leading to reduced confidence in the overall effects of oral microbiota manipulation on depression symptoms. To enhance the knowledge generated by future studies, standardized protocols regarding depression symptom assessment and reporting, harmonization of criteria and guidelines within the field of oral microbiota manipulation interventions, investigating the individual probiotic strains to isolate the most effective intervention compositions that is disorder specific and identifying equivalent dosing of the interventions would be beneficial and necessary if these interventions translate into clinically impactful treatment options for patients with depression.

Supplemental Material

sj-docx-2-cpa-10.1177_07067437251394369 - Supplemental material for Oral Methods of Microbiota Manipulation for Depression Symptoms: A Systematic Review

Supplemental material, sj-docx-2-cpa-10.1177_07067437251394369 for Oral Methods of Microbiota Manipulation for Depression Symptoms: A Systematic Review by Anna Oprea, Joe Steinman, Grace Huang, Omolara Soyinka, Megan Brookbank, James Abesteh, Maya Hartman, Alannah McEvoy, Joanna C. Dionne, Roumen Milev and Zainab Samaan in The Canadian Journal of Psychiatry

Supplemental Material

sj-xlsx-3-cpa-10.1177_07067437251394369 - Supplemental material for Oral Methods of Microbiota Manipulation for Depression Symptoms: A Systematic Review

Supplemental material, sj-xlsx-3-cpa-10.1177_07067437251394369 for Oral Methods of Microbiota Manipulation for Depression Symptoms: A Systematic Review by Anna Oprea, Joe Steinman, Grace Huang, Omolara Soyinka, Megan Brookbank, James Abesteh, Maya Hartman, Alannah McEvoy, Joanna C. Dionne, Roumen Milev and Zainab Samaan in The Canadian Journal of Psychiatry

Footnotes

Registration and Protocol

The review was not registered and was part of a senior student (AO) final thesis. No protocol was published for this review.

Data Access

Supplementary data are provided in appendices, additional data available by reasonable request.

Author Contributions

All authors contributed to the study question, design, data collection, analysis and writing of the manuscript. AO led the search strategy, data collection, and writing first draft. AO, AM, JS, OS, GH, MB, JA, MH completed screening, data extraction and quality checks. AO, OS, GH, MB, JA completed risk of bias assessment. AM contributed to the study design, data collection form design, and analyses. JD provided expertise on microbiota and interpterion of trials methods and results. RM contributed to the study design, data interpretation and manuscript review. ZS led the study design, implementation, analyses, interpretation, manuscripts revisions and final draft.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

Zainab Samaan holds SEAMO Chair in Research and Innovation from The Southeastern Ontario Academic Medical Organization (SEAMO) and Queen's University. The funder has no role in the study design, interpretation or reporting.

ORCID iDs

Roumen Milev

Zainab Samaan

Supplemental Material

Supplemental material for this article is available online.

References

Lam

Kennedy

Adams

, et al. Canadian network for mood and anxiety treatments (CANMAT) 2023 update on clinical guidelines for management of major depressive disorder in adults: reseau Canadien pour les traitements de l'humeur et de l'anxiete (CANMAT) 2023 : mise a jour des lignes directrices cliniques pour la prise en charge du trouble depressif majeur chez les adultes. Can J Psychiatry. 2024;69(9):641–687.

Thursby

Juge

. Introduction to the human gut microbiota. Biochem J. 2017;474(11):1823–1836.

Foster

McVey Neufeld

. Gut-brain axis: how the microbiome influences anxiety and depression. Trends Neurosci. 2013;36(5):305–312.

Barandouzi

Starkweather

Henderson

, et al. Altered composition of gut microbiota in depression: a systematic review. Front Psychiatry. 2020;11:541.

Cresci

Bawden

. Gut microbiome: what we do and don't know. Nutr Clin Pract. 2015;30(6):734–746.

Jandhyala

Talukdar

Subramanyam

, et al. Role of the normal gut microbiota. World J Gastroenterol. 2015;21(29):8787–8803.

Zhang

Gan

, et al. Impacts of gut bacteria on human health and diseases. Int J Mol Sci. 2015;16(4):7493–7519.

Durack

Lynch

. The gut microbiome: relationships with disease and opportunities for therapy. J Exp Med. 2019;216(1):20–40.

Kim

Guevarra

Kim

, et al. Role of probiotics in human gut microbiome-associated diseases. J Microbiol Biotechnol. 2019;29(9):1335–1340.

10.

Lee

Shen

Hwang

, et al. Targeted approaches for in situ gut microbiome manipulation. Genes (Basel). 2018;9(7):581–588.

11.

Quaranta

Guarnaccia

Fancello

, et al. Fecal microbiota transplantation and other gut microbiota manipulation strategies. Microorganisms. 2022;10(12):2424.

12.

Borody

Campbell

. Fecal microbiota transplantation: techniques, applications, and issues. Gastroenterol Clin North Am. 2012;41(4):781–803.

13.

Lee

Cheon

, et al. Comparing the efficacy of different methods of faecal microbiota transplantation via oral capsule, oesophagogastroduodenoscopy, colonoscopy, or gastric tube. J Hosp Infect. 2023;131:234–243.

14.

Zeng

Shen

, et al. Cutting edge: probiotics and fecal microbiota transplantation in immunomodulation. J Immunol Res. 2019;2019:1603758.

15.

Jan

Negi

Sharma

, et al. Diversity, distribution and role of probiotics for human health: current research and future challenges. Biocatalysis and Agricultural Biotechnology. 2023;53:102889.

16.

Pandey

Naik

Vakil

. Probiotics, prebiotics and synbiotics- a review. J Food Sci Technol. 2015;52(12):7577–7587.

17.

Sherwin

Dinan

Cryan

. Recent developments in understanding the role of the gut microbiota in brain health and disease. Ann N Y Acad Sci. 2018;1420(1):5–25.

18.

Carabotti

Scirocco

Maselli

, et al. The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems. Ann Gastroenterol. 2015;28(2):203–209.

19.

Liu

Peng

Zhang

, et al. Crosstalk between the gut microbiota and the brain: an update on neuroimaging findings. Front Neurol. 2019;10:883.

20.

Winter

Hart

Charlesworth

RPG

, et al. Gut microbiome and depression: what we know and what we need to know. Rev Neurosci. 2018;29(6):629–643.

21.

Bruce-Keller

Salbaum

Berthoud

. Harnessing gut microbes for mental health: getting from here to there. Biol Psychiatry. 2018;83(3):214–223.

22.

Liang

, et al. Recognizing depression from the microbiota(-)gut(-)brain axis. Int J Mol Sci. 2018;19(6):1592.

23.

Hofmeister

Clement

Patten

, et al. The effect of interventions targeting gut microbiota on depressive symptoms: a systematic review and meta-analysis. CMAJ Open. 2021;9(4):E1195–E1204.

24.

Ribera

Sanchez-Orti

Clarke

, et al. Probiotic, prebiotic, synbiotic and fermented food supplementation in psychiatric disorders: a systematic review of clinical trials. Neurosci Biobehav Rev. 2024;158:105561.

25.

Zhang

Chen

Zhang

, et al. Effect of prebiotics, probiotics, synbiotics on depression: results from a meta-analysis. BMC Psychiatry. 2023;23(1):477.

26.

Lim

Yaow

CYL

, et al. Effect of probiotic supplementation on gut microbiota in patients with major depressive disorders: a systematic review. Nutrients. 2023;15(6):1351.

27.

Page

McKenzie

Bossuyt

, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Br Med J. 2021;372:n71.

28.

Covidence systematic review software VHI, Melbourne, Australia. Available at www.covidence.org.

29.

Cochrane. Cochrane handbook for systematic reviews of interventions available: https://www.cochrane.org/authors/handbooks-and-manuals/handbook/current.

30.

Guarner

Sanders

Szajewska

, et al. World gastroenterology organisation global guidelines: probiotics and prebiotics. J Clin Gastroenterol. 2024;58(6):533–553.

31.

Lan

Cheng

Hoang

, et al. Automatic categorization of self-acknowledged limitations in randomized controlled trial publications. J Biomed Inform. 2024;152:104628.

32.

Talebi

Karimifar

Heidari

, et al. The effects of synbiotic supplementation on fatigue management and mental health status in levothyroxine-treated patients with hypothyroidism: a randomized, double-blind, placebo-controlled clinical trial study. Journal of Isfahan Medical School. 2020;38(564):74–84.

33.

Baiao

Capitao

Higgins

, et al. Multispecies probiotic administration reduces emotional salience and improves mood in subjects with moderate depression: a randomised, double-blind, placebo-controlled study. Psychol Med. 2023;53(8):3437–3447.

34.

Chahwan

Kwan

Isik

, et al. Gut feelings: a randomised, triple-blind, placebo-controlled trial of probiotics for depressive symptoms. J Affect Disord. 2019;253:317–326.

35.

Majeed

Nagabhushanam

Arumugam

, et al. Bacillus coagulans MTCC 5856 for the management of major depression with irritable bowel syndrome: a randomised, double-blind, placebo controlled, multi-centre, pilot clinical study. Food Nutr Res. 2018;62.

36.

Pinto-Sanchez

Hall

Ghajar

, et al. Probiotic Bifidobacterium longum NCC3001 reduces depression scores and alters brain activity: a pilot study in patients with irritable bowel syndrome. Gastroenterology. 2017;153(2):448–459. e448.

37.

Romijn

Rucklidge

Kuijer

, et al. A double-blind, randomized, placebo-controlled trial of Lactobacillus helveticus and Bifidobacterium longum for the symptoms of depression. Aust N Z J Psychiatry. 2017;51(8):810–821.

38.

Cheng

Tan

Zhu

, et al. Efficacy of fecal microbiota transplantation in patients with Parkinson's disease: clinical trial results from a randomized, placebo-controlled design. Gut Microbes. 2023;15(2):2284247.

39.

Guo

Lin

Chen

, et al. Dynamic changes of intestinal flora in patients with irritable bowel syndrome combined with anxiety and depression after oral administration of enterobacteria capsules. Bioengineered. 2021;12(2):11885–11897.

40.

Knight

Vrbanac

Taylor

, et al. Best practices for analysing microbiomes. Nat Rev Microbiol. 2018;16(7):410–422.

41.

Ciorba

. A gastroenterologist's guide to probiotics. Clin Gastroenterol Hepatol. 2012;10(9):960–968.

42.

Williams

Hirsch

Anderson

, et al.

A comparison of nine scales to detect depression in Parkinson disease: which scale to use?

Neurology. 2012;78(13):998–1006.

43.

Alli

Gorbovskaya

Liu

JCW

, et al. The gut microbiome in depression and potential benefit of prebiotics, probiotics and synbiotics: a systematic review of clinical trials and observational studies. Int J Mol Sci. 2022;23(9):4494.

44.

Liu

Walsh

RFL

Sheehan

. Prebiotics and probiotics for depression and anxiety: a systematic review and meta-analysis of controlled clinical trials. Neurosci Biobehav Rev. 2019;102:13–23.

45.

Goh

Liu

Kuo

, et al. Effect of probiotics on depressive symptoms: a meta-analysis of human studies. Psychiatry Res. 2019;282:112568.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.31 MB

0.59 MB