Ever since Robert Hooke’s first observation of microbes in 1665, these microscopic creatures haven’t failed to fascinate the scientific community. Our knowledge of them has evolved alongside the tools we use to study them. Today we know that these miniscule beings are commensals of our digestive tract. They have been linked to many illnesses inside the gut and beyond it. Their reach to the brain has been the center of many studies. Even though they are still based on animal models, many convincing arguments have risen to establish their role in neuropsychiatric disease. They are briefly reviewed here.
The human gut extends on a surface of 200-300 m2 of mucosa 1. It is so vastly innervated that the enteric nervous system (ENS) has been often called the little brain. It is also the home of many immune response centers including ganglia and gut-associated-lymphoid-tissue (GALT). Not to mention the great role endocrine enterocytes have in regulating appetite and insulin secretion 2,3. It is clear that the role of our gut is way beyond digestion. This makes us wonder about the function of its residing microorganisms. Shelter to over tens of trillions of symbionts belonging to hundreds of different genera and phyla1,4,5, our gut’s inhabitants outnumber the human cells of the entire organism ten times over 5. They have the metabolic capacity of a human liver 6. The extent of their influence is yet to be fully clarified. Today, we’ll tackle the connection between the gut microbiota and the central nervous system. Our focus will be mainly on its relationship with some neuropsychiatric diseases such as autism spectrum disorders, neurodegenerative and anxiety related diseases.
What is the gut microbiota?
Microbiota is the ensemble of microorganisms (archeae, bacteria, fungi, parasites and viruses) present in a specific environment or host. It is present on all surfaces of the body including the skin, the bronchopulmonary, urogenital, and gastrointestinal tract 1,6,7.
The term microbiota is sometimes used interchangeably with the term microbiome 7. The latter refers to the combined genome of the aforementioned microbes which can be 150 times larger than the human one 1.
The study of the human microbiota focuses mostly on that of the gut because it is by far the largest and most dynamic one. It also revolves mostly around bacteria 6.
Gut microbiota’s (GM) composition is variable throughout the gastrointestinal tract. It is a dynamic entity whose composition varies depending on environmental factors such as drugs and diet and host factors such as age and individual genetics 1,6.
It has many crucial roles in our metabolism, such as immune function as well as the development of various organs including our brain 6–8. Indeed, our GM acts as a filter that modifies and tunes chemical signal throughout the body. Not only does it play an essential role in digesting dietary fibers for which we don’t possess the necessary enzymes, it also acts through its metabolites as a modulator of our endocrine enterocytes and helps regulate satiety and carbohydrate metabolism1,6. Furthermore, it helps keep the integrity of the gut barrier and repress pathogens’ growth in the gut 9.
Any disturbance in Gut Microbiota composition can compromise its different functions. This is what is called dysbiosis. It is characterized by a reduced microbial diversity with a predominance of proinflammatory species. Thus, GM can no longer suppress pathogenic organisms that produce toxins, carcinogens and induce inflammation 10.
What is the gut microbiota brain axis ?
The connection between the gut and the brain has long been established. The fact that the enteric nervous system is called the little or second brain is no coincidence 1,7. It ensures a bidirectional communication with the CNS via sympathetic and parasympathetic nerves, hormones and neuromodulatory proteins. This is clearly demonstrated by the existence of stress related gastrointestinal symptoms seen in irritable bowel syndrome (IBS). Also, the gastrointestinal system is speculated to be the starting point of certain neurodegenerative diseases such as Parkinson’s (PD) and links are being established between the latter and inflammatory bowel disease (IBS) 11.
Due to the clear role that gut microbiota possesses in all these phenomena, and due to the fact that the CNS and ENS are so similar in more ways than one. Gut microbiota affecting the latter strongly suggests its influence on the former. Therefore, this axis has been extended to include microbiota and hence the term microbiota gut brain axis (MGBA). According to Morais et al 6, this bidirectional communication between the gut microbiota and the central nervous system occurs through different pathways that could be classified into three: neurological, chemical (or endocrine) and immunologic in nature.
1. The neurologic communication of GM is directed towards the ENS and/or the CNS. Its reach into the ENS is clear as it helps maintain its neuronal network through stimulation of enteric glial cells. It also interferes with gut motility by activating ENS via certain bacterial metabolites such as bacterial wall components 6.
Far from the little brain, gut microbiota’s direct reach to the CNS has also been seen in germ-free (GF) mice in which extrinsic neurons connecting to the brain stem are increasingly activated suggesting that GM has a suppressive effect on certain neuronal pathways.
Last but not least, CNS can also be influenced via the Vagus (Xth) nerve, one of the main connections between the central and enteric nervous system. GM can act as a chemical stimulator of neural endings of the Xth nerve: it can influence the activity of endocrine enterocytes (EECs) via its metabolites (such as short chain fatty acids or SCFA). EECs
therefore secrete hormones, neurotransmitters and metabolites capable of activating the vagus nerve which relays the signal consequently to the brain.
In reverse, the vagus nerve can relay brain signals to the viscera, changing therefore the gut environment and altering the composition of the microbiota 6.
2. The chemical and endocrine pathway involves neurotransmitters such as gamma-amino-butyric-acid or GABA, serotonin (5-HT) or dopamine 6. Indeed, 90% of 5-HT and 50% of dopamine originate from the gut1. Bacterial metabolites such as SCFA can modulate the release of these important neurotransmitters which can directly or indirectly influence the brain. The direct pathway goes from the blood to the brain through the blood brain barrier (BBB). The BBB permeability to some of these molecules is low as in the case of serotonin. Animal models using GF mice have shown a low cerebral level of 5-HT, suggesting a possible influence of the GM on central neurotransmitter synthesis. How this influence occurs remains unknown6. The indirect chemical influence of gut microbiota involves the aforementioned ENS and vagus nerve.
As to hormones, GM can act as modulator of their synthesis by the host 1,6. It is the case of glucagon-like peptide 1 (GLP1) secreted by enteroendocrine cells (EECs) present in the gut epithelium.
3. The immunologic pathway includes the constant challenge of GALT and innate immunity in the gut by the residing microbiota. Additionally, maturation and development of microglial cells is lacking in germ-free mice. It can be palliated by administering certain bacteria at certain key times in their life that are different depending on sex. Meaning that not all bacteria can induce maturation of neurologic macrophages. Also, the time at which these bacterial taxa are administered is of essence and depends on host factors that should be studied further in humans.
Moreover, gut microbiota can modulate cytokines and chemokines secretion and therefore the systemic inflammation. The reach of these cytokines to the brain depends again on the BBB integrity. This could be compromised by partial and reduced expression of tight junction of the barrier as seen in GF mice and in case of inflammation 6,12, suggesting the key role of GM in systemic and cerebral inflammation.
Neuropsychiatric disease and gut microbiota brain axis
Autism spectrum disorder or ASD is a group of neurodevelopmental disorders that manifest early in life by defect in language acquisition, repetitive behavior and lack of sociability. The frequency of gastrointestinal symptoms in this spectrum is among an arsenal of arguments supporting involvement of gut-microbiota-brain axis in the disorder’s pathogenesis.
In fact, animal models have shown that germ-free mice have ASD-like behaviors. While others demonstrated that some antibiotic-treated animals lack sociability.
Finally, administering certain microorganisms can help alleviate autistic traits in ASD animal models.
In humans, the composition of gut microbiota was found to be different in ASD individuals compared to their neurotypical counterparts. That is why some studies investigated fecal transplantation as a treatment for Autism. Results were promising, nevertheless further studies are needed 13.
Neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) are typically seen in older adults. They are thought to be associated with an altered immune response that leads to a defective gut barrier and systemic inflammation. Therefore, increasing BBB permeability and inducing brain degeneration. This would give rise to deposition of ß-amyloid proteins in Alzheimer’s disease, and misfolding of α-synuclein and its accumulation in Parkinson’s disease. The factor precipitating this pathogenesis is thought to be age.
In fact, gut microbiota composition is different in the elderly mainly due to poor diet and medication. This is further supported by AD animal models’ studies in which reduced ß-amyloid deposits were noted when treated with antibiotics. By contrast, animals transplanted with fecal microbiota of Alzheimer’s animals had an increase in said deposits. Besides, in PD animal models, GF mice showed low -synuclein expression while mice with Parkinson-like phenotype colonized with feces from patients with PD showed over-expression in -synuclein and therefore accelerated disease 6,7.
Anxiety and depression are mood disorders in which our brains fail to process psychological stress and restore homeostasis. This leads to hyperactivation of neuroendocrine signaling via the hypothalamic–pituitary–adrenal (HPA) axis and manifests through high glucocorticoid levels in serum. In addition, HPA axis exaggerated activation is seen in germ-free mice. This phenomena can be reversed and glucocorticoid levels normalized when administering certain gut bacteria to these mice 6,14. Moreover, putting aside interindividual differences in GM composition, the microbiota profile of depressive individuals had several predominant genera when compared to controls15.
Another animal study objectified high cortisol blood levels and low microbiota richness in rats’ guts which were colonized with depressives’ GM. They also developed depressive behavior. All arguments point to dysbiosis as a crucial element in depression pathogenesis 16.
It is true that we owe most of what we know today on gut microbiota brain axis to animal models. However, their limitations cannot be overlooked. The complexity of neuropsychiatric disease renders it nearly impossible to be recapitulated by any animal model.
The fact that brain disorders are often multifactorial and vary widely from person to person only adds to the problem. It is very important therefore to work on well-defined populations in order to be able to transpose their phenotypes into an animal model.
Also, the use of novel tools of microbiology and neuroscience is essential in helping develop this line of research. This includes humanized animal models: animals transplanted with human gut-microbiota. This can prove to be a reasonable solution to interspecies variability in composition of GM. It would also help enlighten the pathogenesis of neuropsychiatric diseases by studying the effect of GM of sick individuals in animal models. The aforementioned instance of transplanting PD patients’ GM into PD animal models is a good case in point 6.
The use of probiotics, fecal microbiota transplantation (FMT) as well as helminths-based therapies in the treatment of many brain disorders seem to be a promising area of research in this field 6,7,13,14,17.
The term of psychobiotics has emerged, meaning ‟the family of bacteria that, ingested in appropriate quantities, had a positive mental health benefit” 14. It now includes prebiotics (dietary fibers) that promote the growth of said bacteria. The efficacy of probiotics in treating IBS, combined with the fact that IBS can be anxiety-induced, suggests possible benefit in brain disorders. This is further demonstrated in alleviated stress-related symptoms in groups receiving certain probiotics compared to controls 18.
Similar results were seen in other psychiatric diseases such as autism spectrum disorders when probiotics were administered 1 as well as for certain prebiotics which can have anxiolytic effects 19.
Fecal microbiota transplantation or FMT emerged in the latest decades as an efficient treatment for infectious and inflammatory conditions such as Clostridioides difficile infection (CDI) and inflammatory bowel disease. Thus, it has earned a place in the IDSA (Infectious Diseases’ Society of America) guidelines since 2010. Transplanting healthy microbiota into the gut of the sick can be a seductive solution to the dysbiosis observed in many neuropsychiatric diseases as demonstrated by many animal models. Studies are currently evaluating this indication for FMT 20.
Trichuris suis ova is the purified egg of a worm called T. suis that can have immunomodulatory effects and can reinforce the gut’s mucosal barrier. It has been used in a couple of studies as treatment for Autism spectrum disorders showing promising results 17.
Gut microbiota brain axis is a fascinating example of how complex human physiology is. In the frontier between neuropsychiatry and microbiology, this axis has set scientists on the track of understanding and possibly treating very difficult diseases. Taking the leap from animal models is necessary in order to have more reliable evidence concerning the pathogenic role of gut microbiota brain axis in neuropsychiatric disease, however problems of the ethical and economic order may rise as obstacles to studying this process in humans. Only the future can tell who will rise to that challenge.
1. Adak A, Khan MR. An insight into gut microbiota and its functionalities. Cell Mol Life Sci [Internet]. 2019 Feb [cited 2021 Sep 3];76(3):473–93.
2. Latorre R, Sternini C, De Giorgio R, Greenwood-Van Meerveld B. Enteroendocrine Cells: A Review of Their Role In Brain-Gut Communication. Neurogastroenterol Motil Off J Eur Gastrointest Motil Soc [Internet]. 2016 May [cited 2021 Sep 4];28(5):620–30.
3. Gribble FM, Reimann F. Function and mechanisms of enteroendocrine cells and gut hormones in metabolism. Nat Rev Endocrinol [Internet]. 2019 Apr [cited 2021 Sep 4];15(4):226–37.
4. Mörbe UM, Jørgensen PB, Fenton TM, von Burg N, Riis LB, Spencer J, et al. Human gut-associated lymphoid tissues (GALT); diversity, structure, and function. Mucosal Immunol [Internet]. 2021 Jul [cited 2021 Sep 4];14(4):793–802.
5. Sender: Are we really vastly outnumbered? Revisiting… – Google Scholar [Internet]. [cited 2021 Sep 4].
6. Morais LH, Schreiber HL, Mazmanian SK. The gut microbiota–brain axis in behaviour and brain disorders. Nat Rev Microbiol [Internet]. 2021 Apr [cited 2021 Sep 3];19(4):241–55.
7. Quigley EMM. Microbiota-Brain-Gut Axis and Neurodegenerative Diseases. Curr Neurol Neurosci Rep [Internet]. 2017 Dec [cited 2021 Sep 3];17(12):94.
8. Ogbonnaya ES, Clarke G, Shanahan F, Dinan TG, Cryan JF, O’Leary OF. Adult Hippocampal Neurogenesis Is Regulated by the Microbiome. Biol Psychiatry [Internet]. 2015 Aug [cited 2021 Sep 3];78(4):e7–9.
9. Kamada N, Chen GY, Inohara N, Núñez G. Control of pathogens and pathobionts by the gut microbiota. Nat Immunol [Internet]. 2013 Jul [cited 2021 Sep 10];14(7):685–90.
10. Dysbiosis – an overview | ScienceDirect Topics [Internet]. [cited 2021 Sep 3].
11. Brudek T. Inflammatory Bowel Diseases and Parkinson’s Disease. J Park Dis. 2019;9(s2):S331–44.
12. Braniste V, Al-Asmakh M, Kowal C, Anuar F, Abbaspour A, Tóth M, et al. The gut microbiota influences blood-brain barrier permeability in mice. Sci Transl Med [Internet]. 2014 Nov 19 [cited 2021 Sep 4];
13. Kang D-W, Adams JB, Gregory AC, Borody T, Chittick L, Fasano A, et al. Microbiota Transfer Therapy alters gut ecosystem and improves gastrointestinal and autism symptoms: an open-label study. Microbiome. 2017 Jan 23;5(1):10.
14. Dinan TG, Cryan JF. Brain-Gut-Microbiota Axis and Mental Health. Psychosom Med [Internet]. 2017 Oct [cited 2021 Sep 3];79(8):920–6.
15. Jiang H, Ling Z, Zhang Y, Mao H, Ma Z, Yin Y, et al. Altered fecal microbiota composition in patients with major depressive disorder. Brain Behav Immun. 2015 Aug;48:186–94.
16. Kelly JR, Borre Y, O’ Brien C, Patterson E, El Aidy S, Deane J, et al. Transferring the blues: Depression-associated gut microbiota induces neurobehavioural changes in the rat. J Psychiatr Res. 2016 Nov;82:109–18.
17. Li Q, Zhou J-M. The microbiota–gut–brain axis and its potential therapeutic role in autism spectrum disorder. Neuroscience [Internet]. 2016 Jun [cited 2021 Sep 3];324:131–9.
18. Takada M, Nishida K, Kataoka-Kato A, Gondo Y, Ishikawa H, Suda K, et al. Probiotic Lactobacillus casei strain Shirota relieves stress-associated symptoms by modulating the gut-brain interaction in human and animal models. Neurogastroenterol Motil Off J Eur Gastrointest Motil Soc. 2016 Jul;28(7):1027–36.
19. Schmidt K, Cowen PJ, Harmer CJ, Tzortzis G, Errington S, Burnet PWJ. Prebiotic intake reduces the waking cortisol response and alters emotional bias in healthy volunteers. Psychopharmacology (Berl). 2015 May;232(10):1793–801.
20. Ademe M. Benefits of fecal microbiota transplantation: A comprehensive review. J Infect Dev Ctries. 2020 Oct 31;14(10):1074–80.
21. Long-Smith C, O’Riordan KJ, Clarke G, Stanton C, Dinan TG, Cryan JF. Microbiota-Gut-Brain Axis: New Therapeutic Opportunities. Annu Rev Pharmacol Toxicol [Internet]. 2020 Jan 6 [cited 2021 Sep 21];60(1):477–502. 22. Valdes AM, Walter J, Segal E, Spector TD. Role of the gut microbiota in nutrition and health. BMJ [Internet]. 2018 Jun 13 [cited 2021 Sep 21];k2179.