REVIEW

published: 18 July 2018

doi: 10.3389/fnins.2018.00483

Implications of Systemic
Inflammation and Periodontitis for
Major Depression
Sadayuki Hashioka 1* , Ken Inoue 2 , Maiko Hayashida 1 , Rei Wake 1 , Arata Oh-Nishi 1 and
Tsuyoshi Miyaoka 1
1
Department of Psychiatry, Shimane University, Izumo, Japan, 2 Health Service Center, Kochi University, Kochi, Japan

Increasing evidence suggests that infection and persistent low-grade inflammation

in peripheral tissues are important pathogenic factors in major depression. Major
depression is frequently comorbid with systemic inflammatory diseases/conditions such
as rheumatoid arthritis, allergies of different types, multiple sclerosis, cardiovascular
disease, inflammatory bowel disease, chronic liver disease, diabetes, and cancer, in
which pro-inflammatory cytokines are overexpressed. A number of animal studies
demonstrate that systemic inflammation induced by peripheral administration of
lipopolysaccharide increases the expression of pro-inflammatory cytokines in both
the periphery and brain and causes abnormal behavior similar to major depression.
Edited by:
Systemic inflammation can cause an increase in CNS levels of pro-inflammatory
Akira Monji,
Saga University, Japan cytokines associated with glial activation, namely, neuroinflammation, through several
Reviewed by: postulated pathways. Such neuroinflammation can in turn induce depressive moods
Anindya Bhattacharya, and behavioral changes by affecting brain functions relevant to major depression,
Janssen Research & Development,
United States
especially neurotransmitter metabolism. Although various clinical studies imply a
Kenji Hashimoto, causal relationship between periodontitis, which is one of the most common chronic
Chiba University, Japan
inflammatory disorders in adults, and major depression, the notion that periodontitis is a
*Correspondence:
risk factor for major depression is still unproven. Additional population-based cohort
Sadayuki Hashioka
[email protected] studies or prospective clinical studies on the relationship between periodontitis and
major depression are needed to substantiate the causal link of periodontitis to major
Specialty section:
depression. If such a link is established, periodontitis may be a modifiable risk factor for
This article was submitted to
Neuropharmacology, major depression by simple preventive oral treatment.
a section of the journal
Frontiers in Neuroscience Keywords: major depression, systemic inflammation, periodontitis, pro-inflammatory cytokines, microglia,
neuroinflammation
Received: 31 March 2018
Accepted: 26 June 2018
Published: 18 July 2018
INTRODUCTION
Citation:
Hashioka S, Inoue K, Hayashida M, It has been well documented that inflammation is closely related to major depression, even though
Wake R, Oh-Nishi A and Miyaoka T
it remains uncertain whether inflammation is a cause or a result of the mental illness. The
(2018) Implications of Systemic
Inflammation and Periodontitis
association between inflammation and major depression has been supported by the well-known
for Major Depression. clinical observation that pro-inflammatory cytokines such as interferon (IFN)-α, which is used
Front. Neurosci. 12:483. to treat hepatitis C, renal cancer, and multiple myeloma, and interleukin (IL)-2, which is used
doi: 10.3389/fnins.2018.00483 to treat renal cancer and angiosarcoma, frequently induce depressive symptoms as side effects

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Hashioka et al. Systemic Inflammation, Periodontitis, and Major Depression

(Hashioka et al., 2009). More than 50% of patients treated this is not a case for major depression (Dantzer et al., 2008).
with high dose IFN-α met the diagnostic criteria for major They have established a murine model of inflammation-induced
depression within 3 months after administration of IFN-α depression using systemic administration of LPS and claim that
(Musselman et al., 2001). Moreover, physically ill patients the LPS-induced depressive-like behavior can be distinguished
with chronic inflammation often manifest symptoms of from sickness behavior in the animal model (Dantzer et al.,
major depression (Dantzer, 2017). These clinical observations 2008; O’Connor et al., 2009). Specifically, sickness behavior
parallel findings are observed in a number of animal studies. measured by reduced food intake, decreased social exploration,
Peripheral administration of endotoxin lipopolysaccharide and reduced locomotor activity develop within a few hours
(LPS), a component of Gram-negative bacterial cell wall, after LPS injection and wanes off by 12–16 h post LPS.
into mice has been shown to increase expression of pro- Subsequently, depressive-like behavior occurs 24 h after LPS
inflammatory cytokines, such as IL-1β, IL-6, and tumor necrosis injection as shown by prolonged immobility time in the forced
factor (TNF)-α, in both the periphery and brain, especially swimming test (FST), the tail suspension test (TST), and the
in microglia and perivascular macrophages in the brain reduced sucrose preference. These authors also insist that
(Layé et al., 1994; Godbout et al., 2008), and cause abnormal this dissociation between sickness behavior and depressive-like
behavior similar to major depression (O’Connor et al., 2009; behavior in response to LPS is consistent with the time course
Biesmans et al., 2013). It has also been demonstrated that of the development of symptoms of depression in response to
systemic administration of pro-inflammatory cytokines induces IFN-α in patients with cancer (Dantzer et al., 2008; Dantzer,
depressed behavior in rodents (Anforth et al., 1998; Kaster et al., 2017). In this time course, neurovegetative symptoms, including
2012). reduced appetite, sleep disorders, and fatigue, emerge first in
Major depression seems to be a heterogeneous disease with response to repeated injections of IFN-α, whereas mood and
different genetic and environmental factors contributing to the cognitive symptoms emerge later (Capuron et al., 2002). The
disease development (Shelton, 2007). Systemic infection and experimental finding of mice that depressive-like behavior is
inflammatory processes may also play a role in the pathogenesis present without the confounding effects of sickness behavior
of major depression, at least in a subset of susceptible individuals. 24 h after systemic LPS injection is, however, controversial.
The aim of this article is to review the possible role of systemic Zhu et al. (2010) have shown that depressive-like behavior
inflammation in the pathogenesis of major depression and the appears even at earlier time points (e.g., at 10 min – a few
possible causal link of periodontitis, which is one of the most hours after LPS injection) and others have shown that mice
common inflammatory diseases in adults, to the clinical onset receiving high dose of LPS still exhibit marked sickness behavior
and development of major depression. 24 h after LPS injection (Berg et al., 2004; Godbout et al.,
2008; Biesmans et al., 2013). This inconsistency may stem from
difference in the age of mice used, the LPS dose, the LPS
SYSTEMIC INFLAMMATION AND MAJOR serotype, the application route, and the assays used. It has
DEPRESSION been demonstrated that selective serotonin reuptake inhibitor
and serotonin norepinephrine reuptake inhibitor attenuate LPS-
Major depression is frequently comorbid with systemic induced depressive-like behavior and LPS-induced increase in
inflammatory diseases/conditions such as rheumatoid arthritis, serum levels of pro-inflammatory cytokines in mice (Ohgi et al.,
allergies of different types, multiple sclerosis, cardiovascular 2013).
disease, inflammatory bowel disease, chronic liver disease, The animal studies mentioned above employed single systemic
diabetes, and cancer, in which pro-inflammatory cytokines are administration of LPS, which can cause acute and strong but
overexpressed (Evans et al., 2005; Leonard, 2007; D’Mello and ephemeral activation of peripheral immune system. However,
Swain, 2017). For example, patients with major depression are inflammation-associated depression in human is rather linked
twice as likely to develop heart disease after controlling for effects to chronic inflammation (Leonard, 2018). Recently, there have
of smoking and hypertension (Anda et al., 1993). Therefore, been several animal studies which aim to establish attractive
persistent low-grade inflammation in peripheral tissues may be a translational models for inflammation-associated depression
common mechanism underlying the high comorbidity between in humans. Kubera et al. (2013) have established a mouse
major depression and physical illness. model in which repeated and intermittent LPS administration
Emerging evidence indicates that systemic inflammation has for 4 months causes a chronic state of anhedonia, indicating
a profound impact on behavior. It is well established that that chronic LPS administration might be a more relevant
systemic inflammation causes the synthesis of pro-inflammatory approach to induce depressive-like behavior. Moreau et al.
cytokines, which communicate with the brain to induce the (2005, 2008) have shown that inoculation of Bacillus Calmette-
spectrum of behavioral changes known as sickness behavior Guerin (BCG), an attenuated form of Mycobacterium bovis,
(Perry, 2004). Sickness behavior includes certain signs similar into mice elicits a prolonged increase in serum levels of the
to clinically relevant symptoms of major depression, such as pro-inflammatory cytokine IFN-α for 26 days, and the initial
appetite loss, sleep disturbance, reduced activity, and reduced episode of sickness behavior, which develops in a few days
social interest. However, some neuroscientists suppose that after BCG inoculation, is followed by a long-lasting decrease in
sickness behavior is rather an adaptive response to infection sucrose preference and an increase of immobility in the FST and
by pathogens and fully reversible once the pathogen cleared; the TST.

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Hashioka et al. Systemic Inflammation, Periodontitis, and Major Depression

HOW DOES SYSTEMIC INFLAMMATION secret pro-inflammatory cytokines which activate indoleamine-
AFFECT MOODS AND BEHAVIOR? 2,3-dioxygenase (IDO), the first and rate-limiting enzyme of the
kynurenine pathway. IDO catalyzes the synthesis of kynurenine
How the periphery communicates with the brain, modulates from dietary tryptophan. This could contribute to depressive
neurotransmission, and consequently changes behavior is not symptoms by reducing the availability of tryptophan required for
entirely clear. Nevertheless, several routes of communication the synthesis of serotonin and melatonin.
between the systemic immune system and the brain have been Microglial activation has been linked to depressive behavior.
postulated (Perry, 2004; Capuron and Miller, 2011; D’Mello A number of animal studies have demonstrated that mice
and Swain, 2017). A systemic inflammatory response results whose microglia are activated by systemic LPS injection show
in the secretion of pro-inflammatory cytokines, including sickness and depressive-like behavior (Biesmans et al., 2013;
IL-1β, IL-6, and TNF-α, from activated macrophages and Townsend et al., 2014; Norden et al., 2016). We confirmed that
monocytes. The pro-inflammatory cytokines circulate in the Gunn rats with congenital microgliosis and hyperbilirubinemia
blood and communicate with neurons and microglia in the showed prolonged immobility time in both the FST and the
brain via the communication pathways mentioned below. Any TST, indicating that microglial activation could be related
of these pathways could ultimately lead to an increase of pro- to learned helplessness (Arauchi et al., 2018). Furthermore,
inflammatory cytokines in the brain and microglial activation animal studies have shown that pharmacological inhibition
(hereinafter, referred to as neuroinflammation in this article). of activated microglia improves both sickness behavior and
The first route is the neural pathway through which systemic depressive-like behavior. Administration of minocycline into
cytokines directly activate primary afferent nerves, such as the mice reduced the LPS-induced microglial expression of pro-
vagus nerve. The signal reaches the primary and secondary inflammatory cytokines and ameliorated sickness behavior and
projection of the neural pathway reaching first the nucleus anhedonia (Henry et al., 2008). Minocycline administration
tractus solitaries and subsequently various hypothalamic brain completely inhibited the increase and activation of microglia
nuclei (Capuron and Miller, 2011). It has been shown that in the hippocampus and reduced chronic mild stress-induced
subdiaphragmatic vagotomy blocks the LPS-induced sickness depressive-like behaviors in the FST and open field test (Wang
behavior in rats (Bluthé et al., 1994), while it does not affect et al., 2018). Postmortem studies also indicate that activated
the LPS-induced synthesis of pro-inflammatory cytokines at microglia are involved in the brain of patients with major
the periphery. The second route is the humoral pathway depression (Bayer et al., 1999; Steiner et al., 2011). Iwata et al.
involving the choroid plexus and circumventricular organs, (2016) have recently shown that psychological stress increases
which lack an intact blood–brain barrier (BBB). These leaky extracellular adenosine triphosphate (ATP) in the hippocampus.
regions may be access points for circulating pro-inflammatory The increased extracellular ATP binds to purinergic type 2X7
cytokines to enter into the cerebral parenchyma by volume receptor (P2X7R) on microglia and subsequently activates
diffusion and elicit downstream signaling events important in nucleotide-binding leucine-rich repeat, pyrin domain containing
altering brain function (D’Mello and Swain, 2017). The third (NLRP) 3 inflammasome in microglia to induce microglial release
route is cellular pathway. Systemic inflammation is associated of IL-1β. IL-1β has been shown to decrease neurogenesis in adult
with activation of cerebral endothelial cells (CECs) as well hippocampus and this effect is associated with development of
as an increase in circulating monocytes (D’Mello and Swain, anhedonia (Koo and Duman, 2008). Accordingly, the authors
2017). Systemic pro-inflammatory cytokines activate CECs claim that the ATP/P2X7R-NLRP3 inflammasome cascade in
expressing receptors for TNF-α and IL-1β, which in turn microglia could be a therapeutic target for treatment of stress-
signal to the perivascular macrophages located immediately related depression.
adjacent to CECs (Perry, 2004). These perivascular macrophages The gut-microbiota to brain route has received increasing
subsequently communicate with microglia and thus lead to attention for its ability to modulate brain functions. A recent
microglial activation. Activated microglia secret not only pro- animal study has shown that blockade of peripheral IL-6
inflammatory cytokines but also proteases and chemokines, receptor by anti-mouse IL-6 receptor antibody promotes rapid
including monocyte chemoattractant protein (MCP)-1. MCP-1 is and sustained antidepressant action thorough normalizing the
supposed to be responsible for the recruitment of monocytes into altered composition of gut microbiota in susceptible mice
the motor cortex, hippocampus, and basal ganglia regions, areas after social defeat stress, suggesting that gut–microbiota–brain
of the brain known to be involved in control of behavior (D’Mello communication has a role in robust antidepressant actions of
et al., 2009). anti-IL-6 receptor therapy (Zhang et al., 2017).
Once the pro-inflammatory cytokine signals reach the brain
from the periphery, they could affect several pathophysiological
domains, functions, and neurotransmission relevant to major PERIODONTITIS AND MAJOR
depression, such as anterior cingulate cortex (anxiety and DEPRESSION
arousal), basal ganglia (motivation and motor activity),
neuroendocrine function (glucocorticoid resistance and Periodontitis is a chronic oral multi-bacterial infection and
altered glucocorticoid secretion), synaptic plasticity (impaired one of the most common inflammatory disorders in adults.
neurogenesis), and neurotransmitter metabolism (Capuron and In 2009–2010, the total prevalence of periodontitis in adults
Miller, 2011). Microglia activated by the systemic cytokine signals aged 30 years and older was 47.2% in the United States (Eke

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Hashioka et al. Systemic Inflammation, Periodontitis, and Major Depression

et al., 2012). The World Health Organization reported that 10– POSSIBLE LINK BETWEEN
15% of the world populations suffer from severe periodontitis PERIODONTITIS AND DEVELOPMENT
(Petersen and Ogawa, 2005). Periodontitis can be classified as
gingivitis, when the inflammation is localized in the gingival OF MAJOR DEPRESSION
tissues, or it may assume a more severe destructive form, with
Both psychosocial and biological mechanisms are supposed
the inflammatory process reaching deeper connective and bone
to link periodontitis and development of major depression.
tissue, causing bone and attachment loss, that may ultimately
Periodontitis may increase the risk for depression through
lead to tooth loss. Periodontitis per se is a low-grade chronic
psychosocial effects of halitosis, such as shame, loneliness,
inflammation, but it causes or hastens the other chronic systemic
embarrassment, and diminished well-being (Dumitrescu, 2016).
inflammatory diseases, including atherosclerosis, cardiovascular
Furthermore, edentulousness caused by periodontitis due to
diseases, diabetes, and rheumatoid arthritis (Holmstrup et al.,
inflammatory destruction of tooth supporting tissues (i.e.,
2017). This indicates that periodontitis is a significant source
periodontal ligament and alveolar bone) could affect the patient’s
of systemic inflammatory molecules. Besides affecting the
quality of life. Edentulousness impairs not only chewing, but
systemic inflammatory disorders, recent clinical studies imply
also body image, self-esteem, and social status (Saintrain and de
that periodontitis is a risk factor for such a neuroinflammatory
Souza, 2012).
and neurodegenerative disorder as Alzheimer’s disease (AD).
The biological mechanisms by which periodontitis causes
A preliminary study has shown a cross-sectional association
major depression are presumed to consist of two possibilities:
between increased levels of a serologic marker of Porphyromonas
(1) neuroinflammation (i.e., increased CNS levels of pro-
gingivalis (Pg), the major pathogen of periodontitis, and impaired
inflammatory cytokines associated with glial activation) induced
delayed memory and calculation among patients older than 60
by systemic inflammation associated with periodontitis; (2)
years, suggesting that periodontitis is associated with cognitive
neuroinflammation evoked by direct invasion of periodontal
impairment in the elderly (Noble et al., 2009). A 6-month
pathogen and their inflammatory products into the brain. Within
observational cohort study has reported that the cognitive state of
the periodontal pocket, bacteria exist in a stratified dental
the periodontitis-present AD group signifies declined compared
biofilm, which is made of microorganisms and their components
to that of the periodontitis-absent AD group at the follow-
(e.g., endotoxin LPS and virulence factors; Socransky and
up point (Ide et al., 2016). Moreover, LPS from Pg has been
Haffajee, 2002). The inflamed periodontal pocket can, therefore,
detected in AD brains, but not in control brains (Poole et al.,
be a significant source of inflammatory and pathogen-derived
2013).
mediators. In health, the majority of bacteria are Gram-
Various clinical studies also imply a causal relationship
positive aerobes. In periodontitis, approximately 85% of bacteria
between periodontitis and major depression (Klages et al., 2005;
are Gram-negative, with the major three periodontal bacteria
Rosania et al., 2009). Distress experienced by patients with
called the “red complex,” namely, Tannerella forsythia, and
periodontitis significantly correlated with the progression of
Treponema denticola and Pg (Kamer et al., 2008; summarized
periodontitis (Rai et al., 2011). Chronic stress and depression can
in Table 1). Because these bacteria are capable of invading
mediate risk and progression of periodontitis through change
intact pocket epithelium, periodontal bacteria and their products
in health-related behaviors such as oral hygiene, smoking, and
can gain access to the circulation (Kamer et al., 2008). This
diet (Warren et al., 2014). Also, as periodontitis got chronic,
results in bacteremia and systemic dissemination of bacterial
the occurrence of depression increased (Tang and Cao, 2011).
products. In fact, Gomes et al. (2018) have recently reported
A population-based cohort study for a long-term (10 years)
that subjects with chronic periodontitis and depression show
follow-up period showed a higher incidence of subsequent
highly increased root canal LPS levels compared to subjects with
depression in the periodontitis group (N = 12,708) than in
chronic periodontitis without depression and normal controls.
the non-periodontitis group (N = 50832) with an adjusted
This study also shows a strong positive association between
hazard ratio of 1.73 when adjusted for sex, age, and comorbidity
chronic periodontitis or root canal LPS levels and severity
(Hsu et al., 2015). This result suggests that periodontitis is
an independent risk factor for major depression regardless of
sex, age, and the comorbidities except for diabetes, alcohol TABLE 1 | Characteristics of major Gram-negative bacteria called the “red
abuse, and cancer. Interestingly, an animal study demonstrated complex” in periodontitis.
that tianeptine, the tricyclic antidepressants which have been
Species Virulence factors Neuraminidases Related disease
shown to possess anti-inflammatory properties (Hashioka et al.,
2007, 2009), reduced periodontitis severity, and ameliorated Porphyromonas Lipopolysaccharide PG0352 Rheumatoid arthritis
emotionality- and anxiety-related behavior in the olfactory gingivalis SerB protein Bacterial vaginosis
bulbectomy rat model of depression with ligature-induced Gingipains
Hemagglutinin
periodontitis (Breivik et al., 2006). A cross-sectional clinical Fimbriae
study also showed that intake of fluoxetine, another type of
antidepressants (i.e., selective serotonin reuptake inhibitor), is Tannerella BspA NanH (TF0035) Atherosclerosis
forsythia Hemagglutinin SiaH Bacterial vaginosis
associated with lower bleeding on probing percentages and lower
attachment loss in patients with chronic periodontitis and clinical Treponema CfpA TDE0471 Bacterial vaginosis
depression (Bhatia et al., 2015). denticola

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Hashioka et al. Systemic Inflammation, Periodontitis, and Major Depression

FIGURE 1 | Scheme for presumed mechanisms of reciprocal connection between systemic inflammation, periodontitis and major depression.
LPS, lipopolysaccharide; QOL, quality of life.

of depression as measured using the Hamilton Depression are summarized in Figure 1. Increasing evidence suggests that
Rating Scale and the Beck Depression Inventory. Therefore, infection and persistent low-grade inflammation in peripheral
increased levels of LPS are supposed to link periodontitis to tissues are important pathogenic factors that explain a possible
subsequent depression like peripheral injection of LPS that causes pathophysiological mechanism of major depression. Systemic
depressive-like behavior in mice. Since periodontal pathogen inflammation could induce depressive moods and behavioral
and their products, especially LPS, can induce pro-inflammatory changes by provoking neuroinflammation. Although various
cytokines, such as Il-1β, IL-6, and TNF-α (Liu et al., 2017; clinical studies imply a causal relationship between periodontitis
Wu et al., 2017), these cytokines could also enter the systemic and major depression, the notion that periodontitis is a risk
circulation. Periodontitis-induced systemic dissemination of factor for major depression is still a supposition. Additional
bacteria, their LPS, and inflammatory mediators initiate systemic population-based cohort studies or prospective clinical studies
inflammation or deterioration if the other systemic inflammation on the relationship between periodontitis and major depression
already exists. Systemic inflammation caused by periodontitis are warranted to substantiate the causal link of periodontitis
could affect behavior and moods via possible communication to major depression. If such a link is established, periodontitis
pathways between the periphery and the brain leading to may be a modifiable risk factor for major depression by simple
neuroinflammation as mentioned above. preventive oral hygiene dealings.
Systemic injection of LPS has been demonstrated to
break down the BBB through abnormal activation of matrix
metalloproteinase (Bohatschek et al., 2001; Frister et al., AUTHOR CONTRIBUTIONS
2014). Therefore, it is also presumable that pathogen and
their inflammatory products can enter the brain and directly SH wrote the manuscript. All authors discussed, edited, read and
cause neuroinflammation after periodontitis-induced systemic approved the final manuscript.
dissemination of LPS derived from the “red complex” disrupts
the BBB to some extent. Theoretically, such neuroinflammation
provoked by direct invasion of periodontitis bacteria and their FUNDING
inflammatory products could also induce depressive moods and
behavioral changes, even though there has been no postmortem SH and TM were supported by JSPS KAKENHI Grant Numbers
study which showed the presence of LPS from the “red complex” 15K09830 (SH) and 15H048944B (TM).
in the brains of subjects with major depression.

ACKNOWLEDGMENTS
CONCLUSION
We thank Dr. Edith G. McGeer (Kinsmen Laboratory of
Presumed mechanisms of reciprocal connection between Neurological Research, The University of British Columbia) for
systemic inflammation, periodontitis, and major depression her kind support.

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Hashioka et al. Systemic Inflammation, Periodontitis, and Major Depression

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18, 407–413. doi: 10.1016/j.bbi.2004.01.004 Conflict of Interest Statement: The authors declare that the research was
Poole, S., Singhrao, S. K., Kesavalu, L., Curtis, M. A., and Crean, S. (2013). conducted in the absence of any commercial or financial relationships that could
Determining the presence of periodontopathic virulence factors in short-term be construed as a potential conflict of interest.
postmortem Alzheimer’s disease brain tissue. J. Alzheimers Dis. 36, 665–677.
doi: 10.3233/JAD-121918 Copyright © 2018 Hashioka, Inoue, Hayashida, Wake, Oh-Nishi and Miyaoka. This
Rai, B., Kaur, J., Anand, S. C., and Jacobs, R. (2011). Salivary stress markers, stress, is an open-access article distributed under the terms of the Creative Commons
and periodontitis: a pilot study. J. Periodontol. 82, 287–292. doi: 10.1902/jop. Attribution License (CC BY). The use, distribution or reproduction in other forums
2010.100319 is permitted, provided the original author(s) and the copyright owner(s) are credited
Rosania, A. E., Low, K. G., McCormick, C. M., and Rosania, D. A. (2009). and that the original publication in this journal is cited, in accordance with accepted
Stress, depression, cortisol, and periodontal disease. J. Periodontol. 80, 260–266. academic practice. No use, distribution or reproduction is permitted which does not
doi: 10.1902/jop.2009.080334 comply with these terms.

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