Bidirectional Relationship between Gut Dysbiosis, Anxiety and Depression: Comparison
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Please note this is a comparison between Version 2 by Jason Zhu and Version 1 by Cristina Gabriela Schiopu.

Inflammatory bowel disease represents one of the most life-altering gastrointestinal pathologies, with its multifactorial nature and unclear physiopathology. The most relevant clinical forms, ulcerative colitis and Crohn’s disease, clinically manifest with mild to severe flares and remission periods that alter the patient’s social, familial and professional integration. The chronic inflammatory activity of the intestinal wall determines severe modifications of the local environment, such as dysbiosis, enteric endocrine, nervous and immune system disruptions and intestinal wall permeability changes. These features are part of the gastrointestinal ecosystem that modulates the bottom-to-top signaling to the central nervous system, leading to a neurobiologic imbalance and clinical affective and/or behavioral symptoms. The gut-brain link is a bidirectional pathway and psychological distress can also affect the central nervous system, which will alter the top-to-bottom regulation, leading to possible functional digestive symptoms and local inflammatory responses. In the middle of this neuro-gastrointestinal system, the microbiome is a key player, as its activities offer basic functional support for both relays.

  • inflammation
  • inflammatory bowel disease
  • microbiome
  • gut-brain axis
  • psychiatry

1. Introduction

Inflammatory cytokines, such as IL-1β, TNF- α and IL-6 but also HPA axis imbalanced regulation of glucocorticoids, are mainly present in depression and anxiety patients. Interestingly, the same immune system and endocrine function disruptions appear in IBD and functional gastrointestinal disorders, which are pathologies with associated stress-related, mood and behavioral symptoms. Moreover, oxidative stress’s relation with short-chain fatty acids that are produced by the microbiome brings more arguments in favor of the important connection between the intestinal ecosystem and the CNS [26][1].

2. Functional Considerations over Microbiome and Dysbiosis in Psychiatric Disorders

Through pre-clinical studies, researchers were able to find that the gut microbiome plays the central role in modulating the gut-brain axis, as its composition and activity are able to regulate more than digestive functions. Starting from germ-free mouse studies, it has been revealed that dysbiosis is affiliated with mood and behavior disorders with chronic inflammatory states due to microglial disfunction and neurodegenerative activity, especially in young subjects [27][2].
The current state-of-the-art definitions describe the microbiome as an independently ”living organ” with complex functions and roles. It is involved in the metabolism of SCFAs, the balance between fatty acids’ oxidative process and lipogenesis, vitamin synthesis, endocrine functions by modulating neuropeptides and neurotransmitter secretion and immune functions, as it takes part in inflammatory activation with T cells and cytokine activity signaling. Through these functions, the gut bacteria are able to involve themselves in both HPA and vagal signal modulation [28][3].
Chronic stress, depression, anxiety and sleep disturbances are correlated with the hyperactivity of the HPA axis and immune system. A lack of regulatory feedback over the HPA axis, due to receptor resistance, enables both glucocorticoid and inflammatory marker levels to rise, leading to oxidative stress. On the other hand, dysbiosis and pathologic strains may trigger enteric inflammatory responses due to the dysregulation of local functions. The presence of pathologic strains activates inflammatory markers and activity; a lack of beneficial strains may lead to decreases in tryptophan and SCFA metabolism, with a direct influence the integrity of the intestinal wall and neurotransmitter activity, but also will allow for further production of reactive oxygen species and lipopolysaccharides, which enhance local, systemic and neuronal toxicity [29][4]. SCFAs represent a fermentation product of anaerobic bacteria. SCFAs modulate the secretion of neurotransmitters like glutamate, GABA and the expression of tryptophan by stimulating the apical membrane receptors. This implies a bottom-to-top regulatory effect in the gut-brain axis. Also, a CNS neurotransmitter disruption, due to psycho-social stress, for example, will signal altered information to the gut, influencing the microbiome’s composition. This is part of the pathophysiologic mechanism involved in anxiety and depression [30][5].
Dysbiosis and gut populations with pathologic strains, especially Gram-negative bacteria, will stimulate the production of lipopolysaccharides (LPS), which are immunogenic enzymes. On a local scale, LPS lead to inflammatory responses and hyperactivation of the HPA axis with increasing levels of cortisol. Glucocorticoids lower their own secretion via negative feedback, but in anxiety and depressive patients, there is a level of cortisol-resistant receptors, which would explain the pathologic loop of keep both inflammatory markers and cortisol levels up [31][6]. A lack of beneficial strains, specialized in SCFA metabolism, could cause not only inflammatory responses and neurotransmitter disturbances, but, indirectly, could support oxidative stress and its toxic products. The capacity of blocking reactive oxygen species formation of SCFAs, especially butyrate and acetate, which are mainly produced by gut bacteria fermentation processes, is suspected to have not only neuropsychiatric benefits but they could also be a future therapeutic target in other pathologies, as the antioxidative and anti-inflammatory effect might have general organic benefits, especially in LPS-induced pathophysiologic mechanisms [32,33,34][7][8][9]. Butyrate seems to exert anti-inflammatory properties, and SCFA-producing bacteria could even have a specific role in immune regulation between the gut and the brain. It seems that the anti-inflammatory role of butyrate is given by its inhibitory effect over nuclear factor κB (NF-κB) which activates IL-1β, IL-2, IL-6, TNF-α, nitric oxide synthesis, vascular adhesion molecules and cyclooxygenase-2. Also, NF-κB seems to be constantly active in colorectal cancer and IBD. The complex role of SCFA-producing bacteria brings yet another argument in favor of gut-brain axis pathophysiology [35][10].

3. The Gut Barrier and the Blood-Brain Barrier

The integrity of the intestinal wall represents a primary mechanical defense mechanism against toxic metabolites, pathologic bacteria and inflammatory markers entering the circulatory system and reaching the CNS. The danger of those substances and infectious agents entering the CNS lies in the blood-brain barrier. Both the blood-brain barrier and the intestinal wall barrier share similar structural and functional elements such as lymphatic and blood vessels, epithelial cells, endothelial tissue, macrophagic activity and cellular tight junctions [36][11]. Those tight junctions are represented by specific proteins that form the cytoskeleton of the intestinal wall by binding to the actin base. Occludin, claudins, junctional adhesion molecules and zonulin are the most important proteins of this type. SCFA metabolites regulate the expression of tight junction proteins in the intestinal wall, which makes gut-wall permeability directly dependent on the SCFA-producing microbiome [37][12].
The intestinal barrier is not only a mechanical wall, but also a functional one, as its permeability is dependent on microbiota composition with bacterial strains that produce SCFAs which regulate the expression of these tight junction proteins. The tight junctions of the intestinal wall enclose the functional barrier in order to keep all possible toxic and infectious agents away from the system [38][13].
Dysbiosis will alter gut permeability by depleting SCFAs and, subsequently, the expression of tight junctions. Local inflammatory responses will trigger the production of cytokines; TNF-α and pathogenic bacteria will produce LPS and other toxic by-products. Also, the rate of reactive oxygen species will increase due to chronic inflammatory activity. As such, the antimicrobial substances are exhausted, the mucin layers are destroyed and, as inflammation advances, the epithelial cells are also damaged from both cytokines and TNF-α, but also from oxidative stress, leading to breakage in the tight junctions of the gut barrier and increased blood flow. This will stimulate the release of toxins, inflammatory markers, microbial metabolites, infectious pathogens and reactive oxygen species into systemic circulation [39][14]. Many of these substances, such as inflammatory markers, toxic bacterial metabolites and free radicals, are able to pass through the blood-brain barrier, altering its permeability and leading to functional and structural alterations in the CNS. A recent and interesting study shows a remarkable association between plasma levels of permeability biomarkers of the gut and blood-brain barrier connected to depression and anxiety symptom severity scores. This kind of study could further be expanded to other mechanisms that could offer more details of the pathophysiological aspects of the gut-microbiome-brain axis [40][15]. Neuroinflammation and the disruption of neurotransmitter signaling is part of the connection between gut permeability and neuropsychiatric disorders (Figure 1).
Microorganisms 11 02268 g001
Figure 1. The pathophysiologic interplay between intrinsic and extrinsic factors and mechanisms within the microbiome-gut-brain axis.
Psychological stress, anxiety and depression may cause blood-brain barrier disfunctions through raised inflammatory markers and glucocorticoid levels. Such reactions may release these compounds into the blood stream. Also, disfunctions in the CND may trigger altered signals through the neuro-endocrine communication between the brain and gastrointestinal tract. The combined disruptions will cause modifications to gut motility, microbiome composition and gut barrier permeability in a top-bottom regulatory influence [41,42][16][17]. All these mechanisms support the microbiome’s modulatory role within the gut-brain axis with both digestive and neuropsychiatric alterations.

4. Therapeutic Arguments Linking Dysbiosis, Anxiety and Depression

The gut microbiome is not only an entity dependent on intrinsic physiology and genetic factors, but is also dependent on environmental factors such as diet, lifestyle, exercise and medical conditions that require pharmacologic therapy. The bottom-up regulatory effect of microbial strain variety has been the subject of many preclinical and clinical research projects, all starting from antibiotic exposure and the effects of antibiotic-induced dysbiosis on mood and behavior. The depletion of beneficial gut bacterial strains resulted in increased depressive, anxiety and cognitive symptoms even in subjects with no prior psychiatric manifestations. That could be explained by the fact that dysbiosis enables the pathophysiological mechanism that increases inflammatory activity and oxidative stress, decreases barrier and local defense mechanisms and alters the neuro-endocrine signals alongside barrier function disruptions. Animal model studies have revealed that antibiotic treatment has a positive correlation with anxiety symptoms, depressive symptoms, behavioral changes and cognitive impairments [43][18]. Also, germ-free animal model studies have brough insights for the pathogenic mechanisms involved in the gut-brain-microbiome interplay and pertinent observations of the beneficial role of the gut microbiome. Germ-free intestinal environments permit a specific microbiota population in order to observe accurate improvements in both digestive and neuropsychiatric manifestations [44][19].
Most actual studies and systematic reviews have revealed positive correlations between anxiety and depression symptom improvement and probiotic therapy, although there are still few clinical studies [45,46][20][21]. More research on specific strains as an accurate linkage between bacterial strains and mood and behavioral manifestations is needed (Table 1).
Table 1.
Specific bacterial strains in research for potential IBD/anxiety, mood and cognitive disorders.
Bacteria Species Digestive Effects Psychiatric Effects Source
Lactobacillus reuteri (mice) Decreased inflammatory activity in colitis Improvement in anxiety behavior

Improvement in depressive symptoms		 [47][22]
Lactobacillus

mucosae

Bifidobacterium longum (mice)		 Synergic effect—inhibition of NF-κB 1, TNF-α 2—anti-inflammatory effect Anxiety/depression symptom improvement; BDNF 3 expression [48][23]
Lactobacillus plantarum (mice) Anti-inflammatory effect BDNF and 5-HT 4 expression

Anxiety/depression improvement		 [49][24]
Lactobacillus casei (mice) Anti-inflammatory response, oxidative stress decrease Mood/behavior/anxiety improvement

BDNF expression		 [50][25]
Lactococcus lactis subsp. cremoris (mice) Modulation of inflammatory markers and oxidative stress Cognitive and mood improvement [51][26]
Bacillus subtilis (human) Motility, pain improvement

Anti-inflammatory effect		 Depression symptom improvement [52][27]
Saccharomyces boulardii (mice) Anti-inflammatory effect, oxidative stress reduction;

gut barrier permeability improvement—histological improvement (LPS 5-induced anxiety)		 5-HT expression

Anxiety symptom improvement		 [53][28]
Lactiplanbacillus plantarum (mice) Increased SCFA 6 in induced ulcerative colitis;

Gut barrier permeability modulation;

Histological improvement;		 5-HT expression; mood improvement; [54][29]
Biotop®

(Lactobacillus acidophilus, Clostridium butyricum, Bacillus mesentericus, Streptococcus faecalis) (human)		 Improvement in IBS 7 symptoms of endoscopic remission patients Social function improvement

* L. acidophilus improves depression severity scores in different study with L. casei and B.bifidum		 [55,56][30][31]
A Mediterranean diet, vitamin D, B-group vitamins, minerals like magnesium and prebiotics such as inulin and oligosaccharides have been stated to enhance the beneficial role of probiotics, leading to long-term beneficial effects for both digestive symptoms and psychiatric disorders. The overall inflammatory cycle diminished alongside cortisol levels and oxidative stress rates, with depression and anxiety scale improvement and reductions in digestive symptoms. The complex intervention is based on the fact that probiotic supplementation alone could fail to stabilize the enteric system, and for bacterial strains to survive they need prebiotics, dietary fibers, vitamins and minerals in order for them to replicate and properly populate the gastrointestinal tract. On the other hand, El Dib et al.’s systematic review found that probiotics might improve affective and anxiety symptoms, but larger samples and sustained follow-up of the patients is needed in order to correctly assess therapeutic management of the gut-brain axis [57,58][32][33]. Magnesium supplementation is a newly emerged probiotic adjuvant, especially when combined with orotic acid. Although small group studies are available, their results seem promising. Combined with probiotics, magnesium orotate seem to improve severe depression symptoms, anxiety manifestation and have an overall anti-inflammatory enteric response. Still, stopping the treatment may lead to symptom relapse, which should be taken into consideration in future studies [59][34].
The emerging research in the field of the gut-brain-microbiome axis has taken into consideration the usage of the term ”psycho-biotics” in light of using specific bacterial strains with the capacity to modulate and influence mood, behavior, anxiety and maybe even cognitive manifestations apart from their digestive effects. The term psycho-biotic does not only cover probiotics, but also their adjuvant therapies, such as prebiotics and dietary supplements, that are required for a therapeutic result [60][35].
Probiotic supplementation may induce anti-inflammatory responses and lower the oxidative reaction. A study published in 2022 measured the correlation between oxidative stress biomarkers and bipolar disorder scale measurement, with results showing an inverted proportionality between plasma biomarkers of oxidative stress and symptom severity, especially with mood disruption, after probiotic therapy [61,62][36][37].

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