The microbiome-gut-brain axis in health and disease

Gut microbes are capable of producing most neurotransmitters found in the human brain. While these neurotransmitters primarily act locally in the gut, modulating the enteric nervous system, evidence is now accumulating to support the view that gut microbes through multiple mechanisms can influence central neurochemistry and behavior. This has been described as a fundamental paradigm shift in neuroscience. Bifidobacteria for example can produce and increase plasma levels of the serotonin precursor tryptophan, which is fundamental in regulating mood, appetite and gastrointestinal function. Certain Lactobacilli have been shown to produce gamma-aminobutyric acid (GABA) and to alter brain GABA receptor expression and behavior. IBS is regarded as the prototypic disorder of the brain-gut-microbiota axis which can be responsive to probiotic therapy. Recently, the concept of a psychobiotic has been introduced in the literature. A psychobiotic is a bacteria which when ingested in adequate amounts can have a positive mental health benefit. Translational studies indicate that certain bacteria may impact upon stress responses and cognitive functioning. Manipulating the gut microbiota with psychobiotics, prebiotics or even antibiotics offers a novel approach to altering brain function and treating gut-brain axis disorders such as depression and autism

Interleukin-6 Modulates Colonic Transepithelial Ion Transport in the Stress-Sensitive Wistar Kyoto Rat

Immunological challenge stimulates secretion of the pro-inflammatory cytokine interleukin (IL)-6, resulting in variety of biological responses. In the gastrointestinal tract, IL-6 modulates the excitability of submucosal neurons and stimulates secretion into the colonic lumen. When considered in the context of the functional bowel disorder, irritable bowel syndrome (IBS), where plasma levels of IL-6 are elevated, this may reflect an important molecular mechanism contributing to symptom flares, particularly in the diarrhea-predominant phenotype. In these studies, colonic ion transport, an indicator of absorption and secretion, was assessed in the stress-sensitive Wistar Kyoto (WKY) rat model of IBS. Mucosa-submucosal colonic preparations from WKY and control Sprague Dawley (SD) rats were mounted in Ussing chambers and the basal short circuit current (I(SC)) was electrophysiologically recorded and compared between the strains. Exposure to IL-6 (1 nM) stimulated a secretory current of greater amplitude in WKY as compared to SD samples. Furthermore, the observed IL-6-mediated potentiation of secretory currents evoked by veratridine and capsaicin in SD rats was blunted in WKY rats. Exposure to IL-6 also stimulated an increase in transepithelial resistance in both SD and WKY colonic tissue. These studies demonstrate that the neuroexcitatory effects of IL-6 on submucosal plexi have functional consequences with alterations in both colonic secretory activity and permeability. The IL-6-induced increase in colonic secretory activity appears to neurally mediated. Thus, local increases in IL-6 levels and subsequent activation of enteric neurons may underlie alterations in absorpto-secretory function in the WKY model of IBS

Pilot scale production of a phospholipid-enriched dairy ingredient by means of an optimised integrated process employing enzymatic hydrolysis, ultrafiltration and super-critical fluid extraction

Pilot scale production of a dairy ingredient enriched in phospholipids (PLs) was generated from a buttermilk powder (BMP) substrate utilising a combined process of targeted enzymatic hydrolysis of the innate milk proteins followed by ultrafiltration with a 50 kDa membrane. An 8.5 fold increase in PL was achieved in the 50 kDa retentate (50 R) compared to the BMP, 11.05 ± 0.02% and 1.30 ± 0.00% total PL, respectively. Simultaneously, total lipid content in the retentate increased 8.7 fold with reference to the BMP, 60.07 ± 0.54% and 6.84 ± 0.17% total lipid respectively. Protein reduced to 10.58 ± 0.09% (50 R) from 31.40 ± 0.57% in BMP. Supercritical CO2 fluid extraction (SFE) was employed to generate a purified lipid fraction. SFE with ethanol as a co-solvent yielded a purified lipid extract with enriched PLs level of 56.24 ± 0.07% on a dry matter basis. Industrial relevance: PLs have many associated health and nutritional benefits including those related to cognitive development and repair. Generation of an ingredient enriched in dairy PLs would be advantageous from an industrial view to allow fortification of nutritionals, both infant and geriatric, in promoting brain health. The present work demonstrates a novel pilot scale process for the generation of a PL enriched ingredient from a BMP substrate. Utilising a combined process of targeted protein hydrolysis followed by selective removal by ultrafiltration of the smaller molecular weight peptide material, an ingredient with 8.5 fold increase in PL material was achieved. SFE technology was utilised to generate a purified lipid extract with greater PL levels for future applications in biological assays to determine these pathways. The need for investigate and further develop the knowledge relating to the modes of action of these bioactive compounds would be beneficial from a nutritional perspective

Pilot scale production of a phospholipid-enriched dairy ingredient by means of an optimised integrated process employing enzymatic hydrolysis, ultrafiltration and super-critical fluid extraction

Pilot scale production of a dairy ingredient enriched in phospholipids (PLs) was generated from a buttermilk powder (BMP) substrate utilising a combined process of targeted enzymatic hydrolysis of the innate milk proteins followed by ultrafiltration with a 50 kDa membrane. An 8.5 fold increase in PL was achieved in the 50 kDa retentate (50 R) compared to the BMP, 11.05 ± 0.02% and 1.30 ± 0.00% total PL, respectively. Simultaneously, total lipid content in the retentate increased 8.7 fold with reference to the BMP, 60.07 ± 0.54% and 6.84 ± 0.17% total lipid respectively. Protein reduced to 10.58 ± 0.09% (50 R) from 31.40 ± 0.57% in BMP. Supercritical CO2 fluid extraction (SFE) was employed to generate a purified lipid fraction. SFE with ethanol as a co-solvent yielded a purified lipid extract with enriched PLs level of 56.24 ± 0.07% on a dry matter basis. Industrial relevance: PLs have many associated health and nutritional benefits including those related to cognitive development and repair. Generation of an ingredient enriched in dairy PLs would be advantageous from an industrial view to allow fortification of nutritionals, both infant and geriatric, in promoting brain health. The present work demonstrates a novel pilot scale process for the generation of a PL enriched ingredient from a BMP substrate. Utilising a combined process of targeted protein hydrolysis followed by selective removal by ultrafiltration of the smaller molecular weight peptide material, an ingredient with 8.5 fold increase in PL material was achieved. SFE technology was utilised to generate a purified lipid extract with greater PL levels for future applications in biological assays to determine these pathways. The need for investigate and further develop the knowledge relating to the modes of action of these bioactive compounds would be beneficial from a nutritional perspective

Early-life stress induces persistent alterations in 5-HT1A receptor and serotonin transporter mRNA expression in the adult rat brain

Early-life experience plays a major role in the stress response throughout life. Neonatal maternal separation (MS) is an animal model of depression with an altered serotonergic response. We hypothesize that this alteration may be caused by differences in 5-HT(1A) receptor and serotonin transporter (SERT) mRNA expression in brain areas involved in the control of emotions, memory, and fear as well as in regions controlling the central serotonergic tone. To test this, Sprague–Dawley rats were subjected to MS for 3 h daily during postnatal days 2–12. As control, age matched rats were non-separated (NS) from their dams. When animals reached adulthood (11–13 weeks) brain was extracted and mRNA expression of 5-HT(1A) receptor in amygdala, hippocampus and dorsal raphé nucleus (DRN) and SERT in the DRN was analyzed through in situ hybridisation. Densitometric analysis revealed that MS increased 5-HT(1A) receptor mRNA expression in the amygdala, and reduced its expression in the DRN, but no changes were observed in the hippocampus in comparison to NS controls. Also, MS reduced SERT mRNA expression in the DRN when compared to NS rats. These results suggest that early-life stress induces persistent changes in 5-HT(1A) receptor and SERT mRNA expression in key brain regions involved in the development of stress-related psychiatric disorders. The reduction in SERT mRNA indicates an alteration that is in line with clinical findings such as polymorphic variants in individuals with higher risk of depression. These data may help to understand how early-life stress contributes to the development of mood disorders in adulthood

Brain–Gut–Microbe Communication in Health and Disease

Bidirectional signalling between the gastrointestinal tract and the brain is regulated at neural, hormonal, and immunological levels. This construct is known as the brain–gut axis and is vital for maintaining homeostasis. Bacterial colonization of the intestine plays a major role in the post-natal development and maturation of the immune and endocrine systems. These processes are key factors underpinning central nervous system (CNS) signaling. Recent research advances have seen a tremendous improvement in our understanding of the scale, diversity, and importance of the gut microbiome. This has been reflected in the form of a revised nomenclature to the more inclusive brain–gut–enteric microbiota axis and a sustained research effort to establish how communication along this axis contributes to both normal and pathological conditions. In this review, we will briefly discuss the critical components of this axis and the methodological challenges that have been presented in attempts to define what constitutes a normal microbiota and chart its temporal development. Emphasis is placed on the new research narrative that confirms the critical influence of the microbiota on mood and behavior. Mechanistic insights are provided with examples of both neural and humoral routes through which these effects can be mediated. The evidence supporting a role for the enteric flora in brain–gut axis disorders is explored with the spotlight on the clinical relevance for irritable bowel syndrome, a stress-related functional gastrointestinal disorder. We also critically evaluate the therapeutic opportunities arising from this research and consider in particular whether targeting the microbiome might represent a valid strategy for the management of CNS disorders and ponder the pitfalls inherent in such an approach. Despite the considerable challenges that lie ahead, this is an exciting area of research and one that is destined to remain the center of focus for some time to come

Visceral pain: role of the microbiome-gut-brain axis

A growing body of preclinical and clinical evidence supports a relationship between the complexity and diversity of the microorganisms that inhabit our gut (human gastrointestinal microbiome) and health status. These microbes can influence centrally regulated emotional behaviour through mechanisms including microbially derived bioactive molecules, mucosal immune and enteroendocrine cell activation, as well as vagal nerve stimulation. Changes to the microbial environment, as a consequence of illness, stress or injury can lead to a broad spectrum of local physiological and behavioural effects including a decrease in gut barrier integrity, altered gut motility, inflammatory mediator release, as well as nociceptive and distension receptor sensitization. Impacts at a central level include alterations in the hypothalamic-pituitary-adrenal axis, neuroinflammatory events and concomitant changes to neurotransmitter systems. Thus, both central and peripheral pathways associated with pain manifestation and perception are altered as a consequence of the microbiome-gut-brain axis imbalance. The dogmatic approach of antibiotic treatment in the latter century, for the treatment of many diseases and conditions, has undergone a radical change. We are 90% microbe, and pragmatism suggests that we manipulate this ecosystem for the treatment of various ailments, stress dysfunction and affective disorders, including the alleviation of visceral pain

Psychotropics and the microbiome: A chamber of secrets…

The human gut contains trillions of symbiotic bacteria that play a key role in programming different aspects of host physiology in health and disease. Psychotropic medications act on the central nervous system (CNS) and are used in the treatment of various psychiatric disorders. There is increasing emphasis on the bidirectional interaction between drugs and the gut microbiome. An expanding body of evidence supports the notion that microbes can metabolise drugs and vice versa drugs can modify the gut microbiota composition. In this review, we will first give a comprehensive introduction about this bidirectional interaction, then we will take into consideration different classes of psychotropics including antipsychotics, antidepressants, antianxiety drugs, anticonvulsants/mood stabilisers, opioid analgesics, drugs of abuse, alcohol, nicotine and xanthines. The varying effects of these widely used medications on microorganisms are becoming apparent from in vivo and in vitro studies. This has important implications for the future of psychopharmacology pipelines that will routinely need to consider the host microbiome during drug discovery and development