Microbial Dysbiosis as an Emerging Pathology of Suicidal Behaviour? A Critical Review,Passing Through Depression to Chronic Pain

Abstract

Background

Suicidal behaviour (SB) is one of the most complex neuropsychiatric conditions, with an etiopathogenesis that remains elusive despite a myriad of studies revealing its multifaceted nature, influenced by various biological, psychological, socioeconomic and cultural factors, usually with complex reciprocal and synergistic interactions. Emerging evidence has recently suggested a potential involvement of pathogens and host-tissue derived microbial species in contributing to SB. This review aims to provide a concise synthesis of clinical evidence focusing on the presence of microbial alterations in subjects with SB and in those exhibiting risk factors for SB, thereby exploring a possible new perspective in suicidology.

Summary

We conducted a surveillance of the literature in the PUBMED database, from its inception to 10 May 2025, to identify associations between infection/microbial alterations with SB and some of its risk factors (by focusing on two pathologic examples of psychiatric and somatic origins, respectively: depression and chronic pain, two often closely related conditions). Major clinical findings were selected and synthesised into a hypothetical framework to support the presence of a microbe-related origin of SB. We found that SB was associated with selected infections, such as Toxoplasma gondii and Cytomegalovirus. Dysbiosis, including changes in diversity and/or abundance of selected microbial species, in the oral cavity, gastrointestinal tract, and other mucosal tissues, was observed in subjects with SB and individuals with psychiatric (depression) and somatic (chronic pain) risk factors of SB.

Key Message

Microbial dysbiosis might contribute to SB etiopathogenesis. Further studies in this emerging field of research are expected to provide additional mechanistic insights for an improved understanding, prevention, and therapeutic management of this neuropsychiatric condition.

Keywords

Microbiome microbiota microbial dysbiosis suicide suicidal behaviour neuropsychiatric diseases depression chronic pain

Background

Suicidal behaviour (SB), which includes suicidal attempts (SA) and completed suicides, is one of the leading causes of death and disability worldwide, with substantial healthcare and socioeconomic burdens. Current treatments for SB primarily focus on pharmacological and psychotherapeutic interventions targeting neuropsychiatric symptoms.¹ Since prevention approaches still show limited efficacy, further research into the complex pathophysiology of SB is needed to facilitate advances in clinical care for affected individuals.

SB etiopathogenesis is a multifaceted phenomenon, influenced by various biological, psychological, socioeconomic, and cultural factors, usually with complex reciprocal and synergistic interactions. In particular, growing evidence suggests links between increased suicide risk and immunological inflammation,² neurometabolic dysregulation³ and various neuropsychiatric conditions,⁴ warranting additional research to further elucidate the mechanisms that contribute to these putative pathological pathways of SB. Additionally, recent discoveries have shown how microbial species can modulate and interact with the immune system,⁵ metabolic tissues⁶ and neurobiological processes⁷ via different molecular and cellular pathways. These findings have ignited scientific and clinical interests in exploring the possible role of microbes in SB pathogenesis.

Many types of microorganisms have developed a symbiotic relationship with humans. These symbionts, including bacteria, viruses, fungi, and protozoa, reside on the mucosal surfaces of the human body, such as the skin, nails, hair, oral cavity, and gastrointestinal/respiratory tracts. Together, they constitute the host microbiome, normally present in an eubiotic state. If there is an imbalance in the relative abundance/composition of microbial species and/or changes in their distribution (quantitative/qualitative changes), the host microbiome is no longer in homeostasis, a condition termed dysbiosis.

Dysbiosis has been shown to contribute to the development of various somatic illnesses,⁸ ranging from immune-mediated conditions, such as allergy and asthma, to metabolic disorders, such as gastrointestinal diseases and obesity. Furthermore, the recent discovery of a gut-brain connectome suggests that dysbiosis may be implicated in neurodegenerative and neuropsychiatric illnesses, including Alzheimer’s and Parkinson’s disease, depression, and potentially SB.⁹

This critical review summarises major clinical evidence for the hypothesis that microbial alterations exist in subjects with SB and in those exhibiting risk factors for SB, by focusing on depression and chronic pain (two closely related conditions of psychiatric and somatic origins, respectively).

Methods

In this critical review, we selected representative clinical studies that could highlight the emerging importance of microbial alterations in the pathophysiology of SB. To achieve this goal, we conducted a surveillance of the literature related to the main topic of this review (i.e., the association between different microbes and SB) in the PUBMED database, using the following keywords: [‘microbe’ OR ‘microbiota’ OR ‘microbiome’ OR ‘dysbiosis’ OR ‘infection’] AND [‘suicidal behavior’ OR ‘suicide’ OR ‘suicidal attempt’ OR ‘suicidal ideation’ OR ‘chronic pain’ OR ‘depression’] from the inception of the database until 10 May 2025. Preclinical studies (those employing animal models of psychiatric illnesses) or those reported in languages other than English were excluded. The content of all studies with human subjects was screened, and major findings from relevant studies were categorically summarised in the sections below to highlight the potential association between infection/microbial dysbiosis with SB and its risk factors.

Infections and SB

Infection-induced neurochemical changes in the central nervous system and inflammatory responses that elevate suicide susceptibility may provide a potential mechanistic explanation for the association between infection and elevated suicide risk.² In this regard, one of the earliest indications of a possible association between microbes and SB was suggested by a correlation between increased suicide risk and Toxoplasma gondii infection in the general population across 20 European countries.¹⁰ A follow-up study revealed that T. gondii seropositivity was significantly associated with increased suicide rates in women, particularly among those at 60–74 years of age.¹¹ In a different study of more than 45,000 participants, violent SA risk and self-directed violence risk among infected child-bearing women were, respectively, 1.81 and 1.53 fold higher than those of non-infected counterparts, with a positive correlation between self-directed violence risk and T. gondii IgG titres.¹² Seropositivity for T. gondii was also associated with suicidal ideation (SI) in women attending primary care clinics.¹³ In this study, T. gondii IgG antibody detection rate was 11.9% in individuals with an SA history compared to a control rate of 8.0%. Furthermore, T. gondii seroprevalence (anti-T. gondii IgG titre >150 IU/mL) was associated with the presence and number (>3) of SA in this patient cohort.¹³

In schizophrenia patients, T. gondii infection has also been linked to SA and SI. For example, T. gondii, but not cytomegalovirus (CMV) or herpes simplex virus 1, seropositivity was significantly associated with SB in a subset of schizophrenics who were younger than 38 years of age.¹⁴ In another study that controlled for age and sex, T. gondii seroprevalence was significantly higher in schizophrenia patients with SA while T. gondii seropositivity was not significantly associated with SA.¹⁵ Furthermore, T. gondii infection and plasma level of kynurenine, a metabolite previously implicated in the pathogenesis of SB,¹⁶ were suggested to have cumulative effects on the risk of non-fatal suicidal self-directed violence among patients with schizophrenia.¹⁷ Of note, among patients with T. gondii seropositivity, those with kynurenine levels of the upper 25th percentile showed a 1.95 adjusted odds ratio for the association between non-fatal suicide history and plasma kynurenine concentration.¹⁷

In patients with depression, latent toxoplasmosis (IgG, but not IgM, seropositivity for T. gondii) was associated with SB. In this regard, participants with T. gondii IgG seropositivity showed a 2.9-fold increase in depression odds and a 6.2-fold increase in odds of having an SA history compared to seronegative counterparts.¹⁸ In another study, T. gondii IgG titre was significantly higher in depressed subjects with SI.¹⁹ Higher T. gondii IgM level and IgM seropositivity for T. gondii (an indicator of acute infection) were also observed in suicide attempters with active depressive symptoms.²⁰ In a post-mortem study of suicide victims, the presence of neuroinvasion by T. gondii (8% in a study of 87 subjects) was associated with a history of depression.²¹ Lastly, higher toxoplasmosis titres were also suggested as an indicator for increased susceptibility to SA among older adolescents receiving antidepressant treatment with selective serotonin reuptake inhibitors.²²

Infectious agents other than T. gondii have also been implicated in the pathogenesis of SB. For example, CMV seropositivity was reportedly associated with SA in a large-scale study of subjects with various psychiatric illnesses (n > 2,500).²³ Similarly, CMV IgG levels were higher among depressed suicide attempters.²⁰ Interestingly, this study also revealed a similar association between CMV seropositivity and SA, which had an intriguing additive effect on the association of T. gondii with SA. Infection during the hospitalisation period was also linked to an increase in suicide risk in a cohort study of more than 7 million subjects.²⁴ Importantly, a dose-response relationship between the number of hospital-related infections and the length of infection-related treatment with suicide risk was observed, with an incidence-rate ratio of 2.9 and 2.38 for having more than 7 infections and having been hospitalised for infection-related treatment for more than 3 months, respectively. Most recently, reports of increased neuropsychiatric complications, including SB, have been described in SARS-CoV-2-infected patients.²⁵ In a study of 115 long COVID-19 patients from France, a significant increase in suicide prevalence was observed at 4 months after intensive-care unit admission.²⁶ In another study of 506 adults with a history of COVID-19 diagnosis from the United States, higher SI and SB scores were documented up to one year after infection.²⁷

It is worth noting that some contradictory findings emerged in other studies regarding the association between infections and elevated suicide risk. For example, a recent study demonstrated that rates of T. gondii seropositivity (including IgG) and seroprevalence were similar between controls and suicide attempters.^{28, 29} A lower rate of SA among schizophrenia patients with Toxoplasma IgG seropositivity as compared to seronegative counterparts was also reported.³⁰ Furthermore, a 15-year longitudinal study found no association between general infection status and the risk of suicidal death.³¹ These discrepancies may be attributed to differences in sample sizes and patient selection criteria, as well as the geographical areas and detection methodologies used among the aforementioned studies. Nevertheless, two recent systematic analyses confirmed a potential association between T. gondii infection and SB.^{32, 33} Lastly, some studies suggested that anti-infectives could be associated with an elevated risk of suicide. For example, in a longitudinal study of more than 15,000 Danish participants with documented self-harm behaviours, anti-infective treatments were linked to an increased risk of self-harm with a hazard rate ratio of 1.8.³⁴ The use of the anti-malaria drug hydroxychloroquine/chloroquine has also been linked to increased risk of suicide, possibly via its cardiac and neuroendocrine toxicities.³⁵ A summary of key findings from the primary studies in this section is provided in Table 1.

Table 1.

Association Between Infection and Suicidal Behaviour.

Study	Participants’ Characteristics	Sample Size	Pathogens	Key Findings
Lester D¹⁰	European, general population	n = 432,974,000	Toxoplasma gondii	Infection was linked to an increased suicide rate
Ling et al.¹¹	European, general population, female	n = 432,974,000	T. gondii	Infection was linked to increased suicide rate in females, particularly those at 60-to-74 years of age
Pedersen et al.¹²	Danish, general population, female	n = 45,788	T. gondii	Infection was linked to increased violent SA among childbearing females
Alvarado-Esquivel et al.¹³	Mexican, general population, female	n = 2,045	T. gondii	Infection/seroprevalence was linked to SA history/number of SA, respectively, among females
Okusaga et al.¹⁴	German, schizophrenia	n = 950	T. gondii	Infection was linked to SA history in those < 38 years of age
Akgül et al.¹⁵	Turkish, schizophrenia	n = 117	T. gondii	Seroprevalence, but not infection status, was linked to SA history
Okusaga et al.¹⁷	German, schizophrenia	n = 950	T. gondii	Infection and plasma kynurenine had an additive effect on increased SA risk
Kamal et al.¹⁸	Egyptian, depression	n = 384	T. gondii	Latent infection was linked to SA history
Bahceci et al.¹⁹	Turkish, depression	n = 100	T. gondii	Latent infection was linked to increased SI
Coryell et al.²⁰	American, depression	n = 96	T. gondii	Infection/seroprevalence was linked to increased SA
Alvarado-Esquivel et al.²¹	Mexican, suicide completers	n = 87	T. gondii	Neuroinvasion was linked to depression
Coryell et al.²²	American, depression	n = 108	T. gondii	Seroprevalence was linked to increased SA risk among antidepressant receivers
Mendoza-Larios et al.²⁸	Mexican, suicide completers	n = 89	T. gondii	Infection was not linked to SA prevalence
Sari et al.²⁹	Turkish, suicide completers	n = 50	T. gondii	Infection was not linked to SA prevalence
Ansari-Lari et al.³⁰	Iranian, schizophrenia	n = 99	T. gondii	Infection was linked to lower SA prevalence
Burgdorf et al.²³	Danish, psychiatric illnesses	n = 2,591	Cytomegalovirus	Infection was linked to increased SA
Gasnier et al.²⁶	French, long COVID	n = 115	SARS-CoV2	Infection was linked to increased suicide prevalence
Woodward et al.²⁷	American, long COVID	n = 506	SARS-CoV2	Infection was linked to higher SI and SB scores after one year
Lund-Sørensen et al.²⁴	Dannish, hospitalised infection	n = 7,221,578	General infection	Infection number and treatment length were linked to increased suicide risk
Lindgren et al.³¹	Finnish, general population	n = 6,250	General infection	Infection was not linked to increased suicide risk
Gjervig Hansen et al.³⁴	Danish, infected	n = 1,300,000	General infection	Anti-infectives were linked to increased self-harm

Note: COVID = coronavirus disease 19, SA = suicide attempt, SB = suicidal behaviour, SI = suicidal ideation.

Microbial Dysbiosis in Subjects with SB

There is already some, yet limited, evidence in the literature regarding the presence of dysbiosis during SB development, which is primarily characterised by spatial alterations of microbiome in these subjects (Table 2). The following section will detail the changes detected in various microbiome compartments in subjects with SB.

Table 2.

Microbial Alterations in Subjects with Suicidal Behaviour.

Study	Participants’ Characteristics	Sample Size	Microbiome Compartment	Key Findings
Miranda et al.³⁶	Post-traumatic stress	n = 38,807	Gastrointestinal	Gastrointestinal dysbiosis was linked to increased suicide risk
Lengvenyte et al.³⁷	French, eating disorder	n = 277	Gastrointestinal	Laxative misuse/usage duration was linked to SA history/current SI
Li et al.³⁸	Chinese, general population	n = 23,621	Gastrointestinal	Dietary Index for Gut Microbiota positively correlated with the co-occurrence of MMD and SI
Chen et al.³⁹	Taiwanese, MDD	n = 140	Gastrointestinal	G-Phascolarctobacterium abundance was linked to increased SI scores
Maes et al.⁴⁰	Thai, MDD	n = 32	Gastrointestinal	Correlation between SB and the abundance of Hungatella/Fusicatenibacter (positive) and Butyricicoccus/Clostridium/ Parabacteroides merdae/Desulfovibrio piger (negative)
Maes et al.⁴¹	Thai, MDD	n = 32	Gastrointestinal	Negative correlation between lifetime and current SB and the abundance of Dorea/Faecalobacterium
Thompson et al.⁴²	American, psychiatric illnesses	n = 100	Gastrointestinal	No correlation between gastrointestinal dysbiosis and SI/SI severity
Ahrens et al.⁴³	American, young adults	n = 47	Salivary	SI was linked to increased abundance of Veillonella and lowered abundance of Streptococcus, Prevotella, Rothia, Alloprevotella, Granulicatella, Porphyromonas, Peptostreptococcus, Stomatobaculum, Gemella, and Solobacterium.
Postolache et al.⁴⁴	American, suicide completers with MDD	n = 15	Post-mortem/brain	Decreased antimicrobial peptide Cathelicidin was linked to suicide
Kaszubinski et al.⁴⁵	American, suicide completers	n = 22	Post mortem/nose, mouth, rectum, ears, eyes	Gemmatales, Sphingomonadales, and Salinisphaerales in the nose were linked to suicide
Zhang et al.⁴⁶	American, suicide completers	n = 188	Post mortem/nose, mouth, rectum, ears, eyes	Microbial profile from nose, mouth, rectum, ears, eyes could identify suicide death from other causes
Javan et al.⁴⁷	American, suicide completers	n = 5	Post mortem/liver, spleen	Total number of microbial species was different in death by suicide compared to other causes
Lutz et al.⁴⁸	Italy, suicide completers	n = 40	Post mortem/ brain, heart, liver, spleen, prostate, uterus	An absolute sequence variant in the family Peptostreptococcacea was linked to death by suicide

Note: MMD = major depression, SA = suicide attempt, SB = suicidal behaviour, SI = suicidal ideation.

Gastrointestinal and oral Microbiomes

The gastrointestinal tract contains the largest number of commensals in the human body. Notably, gastrointestinal dysbiosis has recently been linked to the development of SB in specific vulnerable patient populations. For example, a case-control study examining the electronic medical records of over 30,000 patients with post-traumatic stress disorder found that changes in gastrointestinal bacteria were a significant predictor of the risk of suicide-related events, including both SB and completed suicides.³⁶ Similarly, in a cohort study of patients with eating disorders (n = 277), those with a history of SA exhibited a cumulative increase in laxative misuse, which had previously been linked to a disruption of gastrointestinal microflora.³⁷ Notably, duration of laxative usage in the past 4 weeks was also significantly associated with current SI in these subjects.³⁷

Besides these ‘proof of concept’ clinical studies, alterations in the gastrointestinal microbiome have been implicated in suicide development. In this regard, a study of more than 20,000 participants revealed a striking dose-response relationship between the Dietary Index for Gut Microbiota (a measurement of gastrointestinal microbial diversity) with SI in subjects experiencing major depression,³⁸ supporting the influence of gastrointestinal commensals on the evolution of SI. SI has also been linked to the alteration of specific microbial species in the gastrointestinal tract. In this regard, assessment of faecal microbiome in a study of 140 participants from Taiwan revealed a significant positive correlation between the Beck Suicidal Ideation Scale score with the abundance of g-Phascolarctobacterium, particularly among patients with depressive symptoms.³⁹ Similarly, unique gastrointestinal microbial profiles have been identified in subjects with SB. For example, in patients with major depressive disorder (n = 32), 6 microbial taxa were identified as a putative enterotype with clinical association with SB.⁴⁰ Specifically, Hungatella and Fusicatenibacter were positively associated with SB, while Butyricicoccus, Clostridium, Parabacteroides merdae, and Desulfovibrio piger showed an inverse association. Of note, adverse childhood experiences and the recurrence of depressive symptoms served as predictors of this microbial enterotype. Further, the prediction of current SB could be refined by the presence of this enterotype and of a high-density lipoprotein cholesterol level, the latter being predicted by a unique gastrointestinal microbial profile. In a follow-up study of the same research group, SB were confirmed to be related to a dysbiotic phenotype of the gastrointestinal microbiome among depressed participants.⁴¹ Interestingly, lifetime and current SB showed a negative correlation with pathogenic Dorea and Faecalobacterium. Additionally, these SB features could be strongly predicted (63.5%) by the combinatorial usage of this microbial profile along with immunological (Th1 polarisation) and growth factor (increased vascular endothelial growth factor/stem cell growth factor ratio) alterations. It is also worth noting that no alteration in gastrointestinal microbiome was also reported in a study of 100 psychiatric patients,⁴² which might be attributed to variations in demographic and environmental factors with a strong influence on gastrointestinal microbiome analysis.

To date, only one study has shown an association between SI and dysregulated microbial composition in the oral microbiome, the second largest microbial community in the body after the gastrointestinal tract.⁴³ Since the oral microbiome is influenced by sex, dietary, genetic, and sleep factors, propensity score matching was used to examine potential alterations in oral microbes in more than 30 university students with SI versus control subjects. Salivary microbial analysis showed that SI was associated with alterations in microbial abundance. Specifically, an increased abundance of Veillonella and a lowered abundance of Streptococcus, Prevotella, Rothia, Alloprevotella, Granulicatella, Porphyromonas, Peptostreptococcus, Stomatobaculum, Gemella, and Solobacterium was observed in subjects experiencing SI compared to controls. At the species level, Streptococcus oralis, Prevotella melaninogenica, Fusobacterium periodoncitum, Rothia mucilagniosa, Graulicatella adiacens, Streptococcus parasanguinis, Prevotella nanciensis, Solobacterium moorei, Dialister pneumosintes, Peptoanaerobacter stomatis, and Actinomyces naeslundii were more abundant in controls, while Bacteroides dorei and Fusobacterium naviforme were more abundant in subjects with SI. Furthermore, microbial diversity indices were reportedly reduced in subjects with the cooccurrence of SI and sleep disturbance.

Post-mortem Microbiome

While the previous sections discussed the impact of microbial alterations on living subjects with SB, some studies investigated the post-mortem microbiome in completed suicides. Among one of the first implications of microbial changes in post-mortem tissues of completed suicides was the observation that in the brain samples of depressed subjects who completed suicide, reduced level of the antimicrobial peptide cathelicidin (an indicator of changes in microbiome) was observed.⁴⁴ Subsequently, in an investigation of potential associations between the cause and manner of death with microbial communities from nose, mouth, rectum, ears, and eyes of more than 180 police records involving various causes of death,⁴⁵ three microbial orders, Gemmatales, Sphingomonadales, and Salinisphaerales, from the nose bacterial community were significantly associated with suicidal death. Interestingly, gun-shot suicides were distinguishable from homicides by 10 microbial orders, including Tepidisphaerales, Clostridiales, Rhodobacterales, Pirellulales, Corynebacteriales, Bacteroidales, Reyranellales, Cytophagales, Clostridiales, and Micrococcales. In support of these findings, another study demonstrated that the combinatorial use of post-mortem information from the five aforementioned microbial communities could predict the manner of death (accident vs. natural, homicide, or suicide) with >88% accuracy.⁴⁶ However, unlike the previous analysis, this study showed that death by suicide was associated with a higher abundance of Actinomyces species, likely due to potential changes in microbial communities during different time intervals after death. Besides the tissues examined in the studies above, the Chao1 index of microbial richness (the total number of species) in the liver and the spleen of suicide completers was reported to be significantly different from those of subjects who died by other causes.⁴⁷ In a more extensive investigation of microbial changes in the brain, heart, liver, spleen, prostate, uterus of suicide completers, death by suicide showed a significant inverse correlation with an absolute sequence variant in the family Peptostreptococcaceae.⁴⁸

Microbial Dysbiosis in Subjects with Chronic Pain and Depression

Modulating somatic and psychiatric risk factors of SB might represent a potential pathway by which host microbial alterations could contribute to SB development. This section provides an overview of how dysbiosis might contribute to SB development by focusing on chronic pain and depression, two representative somatic and psychiatric risk factors of SB, respectively.

Chronic Pain

Chronic pain has been defined as ‘an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage’.⁴⁹ Importantly, patients with chronic pain not only showed increased rates of SI, SA, and completed suicide⁵⁰ but also experienced various changes in their microbial repertoires. In this regard, some of the most notable observations of dysbiosis in subjects with chronic pain were reported in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), an etiologically complex disease with a high prevalence of chronic visceral pain co-occurrence (>90%)⁵¹ (Table 3). In ME/CFS, lower diversity of the gastrointestinal prokaryotic, but not eukaryotic, microbes was observed along with the expansion of inflammatory species and involution of anti-inflammatory species.^{52, 53} Specifically, increased gastrointestinal abundance of proinflammatory microbes, such as lactic-acid producing Enterococcus/Streptococcus spp,⁵⁴ Gram-positive anaerobic Lactonifactor and Alistipes,⁵⁵ and Gram-negative Bacteroides and Phascolarctobacterium,⁵⁶ were reported. Decreased abundance of several anti-inflammatory Firmicutes and Lachnospiraceae populations was also observed in ME/CFS patients from three independent studies.^{52, 55, 57} Furthermore, increased pain in ME/CFS patients was associated with decreased abundance of beneficial short-chain fatty acid (SCFA)-producing Faecalibacterium species.⁵⁸ Along with the implication of gastrointestinal dysbiosis in ME/CFS, one study also revealed an increased salivary abundance of Rothia dentocariosa,⁵⁶ a species that has been linked to inflammation and endocarditis.⁵⁹

Table 3.

Microbial Alterations in Subjects with Chronic Pain.

Study	Participants’ Characteristics	Sample Size	Microbiome Compartment	Key Findings
Giloteaux et al.⁵²	American, ME/CFS	n = 48	Gastrointestinal	Decreased diversity of prokaryotic microbes and decreased abundance of anti-inflammatory Firmicutes in ME/CFS
Mandarano et al.⁵³	American, ME/CFS	n = 49	Gastrointestinal	No changes in the diversity of eukaryotic microbes in ME/CFS
Sheedy et al.⁵⁴	Australian, ME/CFS	n = 108	Gastrointestinal	Increased abundance of proinflammatory Enterococcus/Streptococcus spp in ME/CFS
Frémont et al.⁵⁵	Norwegian/Belgian, ME/CFS	n = 43	Gastrointestinal	Increased abundance of proinflammatory Lactonifactor/Alistipes and decreased abundance of anti-inflammatory Firmicutes in ME/CFS
Lupo et al.⁵⁶	Italian, ME/CFS	n = 35	Gastrointestinal/Salivary	Increased gastrointestinal abundance of proinflammatory Bacteroides/Phascolarctobacterium and increased salivary abundance of proinflammatory Rothia dentocariosa in ME/CFS
Nagy-Szakal et al.⁵⁷	American, ME/CFS	n = 50	Gastrointestinal	Decreased abundance of anti-inflammatory Firmicutes and Lachnospiraceae in ME/CFS
Guo et al.⁵⁸	American, ME/CFS	n = 106	Gastrointestinal	Pain severity was inversely correlated with abundance of SCFA-producing  Faecalibacterium
Freidin et al.⁶⁰	Dutch, chronic widespread musculoskeletal pain	n = 113	Gastrointestinal	Decreased diversity in chronic widespread musculoskeletal pain
Reichenberger et al.⁶¹	American, complex regional pain	n = 16	Gastrointestinal	Decreased diversity, increased abundance of Proteobacteria and decreased abundance of Firmicutes in complex regional pain
Gonzalez et al.⁶²	Israeli, complex regional pain	n = 53	Gastrointestinal	Decreased abundance of SCFA-producing species in complex regional pain
Minerbi et al.⁶³	Canadian, fibromyalgia	n = 77	Gastrointestinal	Decreased abundance of SCFA-producing species in fibromyalgia
Nickel et al.⁶⁵	American, Urological Chronic Pelvic Pain Syndrome	n = 233	Urinary tract	Increased abundance of Candida and Saccharomyces in urological chronic pelvic pain syndrome
Ju et al.⁶⁶	Korean, burning mouth syndrome	n = 60	Salivary	Increased abundance of Prevotella and  Alloprevotella in burning mouth syndrome
Bai et al.⁶⁷	Chinese adolescent, migraine	n = 40	Gastrointestinal	Reduced diversity and increased abundance of Bacteroidetes, Actinobacteria, Firmicutes, and Proteobacteria in migraine
Chen et al.⁶⁸	Chinese elderly, migraine	n = 108	Gastrointestinal	Reduced diversity and increased abundance of Firmicutes, and decreased abundance of health-promoting species in migraine
Kopchak et al.⁶⁹	Ukrainian, migraine	n = 50	Gastrointestinal	Reduced abundance of Alcaligenes spp correlated inversely with pain severity and headache frequency in migraine
Yong et al.⁷⁰	Korean, migraine	n = 87	Gastrointestinal	Microbial composition was linked to migraine chronicity, negative association between Agathobacter and migraine severity

Note: ME/CFS = myalgic encephalomyelitis/chronic fatigue syndrome, SCFA = short-chain fatty acid.

Besides ME/CFS, dysbiosis has been observed in other diseases of chronic visceral pain. For example, patients with chronic widespread musculoskeletal pain and complex regional pain syndrome showed reduced gastrointestinal microbial diversity.^{60, 61} In the latter condition, increased gastrointestinal abundance of Proteobacteria and decreased abundance of Firmicutes and other SCFA-producing species were also observed.^{61, 62} Similarly, decreased gastrointestinal abundance of several SCFA-producing bacterial species, including Faecalibacterium prausnitzii, Blautia faecis, Haemophilus parainfluenza, Prevotella copri, and Bacteroides uniformis, was reported in patients with fibromyalgia.⁶³ This dysbiosis profile of fibromyalgia was further supported by urine metabolomic analysis of microbial metabolites.⁶⁴ Of note, changes in microbial compartments other than the gastrointestinal tract are present in diseases of chronic visceral pain. In this regard, a recent study of chronic pelvic pain revealed urinary-tract accumulation of the fungal species Candida and Saccharomyces.⁶⁵ In burning mouth syndrome, higher relative salivary abundance of bacterial species was observed compared to controls, with Prevotella and Alloprevotella as the most abundant genera in the patient group.⁶⁶

Similar to visceral chronic pain, recent findings have implicated a role of microbial dysbiosis in neuropathic chronic pain, such as migraine. In a study of adolescents with this chronic pain condition, reduced gastrointestinal microbial diversity and increased abundance of various phyla (Bacteroidetes, Actinobacteria, Firmicutes, and Proteobacteria) were noted.⁶⁷ Similarly, elderly subjects with migraine also exhibited reduced gastrointestinal microbial diversity, with increased abundance of Firmicutes and depletion of health-promoting species (such as Faecalibacterium prausnitzii, Bifidobacterium adolescentis, and Methanobrevibacter smithii).⁶⁸ Furthermore, gastrointestinal Alcaligenes spp was reportedly reduced in migraine patients compared to controls, and its abundance showed a negative correlation with Visual Analogue Scale pain score and headache frequency.⁶⁹ Interestingly, gastrointestinal microbial composition, but not diversity, was shown to be related to the chronicity of migraine, with a negative association between Agathobacter and migraine severity.⁷⁰ Collectively, these diverse alterations of microbial composition and abundance at different anatomical locations in patients with various chronic pain conditions might support the potential presence of tissue-specific roles of microbes in chronic pain.^{71, 72}

Depression

Most studies suggesting an indirect connection between microbial alterations and SB risk have been conducted in subjects with depression. In this regard, depression-associated dysbiosis is characterised by spatial changes in various microbiome compartments in the human body, most frequently documented in the gastrointestinal microbiome. Comprehensive reviews and detailed descriptions of gastrointestinal dysbiosis in depression have been extensively described elsewhere^73–75 and summarised in Table 4a of this review. In this regard, one of the largest recent systematic reviews (44 studies) showed that the majority of analyses carried out in these studies (68 out of 86 analyses) found no difference in alpha-diversity (i.e., overall diversity of the gastrointestinal microbiome within a sample) between patients with depression and controls, while most of the beta-diversity examinations (13 out of 15 analyses) documented dissimilarity in the gastrointestinal microbiome between the two aforementioned study groups.⁷⁵ In terms of microbial abundance, at the phylum level, the most consistent changes were increases in Proteobacteria (5 out of 6 analyses) and Fusobacteria (3 out of 4 analyses). At the family level, increases in Rikenellaceae (6 out of 7 analyses) and Enterobacteriaceae (4 out of 4 analyses) and a decrease in Ruminococcaceae (9 out of 11 analyses) were commonly observed. At the genus level, major alterations included increases in Eggerthella (7 out of 7 analyses), Alistipes (8 out of 10 analyses), Parabacteroides (9 out of 10 analyses), Enterococcus (3 out of 3 analyses), Lactobacillus (3 out of 4 analyses), Veillonella (4 out of 4 analyses), Flavonifractor (6 out of 6 analyses), and Streptococcus (6 out of 6 analyses) as well as a decrease in Faecalibacterium (11 out of 12 analyses). Besides this phylogenetic investigation, functional consequences of gastrointestinal dysbiosis have also been quantified (9 analyses). The most notable changes were enrichment in glycan metabolism/synthesis, lipopolysaccharide and protein synthesis, and transport/catabolism pathways, along with a reduction in cell motility/secretion and membrane transport in patients with depression as compared to controls.

Several emerging studies also indicated alterations in microbes from tissues other than the gastrointestinal tract in patients with depression (Table 4b). For example, in adolescents with depression, increased abundance, but not overall diversity, of the salivary microbiome was associated with higher depressive symptoms.^{76, 77} In contrast, reduced oral microbial diversity was observed in another study of treatment-naïve adolescents,⁷⁸ suggesting a possible influence of antidepressants on oral microbial profile. Furthermore, in these studies, increased abundance of selected bacterial populations (including the phylum Spirochaetes and its order Spirochaetales; and the genus Neisseria and Prevotella nigrescens)^{76, 77} as well as decreased abundance of various other taxa (including the genera Prevotella, Rothia, Treponema, Schaalia, Neisseria, Solobacterium, Lepotrichia, Fusobacterium, Veillonella, Streptococcus, and Hemophilus)^{77, 78} were observed in subjects with higher depressive symptoms.

Table 4.

Microbial Alterations in Subjects with Depression.

A. Summary of the Most Consistent Observations on Gastrointestinal Dysbiosis
	Participants’ Characteristics/ Study Type	Finding’s Consistency	Microbiome Compartment	Key Findings
McGuinness et al.⁷⁵	Depression/systematic review	79% (68 out of 86 analyses)	Gastrointestinal	No differences in alpha-diversity between controls and depressed patients
McGuinness et al.⁷⁵	Depression/systematic review	86% (13 out of 15 analyses)	Gastrointestinal	Dissimilarity in beta-diversity between controls and depressed patients
McGuinness et al.⁷⁵	Depression/systematic review	83% (5 out of 6 analyses)	Gastrointestinal	Increased abundance of the Proteobacteria phylum
McGuinness et al.⁷⁵	Depression/systematic review	75% (3 out of 4 analyses)	Gastrointestinal	Increased abundance of Fusobacteria phylum
McGuinness et al.⁷⁵	Depression/systematic review	85% (6 out of 7 analyses)	Gastrointestinal	Increased abundance of Rikenellaceae family
McGuinness et al.⁷⁵	Depression/systematic review	100% (4 out of 4 analyses)	Gastrointestinal	Increased abundance of Enterobacteriaceae family
McGuinness et al.⁷⁵	Depression/systematic review	81% (9 out of 11 analyses)	Gastrointestinal	Decreased abundance of Ruminococcaceae family
McGuinness et al.⁷⁵	Depression/systematic review	100% (7 out of 7 analyses)	Gastrointestinal	Increased abundance of Eggerthella genus
McGuinness et al.⁷⁵	Depression/systematic review	80% (8 out of 10 analyses)	Gastrointestinal	Increased abundance of Alistipes genus
McGuinness et al.⁷⁵	Depression/systematic review	90% (9 out of 10 analyses)	Gastrointestinal	Increased abundance of Parabacteroides genus
McGuinness et al.⁷⁵	Depression/systematic review	100% (3 out of 3 analyses)	Gastrointestinal	Increased abundance of Enterococcus genus
McGuinness et al.⁷⁵	Depression/systematic review	75% (3 out of 4 analyses)	Gastrointestinal	Increased abundance of Lactobacillus genus
McGuinness et al.⁷⁵	Depression/systematic review	100% (4 out of 4 analyses)	Gastrointestinal	Increased abundance of the Veillonella genus
McGuinness et al.⁷⁵	Depression/systematic review	100% (6 out of 6 analyses)	Gastrointestinal	Increased abundance of Flavonifractor genus
McGuinness et al.⁷⁵	Depression/systematic review	100% (6 out of 6 analyses)	Gastrointestinal	Increased abundance of Streptococcus genus
McGuinness et al.⁷⁵	Depression/systematic review	91% (11 out of 12 analyses)	Gastrointestinal	Decreased abundance of the Faecalibacterium genus
B. Microbial Alterations in Non-gastrointestinal Tissues
	Participants’ Characteristics	Sample Size	Microbiome Compartment	Key Findings
Simspson et al.⁷⁶	Australian, adolescent depression	n = 66	Salivary	Increased abundance of phylum Spirochaetes, the order Spirochaetales depression, no change in diversity
Wingfield et al.⁷⁷	British, adolescent depression	n = 40	Salivary	Increased abundance of genus Neisseria and the species Prevotella nigrescens and decreased abundance of the genera Prevotella, Haemophilus, Rothia, Treponema, Schaalia, Neisseria, Solobacterium, Lepotrichia, Fusobacterium, and Veillonella in depression, no change in diversity
Zeng et al.⁷⁸	Chinese, treatment-naïve adolescent depression	n = 37	Salivary	Decreased abundance of genera Neisseria, Fusobacterium, Streptococcus, and Hemophilus, and reduced diversity in depression
Zheng et al.⁷⁹	Chinese, adult depression	n = 6,212	Salivary	Reduced diversity was linked to increased risk and severity of depression
Liu et al.⁸⁰	Chinese, adult depression	n = 4,692	Salivary	Reduced diversity was linked to increased risk of depression among patients with insufficient sleep
Malan-Müller et al.⁸¹	Spanish, mental health issues	n = 306	Salivary	Higher abundance of Prevotella histicola was linked to increased depression
Alex et al.⁸²	American, pregnant women	n = 224	Salivary	Increased abundance of the phyla Spirochaetes and Firmicutes and the genera Dialister and Eikenella in depression
Agranyoni et al.⁸³	American, pregnant women	n = 400	Salivary	Decreased abundance of Neisseria genus in depression
Ye et al.⁸⁴	Chinese, depression with obstructive apnoea	n = 28	Salivary	Increased abundance of Actinobacteria in depression was linked to higher IL-6
Hoisington et al.⁸⁵	American, adult depression on treatment	n = 10	Salivary	Decreased abundance of Haemophilus after antidepressant treatment, the increased abundance of Blautia and decreased abundance of Bacteroides were linked to lower depression
Li et al.⁸⁶	Chinese, adult depression	n = 285/309	Salivary/Tongue Dorsum	Causal relationships between Lancefieldella in tongue-dorsum and salivary Eggerthia with depression
Ciocan et al.⁸⁷	French, adult depression	n = 56	Blood	Increased abundance of Janthinobacterium and decreased abundance of Neisseria in recurrent depression

In adults with depression, reduced oral microbial diversity has been linked to increased risk and severity of depressive symptoms,⁷⁹ particularly in those with insufficient sleep.⁸⁰ Regarding specific alterations of oral microbial populations, a positive association between oral abundance of Prevotella histicola and depressive scores was observed.⁸¹ In pregnant women with depressive symptoms, lower oral abundance of several bacterial taxa, including the Neisseria genus, and higher oral abundance of the phyla Spirochaetes and Firmicutes, as well as the genera Dialister and Eikenella, have been reported.^{82, 83} In subjects with comorbid obstructive apnoea, increased salivary abundance of Actinobacteria was also observed, and might be modulated by higher circulating level of the inflammatory cytokine IL-6.⁸⁴ Lastly, antidepressant treatment was linked to a decrease in salivary abundance of Haemophilus, with additional associations between decreased depression scores and the abundance of Blautia (negative correlation) and Bacteroides (positive correlation).⁸⁵

Besides these association studies, a two-sample Mendelian randomisation analysis of salivary and tongue dorsum microbiomes (n > 280) suggested potential causal relationships between Lancefieldella in tongue-dorsum microbiome and Eggerthia in salivary microbiome with depression, with the latter as a potential common risk factor for depression and anxiety.⁸⁶ Lastly, changes in the blood microbiome have been reported recently in patients with recurrent depressive disorder (n = 56).⁸⁷ Compared to controls, patient blood samples exhibited higher and lower proportions of Janthinobacterium and Neisseria, respectively.

Combined with findings of dysbiosis in subjects with chronic pain, these observations of microbial alterations in depression suggest that dysregulation of multiple microbiome compartments might be intimately involved in the development of somatic and neuropsychiatric risk factors of SB and may predispose affected individuals to SB. Although the mechanisms by which microbes modulate the development of neuropsychiatric illnesses were not principally explored in these studies, the diverse findings on specific microbial profiles of subjects with chronic pain, depression and SB are consistent with the shift from health-promoting anti-inflammatory microbial species towards a pathogenic pro-inflammatory microbial state. We speculate that this spatial dysbiosis might result in compromised barrier integrity and subsequent dysregulated mucosal immunity and/or aberrant mucosal surface-brain communication, ultimately resulting in abnormal regulation of signalling cascades that have been implicated in SB development, including inflammatory and/or neurological pathways that promote selected somatic and psychiatric risk factors of SB (Figure 1).

Figure 1.

Dysbiosis as a Putative Contributor to the Development of Suicidal Behaviour. Dysbiosis might contribute to suicidal behaviour by disrupting homeostatic interactions between the mucosal surface and other physiological systems (such as the immune and nervous systems), thereby augmenting various risk factors of this condition, including those of immunological (inflammation) and neurobiological (depression and chronic pain) origins.

Therapeutic Implications

Various therapeutic modalities, including prebiotics/probiotics (microorganisms that, upon consumption, restore beneficial microflora), microbe-associated metabolites, and microbial transplantation, have yielded promising clinical outcomes in the treatment of a wide range of human diseases. In this regard, a probiotic blend of B. lactis Bi-07, L. paracasei Lpc-37, Lactobacillus acidophilus NCFM, and B. lactis Bl-04 with omega-3 fatty acid supplementation could reduce circulating high-sensitivity C-reactive protein, a marker of systemic inflammation, in elderly participants.⁸⁸ Similarly, the combinatorial supplementation of Lactobacillus, Bifidobacterium, omega-3 fatty acid, and vitamin D resulted in a significant suppression of the proinflammatory cytokine IL-6 in obese subjects with chronic low-grade inflammation.⁸⁹ As such, targeting the inflammatory pathway, a biological risk factor of SB, by modifying the microbiome may represent a promising preventative approach.

Similarly, probiotic therapies and faecal transplantation were shown to have a positive impact on chronic pain in subjects with fibromyalgia.^{90, 91} Specifically, probiotic supplementation significantly decreased the Beck Depression and Anxiety Indices as well as the Pittsburgh Sleep Quality Index, while prebiotic supplementation only significantly improved the Pittsburgh Sleep Quality Index.⁹⁰ Several randomised trials also showed that microbiome-targeting therapies provide some psychological benefits for depressed patients.^{92, 93} For instance, a probiotic blend consisting of L. acidophilus, Lactobacillus casei, and Bifidobacterium bifidum provided a significant reduction in Beck Depression Inventory scores for clinically depressed patients.⁹⁴ Additionally, prebiotic intervention with 4G-beta-D-Galactosylsucrose has been reported to improve microbiome diversity and the Global Self-Efficacy Scale scores for patients with depressive symptoms.⁹⁵ Therefore, modulating chronic pain and/or depressive symptoms with microbiome-targeting therapies may provide additional preventative benefits to reduce SB risk.

Limitations

A limitation of this review includes the absence of a systematic approach to assess the quality, strength, or consistency of the findings related to SB and its risk factors, owing to the scarcity of studies in this emerging field of research as well as the lack of standardisation methods/difficulties in evaluating human microbiome in subjects with many SB-related conditions. We anticipate that with further efforts invested in this scientific topic of important public health concern, a more comprehensive systematic review will materialise in the near future. Additionally, while implying that microbe-associated inflammation might contribute to SB development, this review did not provide a detailed proposal on the roles of specific microbial populations in the development of SB. We anticipate that future development of methods to delineate the impact of specific microbes on various physiological processes of the host will clarify their role in SB pathobiology.

Conclusions

Dysbiosis in different compartments of the microbiome may indicate a developing pathology in subjects with SB and in individuals with various risk factors for this condition, such as chronic pain and depression. This concise collection of clinically relevant findings aims to serve as a basis for further research into how microbes modulate the biological and psychological processes involved in SB pathogenesis. By gaining new mechanistic insights into the potential dysregulation of crosstalk between microbes and SB-related pathological pathways, we may be able to develop more effective preventive and treatment approaches for this condition.

Footnotes

Abbreviations

CMV: Cytomegalovirus

COVID: Coronavirus Disease 19

ME/CFS: myalgic encephalomyelitis/chronic fatigue syndrome

MMD: Major Depressive Disorder

SA: Suicidal Attempts

SB: Suicidal behaviour

SCFA: short-chain fatty acid

SI: Suicidal Ideation

Acknowledgements

We would like to express our sincere gratitude to Dr Vasileios Chytas, from the Psychiatric Liaison Department of the Geneva University Hospital (HUG), for his insightful contribution to the revision of this manuscript.

Authors Contribution

Conceptualization: KDN, AC, LM.

Writing—original draft: AC, JA, LM, DS, KDN.

Writing—review & editing: AAm, AAg, AP.

Supervision: GS, MA.

Availability of Data and Materials

Not applicable.

Consent for Publication

Not applicable.

Statement of Ethics

Not applicable.

Declaration of Conflicting Interests

KDN is the scientific founder of Tranquis Therapeutics, a biotechnology company that develops novel treatments for neuro-inflammatory and neurodegenerative diseases. KDN is also a scientific advisor for Tochikunda, a biotechnology company that develops SARS-CoV-2 diagnostic devices. All other authors declare no conflict of interest and that they have no commercial associations (e.g., consultancies, stock ownership, equity interest, patent/licensing arrangement, etc.) that might pose a conflict of interest in connection with this work.

Funding

The authors received no financial support for the research, authorship and/or publication of this article.

ORCID iDs

Alessandra Costanza

References

Gonda

, Dome

, Serafini

. How to save a life: From neurobiological underpinnings to psychopharmacotherapies in the prevention of suicide. Pharmacol Ther 2023; 244: 108390.

Serafini

, Costanza

, Aguglia

. The role of inflammation in the pathophysiology of depression and suicidal behavior: Implications for treatment. Med Clin North Am 2023; 107(1): 1–29.

Costanza

, D’Orta

, Perroud

. Neurobiology of suicide: Do biomarkers exist. Int J Legal Med 2014; 128(1): 73–82.

Klonsky

, May

and Saffer

BY.

Suicide, suicide attempts, and suicidal ideation. Annu Rev Clin Psychol 2016; 12: 307–330.

Lloyd

and Saglani

Early-life respiratory infections and developmental immunity determine lifelong lung health. Nat Immunol 2023; 24(8): 1234–1243.

Fan

and Pedersen

Gut microbiota in human metabolic health and disease. Nat Rev Microbiol 2021; 19(1): 55–71.

Rusch

, Layden

and Dugas

LR.

Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis. Front Endocrinol (Lausanne) 2023; 14: 1130689.

Gomaa

EZ.

Human gut microbiota/microbiome in health and diseases: A review. Antonie Van Leeuwenhoek 2020; 113(12): 2019–2040.

Tremlett

, Bauer

, Appel-Cresswell

. The gut microbiome in human neurological disease: A review. Ann Neurol 2017; 81(3): 369–382.

10.

Lester

Brain parasites and suicide. Psychol Rep 2010; 107(2): 424.

11.

Ling

, Lester

, Mortensen

. Toxoplasma gondii seropositivity and suicide rates in women. J Nerv Ment Dis 2011; 199(7): 440–444.

12.

Pedersen

, Mortensen

, Norgaard-Pedersen

. Toxoplasma gondii infection and self-directed violence in mothers. Arch Gen Psychiatry 2012; 69(11): 1123–1130.

13.

Alvarado-Esquivel

, Estrada-Martínez

, Ramos-Nevárez

. Association between Toxoplasma gondii exposure and suicidal behavior in patients attending primary health care clinics. Pathogens 2021; 10(6): 677.

14.

Okusaga

, Langenberg

, Sleemi

. Toxoplasma gondii antibody titers and history of suicide attempts in patients with schizophrenia. Schizophr Res 2011; 133(1–3): 150–155.

15.

Akgül

, Demirel

ÖF

, Aksoy Poyraz

. Toxoplasma gondii infection by serological and molecular methods in schizophrenia patients with and without suicide attempts: An age-sex-matched case-control study. Int J Clin Pract 2021; 75(8): e14449.

16.

Bryleva

and Brundin

Suicidality and activation of the kynurenine pathway of tryptophan metabolism. Curr Top Behav Neurosci 2017; 31: 269–284.

17.

Okusaga

, Duncan

, Langenberg

. Combined Toxoplasma gondii seropositivity and high blood kynurenine: Linked with nonfatal suicidal self-directed violence in patients with schizophrenia. J Psychiatr Res 2016; 72: 74–81.

18.

Kamal

, Kamal

, Abd El-Fatah

. Latent toxoplasmosis is associated with depression and suicidal behavior. Arch Suicide Res 2022; 26(2): 819–830.

19.

Bahceci

, Bahceci

, Senturk

. Correlation of suicidal thoughts and toxoplasmosis in patients with depression. Cureus 2021; 13(2): e13369.

20.

Coryell

, Wilcox

, Evans

. Latent infection, inflammatory markers and suicide attempt history in depressive disorders. J Affect Disord 2020; 270: 97–101.

21.

Alvarado-Esquivel

, Mendoza-Larios

, García-Dolores

. Association between Toxoplasma gondii infection in brain and a history of depression in suicide decedents: A cross-sectional study. Pathogens 2021; 10(10): 1313.

22.

Coryell

, Yolken

, Butcher

. Toxoplasmosis titers and past suicide attempts among older adolescents initiating SSRI treatment. Arch Suicide Res 2016; 20(4): 605–613.

23.

Burgdorf

, Trabjerg

, Pedersen

. Large-scale study of Toxoplasma and Cytomegalovirus shows an association between infection and serious psychiatric disorders. Brain Behav Immun 2019; 79: 152–158.

24.

Lund-Sørensen

, Benros

, Madsen

. A nationwide cohort study of the association between hospitalization with infection and risk of death by suicide. JAMA Psychiatry 2016; 73(9): 912–919.

25.

Costanza

, Amerio

, Aguglia

. Hyper/neuroinflammation in COVID-19 and suicide etiopathogenesis: Hypothesis for a nefarious collision. Neurosci Biobehav Rev 2022; 136: 104606.

26.

Gasnier

, Choucha

, Radiguer

. Comorbidity of long COVID and psychiatric disorders after a hospitalisation for COVID-19: A cross-sectional study. J Neurol Neurosurg Psychiatry 2022; jnnp-2021-328516.

27.

Woodward

, Bari

, Vike

. Anxiety, Post-COVID-19 Syndrome-Related Depression, and Suicidal Thoughts and Behaviors in COVID-19 Survivors: Cross-sectional Study. JMIR Form Res 2022; 6(10): e36656.

28.

Mendoza-Larios

, García-Dolores

, Sánchez-Anguiano

. Association between suicide and Toxoplasma gondii seropositivity. Pathogens 2021; 10(9): 1094.

29.

Sari

and Kara

Association of suicide attempt with seroprevalence of Toxoplasma gondii in adolescents. J Nerv Ment Dis 2019; 207(12): 1025–1030.

30.

Ansari-Lari

, Farashbandi

and Mohammadi

Association of Toxoplasma gondii infection with schizophrenia and its relationship with suicide attempts in these patients. Trop Med Int Health 2017; 22(10): 1322–1327.1

31.

Lindgren

, Holm

, Markkula

. Exposure to common infections and risk of suicide and self-harm: A longitudinal general population study. Eur Arch Psychiatry Clin Neurosci 2020; 270(7): 829–839.

32.

Soleymani

, Faizi

, Heidarimoghadam

. Association of T. gondii infection with suicide: A systematic review and meta-analysis. BMC Public Health 2020; 20(1): 766.

33.

Amouei

, Moosazadeh

, Nayeri Chegeni

. Evolutionary puzzle of Toxoplasma gondii with suicidal ideation and suicide attempts: An updated systematic review and meta-analysis. Transbound Emerg Dis 2020; 67(5): 1847–1860.

34.

Gjervig Hansen

, Köhler-Forsberg

, Petersen

. Infections, anti-infective agents, and risk of deliberate self-harm and suicide in a young cohort: A nationwide study. Biol Psychiatry 2019; 85(9): 744–751.

35.

Costanza

, Placenti

, Amerio

. Chloroquine/hydroxychloroquine use and suicide risk: Hypotheses for confluent etiopathogenetic mechanisms. Behav Sci (Basel) 2021; 11(11): 154.

36.

Miranda

, Fan

, Qi

. DeepBiomarker: Identifying important lab tests from electronic medical records for the prediction of suicide-related events among PTSD patients. J Pers Med 2022; 12(4): 524.

37.

Lengvenyte

, Strumila

, Maimoun

. A specific association between laxative misuse and suicidal behaviours in patients with anorexia nervosa and bulimia nervosa. Eat Weight Disord 2022; 27(1): 307–315.

38.

, Lyu

, Zhang

. Association between dietary patterns and suicide ideation among depressed adults: Insights from NHANES 2007–2020. J Affect Disord 2025; 377: 235–244.

39.

Chen

and Wu

SI.

An exploratory analysis on the association between suicidal ideation and the microbiome in patients with or without major depressive disorder. J Affect Disord 2025; 370: 362–372.

40.

Maes

, Vasupanrajit

, Jirakran

. Adverse childhood experiences and reoccurrence of illness impact the gut microbiome, which affects suicidal behaviours and the phenome of major depression: Towards enterotypic phenotypes. Acta Neuropsychiatr 2023; 35(6): 328–345.

41.

Maes

, Zhou

, Vasupanrajit

. A further examination of growth factors, T helper 1 polarization, and the gut microbiome in major depression: Associations with reoccurrence of illness, cognitive functions, suicidal behaviors, and quality of life. J Psychiatr Res 2024; 176: 430–441.

42.

Thompson

, Fowler

, Bradshaw

. Is the gut microbiota associated with suicidality? Non-significant finding among a large cohort of psychiatrically hospitalized individuals with serious mental illness. J Affect Dis Rep 2021; 6: 100266.

43.

Ahrens

, Sanchez-Padilla

, Drew

. Saliva microbiome, dietary, and genetic markers are associated with suicidal ideation in university students. Sci Rep 2022; 12(1): 14306.

44.

Postolache

, Akram

, Lee

. Increased brain vitamin D receptor expression and decreased expression of cathelicidin antimicrobial peptide in individuals who died by suicide. J Psychiatr Res 2020; 125: 75–84.

45.

Kaszubinski

, Pechal

, Smiles

. Dysbiosis in the dead: Human postmortem microbiome beta-dispersion as an indicator of manner and cause of death. Front Microbiol 2020; 11: 555347.

46.

Zhang

, Pechal

, Schmidt

. Machine learning performance in a microbial molecular autopsy context: A cross-sectional postmortem human population study. PLoS One 2021; 14(4): e0213829.

47.

Javan

, Finley

, Smith

. Cadaver Thanatomicrobiome Signatures: The Ubiquitous Nature of Clostridium Species in Human Decomposition. Front Microbiol 2017; 8: 2096.

48.

Lutz

, Vangelatos

, Gottel

. Effects of Extended Postmortem Interval on Microbial Communities in Organs of the Human Cadaver. Front Microbiol 2020; 11: 569630.

49.

Meehan

and Carter

Moving with pain: What principles from somatic practices can offer to people living with chronic pain. Front Psychol 2020; 11: 620381.

50.

Costanza

, Chytas

, Piguet

. Meaning in life among patients with chronic pain and suicidal ideation: Mixed methods study. JMIR Form Res 2021; 5: e29365.

51.

Muirhead

, Vyas

, Ephgrave

. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Impact on Quality of Life (QoL) of Persons with ME/CFS. Medicina (Kaunas) 2024; 60(8): 1215.

52.

Giloteaux

, Goodrich

, Walters

. Reduced diversity and altered composition of the gut microbiome in individuals with myalgic encephalomyelitis/chronic fatigue syndrome. Microbiome 2016; 4: 30.

53.

Mandarano

, Giloteaux

, Keller

. Eukaryotes in the gut microbiota in myalgic encephalomyelitis/chronic fatigue syndrome. PeerJ 2018; 6: e4282.

54.

Sheedy

, Wettenhall

, Scanlon

. Increased d-lactic Acid intestinal bacteria in patients with chronic fatigue syndrome. InVivo 2009; 23: 621–628.

55.

Frémont

, Coomans

, Massart

. High-throughput 16S rRNA gene sequencing reveals alterations of intestinal microbiota in myalgic encephalomyelitis/chronic fatigue syndrome patients. Anaerobe 2013; 22: 50–56.

56.

Lupo

GFD

, Rocchetti

, Lucini

. Potential role of microbiome in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME). Sci Rep 2011; 11: 7043.

57.

Nagy-Szakal

, Williams

, Mishra

. Fecal metagenomic profiles in subgroups of patients with myalgic encephalomyelitis/chronic fatigue syndrome. Microbiome 2017;  5: 44.

58.

Guo

, Che

, Briese

. Deficient butyrate-producing capacity in the gut microbiome is associated with bacterial network disturbances and fatigue symptoms in ME/CFS. Cell Host Microbe 2023; 31: 288–304.e8.

59.

Boukobza

, Raffoul

and Laissy

JP.

Multimodality Imaging in Rothia dentocariosa Infective Endocarditis and Internal Iliac Artery Infectious Aneurysm. Vasc Endovascular Surg 2024; 58(7): 773–776.

60.

Freidin

, Stalteri

, Wells

. An association between chronic widespread pain and the gut microbiome. Rheumatology (Oxford) 2021; 60(8): 3727–3737.

61.

Reichenberger

, Alexander

, Perreault

. Establishing a relationship between bacteria in the human gut and complex regional pain syndrome. Brain Behav Immun 2013; 29: 62–69.

62.

Gonzalez

, Sahar

, Haddad

. Altered Gut Microbiome Composition and Function in Individuals with Complex Regional Pain Syndrome. Anesthesiology 2025; DOI: 10.1097/ALN.0000000000005435

63.

Minerbi

, Gonzalez

, Brereton

NJB

. Altered microbiome composition in individuals with fibromyalgia. Pain 2019; 160(11): 2589–2602.

64.

Malatji

, Mason

, Mienie

. The GC-MS metabolomics signature in patients with fibromyalgia syndrome directs to dysbiosis as an aspect contributing factor of FMS pathophysiology. Metabolomics 2019; 15(4): 54.

65.

Nickel

, Stephens

, Landis

. Assessment of the lower urinary tract microbiota during symptom flare in women with urologic chronic pelvic pain syndrome: A MAPP Network study. J Urol 2016; 195(2): 356–362.

66.

, Ahn

, Ok

. Distinctive salivary oral microbiome in patients with burning mouth syndrome depending on pain intensity compared to healthy subjects. J Dent Sci 2025; 20(1): 462–469.

67.

Bai

, Shen

and Liu

Associations between the gut microbiome and migraines in children aged 7–18 years: An analysis of the American Gut Project cohort. Pain Manage Nurs 2023; 24: 35–43.

68.

Chen

, Wang

. Structural and functional characterization of the gut microbiota in elderly women with migraine. Front Cell Infect Microbiol 2019; 9: 470.

69.

Kopchak

, Hrytsenko

and Pulyk

OR.

Peculiarities of the gut microbiota in patients with migraine comparing to healthy individuals. Wiad Lek 2022; 75: 2218–2221.

70.

Yong

, Lee

, Min

. Altered gut microbiota in individuals with episodic and chronic migraine. Sci Rep 2023; 13: 626.

71.

Shiro

, Arai

, Nakaso

. Differences in gut microbiota composition depending on the site of pain in patients with chronic pain. J Pain Res 2025; 18: 769–782.

72.

Cai

, Wen

, Hu

. Multiple reports on the causal relationship between various chronic pain and gut microbiota: A two-sample Mendelian randomization study. Front Neurosci 2024; 18: 1369996.

73.

Cao

, Cheng

, Pan

. Gut microbiota variations in depression and anxiety: A systematic review. BMC Psychiatry 2025; 25(1): 443.

74.

Gao

, Wang

, Liu

. Gut microbiota composition in depressive disorder: A systematic review, meta-analysis, and meta-regression. Transl Psychiatry 2023; 13(1): 379.

75.

McGuinness

, Davis

, Dawson

. A systematic review of gut microbiota composition in observational studies of major depressive disorder, bipolar disorder and schizophrenia. Mol Psychiatry 2022; 27(4): 1920–1935.

76.

Simpson

, Adler

, du Plessis

. Oral microbiome composition, but not diversity, is associated with adolescent anxiety and depression symptoms. Physiol Behav 2020; 226: 113126.

77.

Wingfield

, Lapsley

, McDowell

. Variations in the oral microbiome are associated with depression in young adults. Sci Rep 2021; 11(1): 15009.

78.

Zeng

, Jia

, Li

. Oral microbiota among treatment-naive adolescents with depression: A case-control study. J Affect Disord 2025; 375: 93–102.

79.

Zheng

, Xu

, Xiao

. Association between oral microbiome and depression: A population-based study. J Affect Disord 2025; 379: 441–447.

80.

Liu

, Zhang

, Yang

. Oral microbiome diversity shapes the association between sleep duration and depression. Front Neurol 2024; 15: 1442557.

81.

Malan-Müller

, Vidal

, O’Shea

. Probing the oral-brain connection: Oral microbiome patterns in a large community cohort with anxiety, depression, and trauma symptoms, and periodontal outcomes. Transl Psychiatry 2024; 14(1): 419.

82.

Alex

, Levendosky

, Bogat

. Stress and mental health symptoms in early pregnancy are associated with the oral microbiome. BMJ Ment Health 2024; 27(1): e301100.

83.

Agranyoni

, Rowley

, Johnson

. Oral microbiome composition is associated with depressive symptoms during pregnancy. Brain Behav Immun Health 2025; 45: 100978.

84.

, Lv

, Xie

. Whole-genome metagenomic analysis of the oral microbiota in patients with obstructive sleep apnea comorbid with major depressive disorder. Nat Sci Sleep 2024; 16: 1091–1108.

85.

Hoisington

, Stearns-Yoder

, Stamper

. Longitudinal influence of prescribed antidepressants on fecal and oral microbiomes among veterans with major depressive disorder. J Neuropsychiatry Clin Neurosci 2024; 36(2): 151–159.

86.

, Chen

, Wen

. A genetic association study reveals the relationship between the oral microbiome and anxiety and depression symptoms. Front Psychiatry 2022; 13: 960756.

87.

Ciocan

, Cassard

, Becquemont

. Blood microbiota and metabolomic signature of major depression before and after antidepressant treatment: A prospective case-control study. J Psychiatry Neurosci 2021; 46(3): E358–E368.

88.

Tingö

, Hutchinson

, Bergh

. Potential modulation of inflammation by probiotic and omega-3 supplementation in elderly with chronic low-grade inflammation: A randomized, placebo-controlled trial. Nutrients 2022; 14(19): 3998.

89.

Kopp

, Schweinlin

, Tingö

. Potential modulation of inflammation and physical function by combined probiotics, omega-3 supplementation and vitamin D supplementation in overweight/obese patients with chronic low-grade inflammation: A randomized, placebo-controlled trial. Int J Mol Sci 2023; 24(10): 8567.

90.

Aslan Çin

, Açik

, Tertemiz

. Effect of prebiotic and probiotic supplementation on reduced pain in patients with fibromyalgia syndrome: A double-blind, placebo-controlled randomized clinical trial. Psychol Health Med 2023; 29(3): 528–541.

91.

Fang

, Hou

, Zhang

. Fecal microbiota transplantation improves clinical symptoms of fibromyalgia: An open-label, randomized, nonplacebo-controlled study. J Pain 2024; 25(9): 104535.

92.

Pirbaglou

, Katz

, de Souza

. Probiotic supplementation can positively affect anxiety and depressive symptoms: A systematic review of randomized controlled trials. Nutr Res 2016; 36(9): 889–898.

93.

Zhang

, Chen

, Zhang

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

94.

Akkasheh

, Kashani-Poor

, Tajabadi-Ebrahimi

. Clinical and metabolic response to probiotic administration in patients with major depressive disorder: A randomized, double-blind, placebo-controlled trial. Nutrition 2016; 32(3): 315–320.

95.

Tarutani

, Omori

, Ido

. Effects of 4G-beta-D-galactosylsucrose in patients with depression: A randomized, double-blinded, placebo-controlled, parallel-group comparative study. J Psychiatr Res 2022; 148: 110–120.