10 Mental Health and Multi-Microbiome Interactions

Mental Health and Multi-Microbiome Interactions

It may seem obvious that localized microbiomes are responsible for diseases related to their respective areas (e.g., IBD and the gut microbiome or AD and the skin microbiome), however, it is a fascinating phenomenon that various microbiomes can affect each other and influence health in different parts of the body. Even more captivating is the link between certain microbiomes and mental health conditions presuming the brain is devoid of microbes.

These links between microbiomes are referred to as axes, and initial connections began with the most well-studied microbiome, the gut. Since many gut-derived microbial-produced molecules and compounds are spread through the bloodstream, associations with various organs are formed, such as the gut-brain axis, gut-skin axis, gut-lung axis, or a combination of multiple; gut-brain-skin axis. There are likely overlapping connections between all microbial components that form the human holobiome, thus teasing apart the exact members and their functions is a dutiful task.

Gut Interaction with Other Microbiomes

As mentioned earlier, the dissemination of molecules and compounds from the gut to the rest of the body creates an interconnected highway affecting most, if not all, parts of the body.  Certainly, juxtaposed regions such as the oral cavity and the proximal portions of the GI tract have a relationship between their microbiomes, which it termed the gut-oral axis (GOA). These linked microbiomes have been shown to have immunomodulatory roles in the development of rheumatoid arthritis (RA) and osteoarthritis (OA) under dysbiosis, where the abundance of oral Porphyromonas gingivalis and intestinal Prevotella copri could be responsible (Drago et al., 2019, du Teil Espina et al., 2019). It has also been proposed that dysbiosis of the gut-oral microbiome axis is implicated in cirrhosis of the liver through pathogen invasion, resultant systemic inflammation, and impaired immunity and liver function (Acharya et al., 2017). Even gastrointestinal conditions like IBD and cancer of the colon, liver, and pancreas are linked with both the gut and oral microbiome dysbiosis, further demonstrating this strong interorgan connection to human health (Park et al., 2021).

The gut and the skin microbiomes are also linked via the gut-skin axis (GSA), and as the primary interface to the environment, they have major roles in physiological health (Figure 1). Dysbiosis of the gut-skin microbiome axis has influence on both GI and cutaneous disorders such as IBD, celiac disease, atopic dermatitis, psoriasis, acne, and other dermatologic issues, where each of these diseases can be associated with the ‘partner disease’ (i.e. a disease in one system linked to a disease in another system) (O’Neill et al., 2016, Salem et al., 2018, De Pessemier et al., 2021). Though crosstalk is bidirectional, more research seems to have focused on skin disorders and homeostasis as a result of gut microbiome health, where diet, immunomodulation, intestinal permeability, and metabolite secretion are major contributing factors (De Pessemier et al., 2021). However, there is evidence that Mallassezia restricta, a fungal member of the skin microbiota, is associated with Crohn’s disease and can exacerbate colitis (Limon et al., 2019, Sinha et al., 2021).

Microbiome and immune system connection between the skin and gut.
Figure 1. Inflammatory and microbial influences between the gut and skin for a healthy state (left) and a dysbiotic state (right): The intestinal and epidermal barriers are connected through the systemic circulation (blood and lymph) and are visualized here together in a simplistic manner. The dysbiotic state is characterized by an impaired gut barrier (imbalance in gut microbiome, reduced mucus layer, reduced IgA secretion, barrier disruption, intestinal permeation into the bloodstream, and gut inflammation) and an impaired skin barrier (imbalance in skin microbiome, reduced human and microbial antimicrobial peptides (AMP) production, skin rashes/thickening/lesions, and skin inflammation). Gut and skin dysbiosis are connected through an immune imbalance (Th2 skewing in this example), whereas crosstalk can be bidirectional (De Pessemier et al., 2021).

The gut-lung axis (GLA) has roles in the regulation of immunity and the development of various respiratory diseases. (Frati et al., 2019). The respiratory system and GI tract are connected by the mesenteric lymphatic system, where intact or fragmented microbes and their metabolites enter systemic circulation after passing through the intestinal barrier and can migrate to the pulmonary system to modulate immune responses (Enaud et al., 2020). The pathophysiology of diseases such as atopy and asthma are complicated and can be contributed to a variety of factors, however, there is evidence that dysbiosis of the gut microbiome contributes to the development of asthma, particularly in youths who exhibit a decrease in Lachnospira and increase in Clostridium spp. (Penders et al., 2007, Watson et al.,2019). Gut dysbiosis is also involved in chronic obstructive pulmonary disease (COPD) exacerbation, where fiber deficiency in an individual’s diet can contribute to chronic inflammation. Metabolism of fiber by gut microbes produces anti-inflammatory short-chain fatty acids (SCFAs), which could reduce inflammation both systemically and in the lungs, and so targeted dietary intervention for these patients may be a viable treatment addition for COPD and other respiratory diseases associated with inflammation like COVID-19 (Li et al., 2018, Vaughan et al., 2019, Allali et al., 2021). Moreover, SCFAs also have an important role in the defense against secondary infections in those afflicted by viral respiratory infections, further demonstrating the importance of gut microbiome health in connection with the GLA (Sensio et al., 2020).

Like other axes, immunomodulation by the gut microbiome also has influence on the gut-vagina axis (GVA), though it is less extensively studied. One promising avenue of treating vaginal diseases, specifically cervical cancer associated with human papilloma virus (HPV), is the use of mucosal lactic-acid bacteria (LAB)-based vaccines to modulate the gut microbiome. The approach could work as a prophylactic or for direct therapy, and be more easily administered via an oral route instead of parenteral (Taghinezhad-S, et al., 2021). Endometriosis and infertility are also disorders associated with sex hormone levels and inflammation, which once again are influenced by the gut microbiome composition and state. Specifically, there are some members in the gut who can affect the levels of circulating estrogen through metabolic processes and an altered state could lead to increased risk or symptom severity of these disorders (Salliss et al., 2022). Other female reproductive-associated diseases such as polycystic ovarian syndrome (PCOS), also associated with gut dysbiosis, could be ameliorated by diet modification and restoration of gut homeostasis. Here, the use of flaxseed oil could increase diminished levels of SCFAs observed in those with PCOS and protect against inflammation characteristic of the disease (Wang et al., 2020).

The maternal microbiome, including gut, vagina, and breast milk, can greatly influence the colonization and health of the infant after birth, but also affect the fetus prior to delivery. Fetal immune development is most likely influenced in the womb from translocation of maternal gut microbes and/or their metabolites across the placental barrier or ingestion of amniotic fluids (Walker et al., 2017, Nyangahu and Jaspan, 2019). Post-reproduction, the infant gut microbiome is continually developed through initial diet, and more specifically vertical transmission of the contents in the mother’s breast milk which includes its own unique microbiome (Ojo-Okunola et al., 2018, Ojo-Okunola et al., 2019, Quin et al., 2020). The human milk microbiome promotes infant gut colonization of probiotic strains which have roles in programming the immune and metabolic systems, as well as anti-infective, anti-allergic, and anti-tumor properties (Heikkila and Saris, 2003, Olivares et al., 2006, Lara-Villoslada et al., 2007, Civardi et al., 2015, Hassan et al., 2015, Walker and Iyengar, 2015, Boix-Amoros et al., 2016Ojo-Okunola et al., 2018).

Mental Health Axes

The thought of microorganisms controlling aspects of cognitive function in their host, especially humans, is fascinating to say the least. While connections between other microbiomes, organ systems, and diseases may be less surprising, the microbial link to psychiatric, neurodevelopmental, age-related, and neurodegenerative disorders is very much intriguing. The human microbiome can communicate with the brain in a variety of ways; through the immune system, metabolism, endocrine system, circulatory system, and the nervous system, where microbes, their induced immune response, and their metabolites such as short-chain fatty acids, branched chain amino acids, and peptidoglycans are involved (Figure 2) (Liang et al., 2018, Cryan et al., 2019, Olsen and Hicks, 2019, Hadian et al., 2020, Bear et al., 2021). Several local microbiomes each contribute affects to the mental state, and whether it is gut-, skin-, oral-, lung-, etc. derived can dictate roles in various disorders. This is not just a one-way street though, as microbes around the body can alter mental states but also be affected by governance of the brain in a bi-directional manner (Ma et al., 2019).

Interactions between the microbiome-gut-brain axis which dictate various composition and functions.
Figure 2. The proposed mechanisms of the microbiome-gut-brain axis (MGBA) are complex and intertwined. Emerging research shows that psychological stress interacts not only directly with the brain and mood, but also with many of the MGBA mechanisms thought to contribute to changes in mood with alteration of the gut microbiota. Solid lines indicate strong evidence of an effect, and dotted lines show proposed mechanisms with limited but emerging evidence. Abbreviations: HPA; Hypothalamic-Pituitary-Adrenal (Bear et al., 2021).


Similar to other types of microbiome and organ interactions, the gut’s role in mental health is central and most well studied, which makes sense as it is the largest repository of microorganisms associated with the human body. The gut-brain axis (GBA; and gut plus essentially every other microbiome and brain axis, e.g., gut-skin-brain)  is implicated in a number of cognitive functions and disorders including autism, anxiety, depression, stress, pain sensitivity, learning capacities, memory loss, moods and emotions, behavior (dietary, social, and reproductive), schizophrenia, Parkinson’s disease, and Alzheimer’s disease (Desbonnet et al., 2013, Stumpf et al., 2013, Dash et al., 2015, Gareau, 2016, Luczynski et al., 2016, Hoban et al., 2017, Liang et al., 2018, Manderino et al., 2017, Nishida and Ochman, 2017, Vuong et al., 2017, Cowan et al., 2018, Cryan et al., 2019, Bear et al., 2021, Narengaowa et al., 2021). The gut microbiome actually develops in sync with the brain and psychology, and disturbances during different stages of growth can result in the onset of different diseases (Figure 3) (Borre et al., 2014, Gur et al., 2015, Sampson and Mazmanian, 2015, Dinan and Cryan, 2016, Luczynski et al., 2016, Sharon et al., 2016, Kundu et al., 2017, Vuong et al., 2017, Carlson et al., 2018, Liang et al., 2018).

Development of mental faculties in relation to the gut-brain axis.
Figure 3. The gut-brain, brain, and mentality develop almost synchronously throughout the lifespan. The gut-brain, brain, and mentality undergo similar developmental patterns; all three are susceptible to several factors that influence the gut microbiota. Myelination, intestinal length, and the gut microbiota develop almost synchronously. Diet plays an important role in the maturation of the gut-brain and brain, and mentality is regulated by the development of the brain and gut-brain. Microbiota disruption at different stages is likely to increase the incidence of different mental disorders (Liang et al., 2018).

Early perturbation of the gut microbiome during the post-natal period, and even within the womb, can especially increase susceptibility to developing mental disorders since these are critical stages for development of the gut-brain axis and mind (Borre et al., 2014, Gur et al., 2015, Diaz Heijtz, 2016, Mika et al., 2016, Slykerman et al., 2016, O’Mahony et al., 2017, Liang et al., 2018). Even up through senescence, an abnormal gut microbiota is linked with several mental disorders, though the good news is that they can be remedied or improved by returning the gut to a homeostatic state. As the prevalence of mental disorders and neurological diseases have been steadily increasing, healing mental health by exploring and implementing options such as fecal microbiota transplant, diet intervention, probiotics, prebiotics, and psychobiotics are a must (Cryan and Dinan, 2012, Dinan et al., 2013, Liang et al., 2015, Pirbaglou et al., 2016, He et al., 2017, Kang et al., 2017, Mika et al., 2017, Bruce-Keller et al., 2018, Liang et al., 2018, Yang et al., 2018, Kesika et al., 2021, Margolis et al., 2021).

There are several ideas as to why there has been an increase in mental and neurological disorders in relation to the human microbiome.  The “Gut Microbiota” hypothesis suggests this escalation is a direct result from gut microbiome dysbiosis due to factors of modern society such as diet, antibiotics, and stress (Liang et al., 2018b). The “Old Friends” hypothesis proposes that the co-evolution of early humanity with its microbiota in a less civilized and more natural ecosystem promoted the development of a stronger immune system, but now changes in lifestyle and environment leads to weaker immunity and subsequent disorders (Strachan, 1989, Rook and Lowry, 2008, Kramer et al., 2013, Rook, 2013). Lastly, the “Leaky Gut” theory implies that damage to the mucosal barrier of the gut increases intestinal permeability, which allows biomolecules and microorganisms to gain access various parts of the body that they normally couldn’t, and thereafter cause disease (Leclercq et al., 2012, Smythies and Smythies, 2014, Kelly et al., 2015, Potgieter et al., 2015, Slyepchenko et al., 2017, Liang et al., 2018). All of theses propositions are clear in their indication that the gut microbiome and its part in immune development has a definite role in the functioning of the mind, though the exact extent and mechanisms remain to be discovered.

Other Microbiomes and Mental Health

The majority of human microbiome interaction with regards to human health usually includes the gut to some degree, though there are some questions as to whether certain microbiomes create their own axes with the brain.

The oral microbiome can potentially get direct or indirect access to the brain through the olfactory tract, or via the circulatory system where blood can transport microbes to the blood-brain barrier (BBB), perivascular spaces, and circumventricular organs (Figure 4) (Olsen and Singhrao, 2015, Ranjan et al., 2018, Olsen and Hicks, 2019). Microbial access to the bloodstream can commonly occur during dental procedures, and pathogen invasion of the brain can impact neuro-immune activity and inflammation (Olsen, 2008). These oral-brain axis-derived infections could contribute to mental disorders such as Alzheimer’s disease (AD), dementia, Down’s syndrome, bipolar disorder, and autism spectrum disorder (ASD; which can lead to oral dysbiosis) (Ilievski et al., 2018, Olsen and Hicks, 2019, Maitre et al., 2020). Oral dysbiosis can also promote the development of ASD by affecting the metabolome and thus can create a troublesome positive feedback loop (Mussap et al., 2016, Wang et al., 2016).

Interactions between the oral microbiome and brain function, including direct and indirect mechanisms.
Figure 4. Direct and indirect mechanisms of infecting the brain. In the direct mechanism, the oral cavity infects the olfactory tract, and the olfactory nerve transfer the bacteria to the brain. In other mechanisms, bacteria inside the mouth infect the blood and find their way via blood, blood–brain barrier (BBB), perivascular spaces and circumventricular organs to the brain (Olsen and Hicks, 2019).

Concerning the skin-brain axis, dysbiosis of the skin microbiome and chronic wounds can elicit systemic effects and induce neural responses that eventually affect the central nervous system (Figure 5) (Hadian et al., 2020). Chronic wounds exhibit persistent inflammation and can have various etiologies including diabetic foot ulcers (DFU), venous ulcers, arterial ulcers, pressure ulcers, surgical wounds, and other traumatic wounds (Green et al., 2014, Renner and Erfurt-Berge, 2017, Bui et al., 2018, Pedras et al., 2018, Hadian et al., 2020). In these cases, a compromised skin barrier can allow pathogens and their derivatives to enter the bloodstream, and if the skin is in a dysbiotic state, then abundant pathogens such as Staphylococcus aureus and Pseudomonas aeruginosa can amplify this effect by inducing epithelial permeability (Roy et al., 2014, Basler et al., 2017). These microbes, metabolites, pro-inflammatory mediators, and other constituents circulate within the blood, potentially induce permeability in the blood-brain barrier (BBB), and eventually reach the brain to cause disorders such as wound-associated depression, anxiety, and other cognitive disorders (Wang et al., 2011, Zhang et al., 2015, Hadian et al., 2020). The skin-brain axis acts in a bi-direction manner too, with studies showing connections between certain mental disorders like post-traumatic stress disorder, and skin diseases associated with dysbiosis like psoriasis, chronic urticaria (hives), and atopic  dermatitis (Gupta et al., 2017, Beri, 2018).

Pathway of chronic wounds affecting the brain and behavior effects.
Figure 5. The chronic wound with its microbiota induces localized inflammatory alterations that can result in systemic effects by increasing both epidermal and vascular permeability and activating neurons to generate nocioceptive signals—all ultimately culminating in central nervous system effects. Red: Proposed mediators. Yellow: Proposed downstream events. BBB: blood brain barrier, CNS: central nervous system, PAMP: pathogen associated molecular pattern, TLR: toll like receptor (Hadian et al., 2020).

The lung-brain axis connects pulmonary microbes to neurodegenerative disorders and behavior characteristics, and though not much research has focused on this specific link, there are indications that air pollution can be a trigger. Pollutants in the air come from a variety of sources including engine emissions, coal combustion, biomass burning, and secondary photochemical products, such as ground level ozone (O3) (Mumaw et al., 2016). These compounds can be a source of chronic neuroinflammation and persistently affect microglial cells in the central nervous system, which in turn can increase risk of diseases such as Alzheimer’s disease, Parkinson’s disease, and autism,  as well as elicit a decline in cognitive function in the elderly (Power et al., 2011, Wellenius et al., 2012, Roberts et al., 2013, Volk et al., 2013, Heneka et al., 2014, Jung et al., 2015, Kirrane et al., 2015, Mumaw et al., 2016). It is likely that air pollution also negatively affects the lung microbiome, and dysbiosis could further aggravate immune responses and cognitive disruption (Mousavi et al., 2021, Whiteside et al., 2021).

Is there a brain microbiome?

That is, are there resident microbes residing with a living brain? With many neurodegenerative and neuropsychiatric diseases lacking a clear etiology, determining any and all potential associations could help in therapeutic efforts (Link, 2021). The healthy brain is an assumedly sterile environment, though the same was once thought about other organs like the lungs. Interestingly, one study found evidence for the existence of viable bacteria in the human brain. Here, researchers were interested to see whether microbial invasion accompanied damaged brains observed in HIV/AIDS. After sequencing total RNA from cerebral white matter, they found bacteria and phage sequences in both experimental and control brain samples, which was further validated by 16S rRNA gene target amplification and in situ staining (Branton et al., 2013, Link, 2021).

If there were resident microbes in the brain, they would certainly be at much lower abundances as compared with other regions such as the gut or the oral cavity. Though there has been much interest in characterizing the presence of pathogens in unhealthy brains for disorders like Alzheimer’s disease, which is an arduous feat in itself, finding residents in a healthy state could prove even more difficult (Zhan et al., 2016, Alonzo et al., 2018, Dominy et al., 2019, Link, 2021). That is, identification approaches could easily miss novel or fastidious microorganisms, and contamination is hard to avoid. Furthermore, a wide-range of controlled and unbiased studies are necessary to catalogue a possible brain microbiome, however, completing this task in humans brings about ethical implications and sampling limitations (Link, 2021). It is fascinating to consider the prospect of symbiotic brain microorganisms, and how they could influence our health or who we are.


Mental faculties contribute greatly to human health, and therefore characterizing the involvement of the human microbiome is of substantial importance. Many of these select microbiomes overlap, and the disorders associated with each are likely entangled in a complex array. Brain functions are extremely complex as is, and piecing together the microbial puzzle within their reach further complicates matters. However, there is great optimism in considering the human microbiome as a source or target for advanced therapy to resolve mental disorders and other diseases, which could drastically change the way we think about medicine.


Discussion Concept Mapping

With a partner or as a class, connect two or more microbiomes using a concept map. Explain how and/or why the various microbiomes are linked (e.g., disease cause vs. effect, direct vs. indirect, pathways, consortia translocation, factors affecting composition, etc.).


Check your Understanding

  • In what ways does the gut microbiome connect with other microbiomes and regions of the body? How does it influence the development of diseases in these areas?
  • How could early use of antibiotics influence the development of asthma in children?
  • How could gut microbiome metabolites (SCFAs) contribute to healthy human states?
  • In what ways does the human microbiome communicate with the brain?
  • What options are available to treat mental disorders through the gut microbiome?
  • Why have mental illnesses been increasing in prevalence and how could the gut microbiome be involved?
  • How are microbiomes, other than the gut, implicated in mental health?
  • What role does skin microbiome dysbiosis and chronic wounds have in the development of cognitive disorders?

Media Attributions


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