Gastrointestinal microbiota, diet and brain functioning

A growing interest for research in the relationship between the gastrointestine (GI), GI microbiota, health and disease is due to the potential for research identifying intervention strategies. Preclinical and clinical studies have indicated that initial colonisation of bacteria in the GI tract can affect the individual’s health condition in later life. Diet is an influential factor in modulating this complex ecosystem and consequently can help to modulate physiological conditions. The broader role of the GI microbiota in modulation of pathology and physiology of various diseases has pointed to the importance of bidirectional communication between the brain and the GI microbiota in maintaining homeostasis. An association of diet with metabolic diseases is well known and there are dietary supplements reported to improve brain function and cognitive decline. In addition to the plausible mechanisms of inflammation and oxidative stress for psychological conditions, more research into the role of the GI microbiota in combination with dietary factors as a component in psychological condition is warranted. From this work, targeted interventions could result.

Although a link between GI function and health or disease in an individual has been determined, the underlying mechanisms are not clearly understood. The GI tract of a newborn is rapidly colonised by microbiota during the birth process through maternal contact and from the surrounding environment. This microbial ecosystem stabilises in first 2–3 years of life and reaches maturity in the human adult¹. By adulthood, the intestine contains approximately 10¹² bacteria per gram of colonic content², which is 10 times the number of cells in the human body. Based on 16S rRNA gene analyses, it was estimated that an adult GI tract harbours between 500 to 1000 different species³ from three major bacterial phyla, Bacteroidetes (Gram-negative), Firmicutes (Gram-positive) and Actinobacteria (Gram-positive). The proportion of these phyla in any individual depends upon that individual’s genetic makeup, dietary habits and surrounding environment.

The initial inoculation then colonisation of the GI impacts the GI microbiota throughout life and the dynamic microbial ecosystem is highly influenced by the surrounding environment and dietary factors. Any modifications in this highly organised and complex ecosystem have the potential to influence the normal physiological functions and are suspected to play a role in obesity, fatty liver disease, inflammation, diabetes and also psychological conditions^4–8.

Upon ageing, weakening of dentition, salivary function, digestion and intestinal transit time may affect the intestinal microbiota^9,10. One manageable environmental factor is diet, which has been shown to significantly impact the GI microbial composition. The types of bacteria present are dependent on the type of substrates available, with some bacteria prospering on a specific substrate while others are unable to utilise that compound¹¹. This selective substrate usage therefore enables modulation of the composition of GI microbiota via the diet, which can occur at any stage of life. However, diet in infancy can greatly affect the maturation process of the microbial profile, gastrointestinal health and immune system.

Human milk is normally the first dietary exposure to an infant. This is fermented in the colon, stimulating the growth of specific bacteria (including Gram positive Bifidobacterium spp.). Infants fed with breast milk and those on milk formula developed and harboured different and diverse bacterial populations in their GI tract¹². Moreover, the composition of different milk formula facilitates different types of bacterial colonisation. Infants fed with oligosaccharide enriched formula harbour higher counts of Bifidobacterium spp. and Lactobacillus spp. compared to infants fed on unsupplemented formulae¹³. This prebiotic effect of infant food could be of a major concern as it plays a role in shaping the GI microbiota that is believed to influence an individual’s health for their entire life. A significant shift in the GI microbial ecology occurs when infants switch to a more solid and varied diet, including substantial reduction in the percentage of Bifidobacterium spp. and Lactobacillus spp. in the total microbiota¹⁴. Throughout adulthood GI microbiota appears to become more stable¹⁵ as with more stable dietary habits. The final shift in composition and function of gut microbiota occurs during the older age of lifespan. In general, aging is associated with a decline in physiological function including in the immune system and metabolism that consequently affects the microbial composition, or vice versa. Human age-related changes reported in the GI microbial composition include a numerical decrease in Bifidobacteruim spp. and Lactobacillus spp. and an increase in Enterobacteriaceae and obligate anaerobes such as Clostridium spp.¹⁶

Numerous dietary components have been identified as having positive or negative effect on brain function and behaviour, this effect can be improved by GI microbiota. Animal studies and human clinical trials have well demonstrated the role of omega-3 polyunsaturated fatty acid in normal brain functioning. Administration of Bifidobacterium spp. in combination with a substrate for eicosapentaenoic acid (EPA), alpha-linolenic acid results in increased concentration of EPA in liver tissue and docosahexaenoic acid in brain tissues^17,18. In wild mice model, probiotics such as L. helveticus prevented high fat diet-induced anxiety-like behaviour¹⁹. Diet can modulate the GI microbial composition by providing a favourable environment while the contrary is also true that GI microbiota can modulate the effect of diet and in turn host physiological and psychological function.

The GI microbiota can produce a vast range of metabolites and/or structural components whose generation depends on the availability of nutrients and the luminal environment. These metabolites are subsequently taken up by GI tissues, potentially reach circulation and other distant tissues and can be excreted in urine and breath. GI microbiota have been linked to very important health functions such as development and role of the immune system⁷, resistance to infection by preventing pathogen colonisation²⁰, bioactivation of beneficial constituents such as polyphenols²¹, detoxification of xenobiotics and metabolism of luminal components leading to formation of a variety of metabolites such as short chain fatty acids (SCFA), vitamins and several gases^11,22,23.

SCFAs such as n-butyrate, acetate and propionate act as key sources of energy for tissues and promote cellular mechanisms that maintain tissue integrity. When SCFAs reach the circulatory system, they impact immune function and inflammation⁸. SCFAs are also involved in host-microbe signalling and control of colonic pH with subsequent effects on microbial composition, intestinal motility and epithelial cell proliferation²⁴. Microbes have also been involved in enzymatic degradation of complex substrates particularly many forms of polysaccharides from ingested food²⁵. For example Bacteroides thetaiotamicron, produces an array of enzymes for carbohydrate breakdown²⁶. During metabolism some gases such as methane, hydrogen, hydrogen sulfide and carbon dioxide are produced within the GI tract. Excess production of these gases may cause GI problems such as bloating and pain. These gases may serve useful purposes however, it is debatable whether hydrogen sulfide for example, is largely beneficial or harmful!²⁷.

Furthermore, GI microbiota can influence behaviour and brain function by influencing the expression of certain body chemicals such as hormons, neurotransmitters and neurotrophic factors. Commensal bacteria such as Bifidobacteria infantis can modulate tryptophan metabolism, this suggest that GI microbiota may influence the precursor pool for serotonin (5-HT)²⁸. Animal studies have demonstrated that GI microbioa can also modulates brain chemistry such as Brain-Derived Neurotropic Factor (BDNF) expression in the hypothalamus and the brainstem²⁹. BDNF is crucially involved in neurogenesis, brain development and neural circuit formation. BDNF has also been recognised as an important antiobesity factor. GI microbiota maintain communication with the host using metabolic, neural, immune and endocrine pathways. For health, homeostasis between the GI microbiota and the host system is essential, since any imbalance in this arrangement may result in a disease condition^4,5,7.

The evidence is increasing for a bidirectional route of communication between brain, gut and GI microbiota which use immune, neural and endocrine pathways and by this means influence gut-brain communication, brain function and even human behaviour^4,5. The top-down mechanism of the effect of stress and psychological condition on the GI functions is known from extensive research, in particular with Inflammatory Bowel Disease, Irritable Bowel Syndrome and Crohn’s disease. However, the role of GI microbiota in brain functions such as stress, cognition and mood need to be explored more comprehensively.

The GI microbiota influences the release of the major neurotransmitters tryptophan, serotonin, endocannabinoid ligands, ghrelin and cholecystokinin, which can influence food intake, energy balance and some brain tasks such as emotion, cognition and motor functions^28,30. Changes in microbial composition and metabolism correlate with the concept of ‘inflamm-ageing’, a low-grade chronic pro-inflammatory status as a common basis for a broad spectrum of age associated pathologies including cognitive decline and immunosenescence³¹. Age-associated changes may increase intestinal permeability and ease the passage of bacterial lipopolysaccharides (LPS) into circulation, resulting in an elevated systemic LPS level. When LPS binds to pattern recognition receptors such as toll-like receptor 4 on immune cells, there is induction of inflammation by production and release of cytokines, leukotrienes and prostaglandin³². Animal studies with probiotic supplementation demonstrated that probiotics can normalise immune responses, reverse behavioural deficits and restore basal noradrenaline level in response to stress⁶. The probiotics also normalise central nervous system (CNS) biochemistry and improve behaviour in a mouse model of colitis, through vagal nerve pathways for gut-brain communication³³. Psychological responses to the GI microbiome composition may be an important factor in understanding the increasing prevalence of psychological conditions in the community and research into this topic should be promoted.

Clinically, a psychological condition does not stand alone since there are frequently immune system and GI comorbidities. Antidepressants are the commonest treatment, and as such are focused on a top-down approach. However, growing evidence from increasing numbers of animal studies and human trials suggest that the GI microbiota composition can be correlated with the incidence of complex conditions such as cognitive decline, anxiety and depression. Detailed clinical interpretation is warranted so that novel interventions in neuropsychological conditions can be employed. Preclinical research combining detailed exploration of the GI microbiota in well-designed human cohort studies investigating the impact of antibiotics, probiotics and diet on the brain and CNS functions will inform us of the importance of bottom-up mechanisms in neuropsychological conditions. Further research in this emerging area will provide novel targets for interventions in psychological disorders.