Fundamentals of Neurogastroenterology: Basic Science.
Vanner Stephen,Greenwood-Van Meerveld Beverley,Mawe Gary,Shea-Donohue Terez,Verdu Elena F,Wood Jackie,Grundy David
This review examines the fundamentals of neurogastroenterology that may underlie the pathophysiology of functional GI disorders (FGIDs). It was prepared by an invited committee of international experts and represents an abbreviated version of their consensus document that will be published in its entirety in the forthcoming book and online version entitled ROME IV. It emphasizes recent advances in our understanding of the enteric nervous system, sensory physiology underlying pain, and stress signaling pathways. There is also a focus on neuroimmmune signaling and intestinal barrier function, given the recent evidence implicating the microbiome, diet, and mucosal immune activation in FGIDs. Together, these advances provide a host of exciting new targets to identify and treat FGIDs and new areas for future research into their pathophysiology.
The intestinal microbiota programs diurnal rhythms in host metabolism through histone deacetylase 3.
Kuang Zheng,Wang Yuhao,Li Yun,Ye Cunqi,Ruhn Kelly A,Behrendt Cassie L,Olson Eric N,Hooper Lora V
Science (New York, N.Y.)
Circadian rhythmicity is a defining feature of mammalian metabolism that synchronizes metabolic processes to day-night light cycles. Here, we show that the intestinal microbiota programs diurnal metabolic rhythms in the mouse small intestine through histone deacetylase 3 (HDAC3). The microbiota induced expression of intestinal epithelial HDAC3, which was recruited rhythmically to chromatin, and produced synchronized diurnal oscillations in histone acetylation, metabolic gene expression, and nutrient uptake. HDAC3 also functioned noncanonically to coactivate estrogen-related receptor α, inducing microbiota-dependent rhythmic transcription of the lipid transporter gene and promoting lipid absorption and diet-induced obesity. Our findings reveal that HDAC3 integrates microbial and circadian cues for regulation of diurnal metabolic rhythms and pinpoint a key mechanism by which the microbiota controls host metabolism.
Altered bile acid profile in mild cognitive impairment and Alzheimer's disease: Relationship to neuroimaging and CSF biomarkers.
Nho Kwangsik,Kueider-Paisley Alexandra,MahmoudianDehkordi Siamak,Arnold Matthias,Risacher Shannon L,Louie Gregory,Blach Colette,Baillie Rebecca,Han Xianlin,Kastenmüller Gabi,Jia Wei,Xie Guoxiang,Ahmad Shahzad,Hankemeier Thomas,van Duijn Cornelia M,Trojanowski John Q,Shaw Leslie M,Weiner Michael W,Doraiswamy P Murali,Saykin Andrew J,Kaddurah-Daouk Rima,
Alzheimer's & dementia : the journal of the Alzheimer's Association
INTRODUCTION:Bile acids (BAs) are the end products of cholesterol metabolism produced by human and gut microbiome co-metabolism. Recent evidence suggests gut microbiota influence pathological features of Alzheimer's disease (AD) including neuroinflammation and amyloid-β deposition. METHOD:Serum levels of 20 primary and secondary BA metabolites from the AD Neuroimaging Initiative (n = 1562) were measured using targeted metabolomic profiling. We assessed the association of BAs with the "A/T/N" (amyloid, tau, and neurodegeneration) biomarkers for AD: cerebrospinal fluid (CSF) biomarkers, atrophy (magnetic resonance imaging), and brain glucose metabolism ([F]FDG PET). RESULTS:Of 23 BAs and relevant calculated ratios after quality control procedures, three BA signatures were associated with CSF Aβ ("A") and three with CSF p-tau181 ("T") (corrected P < .05). Furthermore, three, twelve, and fourteen BA signatures were associated with CSF t-tau, glucose metabolism, and atrophy ("N"), respectively (corrected P < .05). DISCUSSION:This is the first study to show serum-based BA metabolites are associated with "A/T/N" AD biomarkers, providing further support for a role of BA pathways in AD pathophysiology. Prospective clinical observations and validation in model systems are needed to assess causality and specific mechanisms underlying this association.
Bacteroides fragilis polysaccharide A induces IL-10 secreting B and T cells that prevent viral encephalitis.
Ramakrishna Chandran,Kujawski Maciej,Chu Hiutung,Li Lin,Mazmanian Sarkis K,Cantin Edouard M
The gut commensal Bacteroides fragilis or its capsular polysaccharide A (PSA) can prevent various peripheral and CNS sterile inflammatory disorders. Fatal herpes simplex encephalitis (HSE) results from immune pathology caused by uncontrolled invasion of the brainstem by inflammatory monocytes and neutrophils. Here we assess the immunomodulatory potential of PSA in HSE by infecting PSA or PBS treated 129S6 mice with HSV1, followed by delayed Acyclovir (ACV) treatment as often occurs in the clinical setting. Only PSA-treated mice survived, with dramatically reduced brainstem inflammation and altered cytokine and chemokine profiles. Importantly, PSA binding by B cells is essential for induction of regulatory CD4 and CD8 T cells secreting IL-10 to control innate inflammatory responses, consistent with the lack of PSA mediated protection in Rag, B cell- and IL-10-deficient mice. Our data reveal the translational potential of PSA as an immunomodulatory symbiosis factor to orchestrate robust protective anti-inflammatory responses during viral infections.
The Intestinal Microenvironment and Functional Gastrointestinal Disorders.
Barbara Giovanni,Feinle-Bisset Christine,Ghoshal Uday C,Quigley Eamonn M,Santos Javier,Vanner Steve,Vergnolle Nathalie,Zoetendal Erwin G
For decades, interactions between the enteric neuromuscular apparatus and the central nervous system have served as the primary focus of pathophysiological research in the functional gastrointestinal disorders. The accumulation of patient reports, as well as clinical observations, has belatedly led to an interest in the role of various luminal factors and their interactions with each other and the host in functional gastrointestinal disorders. Most prominent among these factors has been the role of food. As a consequence, while not always evidence-based, dietary interventions are enjoying a renaissance in irritable bowel syndrome management. Not surprisingly, given its exploration in many disease states, the gut microbiota has also been studied in functional gastrointestinal disorders; data remain inconclusive. Likewise, there is also a considerable body of experimental and some clinical data to link functional gastrointestinal disorders pathogenesis to disturbances in epithelial barrier integrity, abnormal entero-endocrine signaling and immune activation. These data provide growing evidence supporting the existence of micro-organic changes, particularly in subgroups of patients with functional dyspepsia and IBS. However, their exact role in the complex pathophysiology and symptom generation of functional gastrointestinal disorders needs to be further studied and elucidated particularly with longitudinal and interventional studies.
Effects of Serotonin and Slow-Release 5-Hydroxytryptophan on Gastrointestinal Motility in a Mouse Model of Depression.
Israelyan Narek,Del Colle Andrew,Li Zhishan,Park Yeji,Xing Albert,Jacobsen Jacob P R,Luna Ruth Ann,Jensen Dane D,Madra Moneek,Saurman Virginia,Rahim Ray,Latorre Rocco,Law Kimberly,Carson William,Bunnett Nigel W,Caron Marc G,Margolis Kara G
BACKGROUND & AIMS:Mood disorders and constipation are often comorbid, yet their shared etiologies have rarely been explored. The neurotransmitter serotonin (5-HT) regulates central nervous system and enteric nervous system (ENS) development and long-term functions, including gastrointestinal (GI) motility and mood. Therefore, defects in neuron production of 5-HT might result in brain and intestinal dysfunction. Tryptophan hydroxylase 2 (TPH2) is the rate-limiting enzyme in 5-HT biosynthesis. A variant of TPH2 that encodes the R441H substitution (TPH2-R441H) was identified in individuals with severe depression. We studied mice with an analogous mutation (TPH2-R439H), which results in a 60%-80% decrease in levels of 5-HT in the central nervous system and behaviors associated with depression in humans. Feeding chow that contains 5-HTP slow release (5-HTP SR) to TPH2-R439H mice restores levels of 5-HT in the central nervous system and reduces depressive-like behaviors. METHODS:We compared the effects of feeding chow, with or without 5-HTP SR, to mice with the TPH2-R439H mutation and without this mutation (control mice). Myenteric and submucosal plexuses were isolated from all 4 groups of mice, and immunocytochemistry was used to quantify total enteric neurons, serotonergic neurons, and 5-HT-dependent subsets of neurons. We performed calcium imaging experiments to evaluate responses of enteric neurons to tryptamine-evoked release of endogenous 5-HT. In live mice, we measured total GI transit, gastric emptying, small intestinal transit, and propulsive colorectal motility. To measure colonic migrating motor complexes (CMMCs), we isolated colons and constructed spatiotemporal maps along the proximodistal length to quantify the frequency, velocity, and length of CMMCs. We measured villus height, crypt perimeter, and relative densities of enterochromaffin and enteroendocrine cells in small intestinal tissue. RESULTS:Levels of 5-HT were significantly lower in enteric neurons from TPH2-R439H mice than from control mice. TPH2-R439H mice had abnormalities in ENS development and ENS-mediated GI functions, including reduced motility and intestinal epithelial growth. Total GI transit and propulsive colorectal motility were slower in TPH2-R439H mice than controls, and CMMCs were slower and less frequent. Villus height and crypt perimeter were significantly decreased in colon tissues from TPH2-R439H mice compared with controls. Administration of 5-HTP SR to adult TPH2-R439H mice restored 5-HT to enteric neurons and reversed these abnormalities. Adult TPH2-R439H mice given oral 5-HTP SR had normalized numbers of enteric neurons, total GI transit, and colonic motility. Intestinal tissue from these mice had normal measures of CMMCs and enteric epithelial growth CONCLUSIONS: In studies of TPH2-R439H mice, we found evidence for reduced release of 5-HT from enteric neurons that results in defects in ENS development and GI motility. Our findings indicate that neuron production of 5-HT links constipation with mood dysfunction. Administration of 5-HTP SR to mice restored 5-HT to the ENS and normalized GI motility and growth of the enteric epithelium. 5-HTP SR might be used to treat patients with intestinal dysfunction associated with low levels of 5-HT.
Role of TLR4 in the gut-brain axis in Parkinson's disease: a translational study from men to mice.
Perez-Pardo Paula,Dodiya Hemraj B,Engen Phillip A,Forsyth Christopher B,Huschens Andrea M,Shaikh Maliha,Voigt Robin M,Naqib Ankur,Green Stefan J,Kordower Jeffrey H,Shannon Kathleen M,Garssen Johan,Kraneveld Aletta D,Keshavarzian Ali
OBJECTIVE:Recent evidence suggesting an important role of gut-derived inflammation in brain disorders has opened up new directions to explore the possible role of the gut-brain axis in neurodegenerative diseases. Given the prominence of dysbiosis and colonic dysfunction in patients with Parkinson's disease (PD), we propose that toll-like receptor 4 (TLR4)-mediated intestinal dysfunction could contribute to intestinal and central inflammation in PD-related neurodegeneration. DESIGN:To test this hypothesis we performed studies in both human tissue and a murine model of PD. Inflammation, immune activation and microbiota composition were measured in colonic samples from subjects with PD and healthy controls subjects and rotenone or vehicle-treated mice. To further assess the role of the TLR4 signalling in PD-induced neuroinflammation, we used TLR4-knockout (KO) mice in conjunction with oral rotenone administration to model PD. RESULTS:Patients with PD have intestinal barrier disruption, enhanced markers of microbial translocation and higher pro-inflammatory gene profiles in the colonic biopsy samples compared with controls. In this regard, we found increased expression of the bacterial endotoxin-specific ligand TLR4, CD3+ T cells, cytokine expression in colonic biopsies, dysbiosis characterised by a decrease abundance of SCFA-producing colonic bacteria in subjects with PD. Rotenone treatment in TLR4-KO mice revealed less intestinal inflammation, intestinal and motor dysfunction, neuroinflammation and neurodegeneration, relative to rotenone-treated wild-type animals despite the presence of dysbiotic microbiota in TLR4-KO mice. CONCLUSION:Taken together, these studies suggest that TLR4-mediated inflammation plays an important role in intestinal and/or brain inflammation, which may be one of the key factors leading to neurodegeneration in PD.
Brain-gut microbiome interactions and functional bowel disorders.
Mayer Emeran A,Savidge Tor,Shulman Robert J
Alterations in the bidirectional interactions between the intestine and the nervous system have important roles in the pathogenesis of irritable bowel syndrome (IBS). A body of largely preclinical evidence suggests that the gut microbiota can modulate these interactions. A small and poorly defined role for dysbiosis in the development of IBS symptoms has been established through characterization of altered intestinal microbiota in IBS patients and reported improvement of subjective symptoms after its manipulation with prebiotics, probiotics, or antibiotics. It remains to be determined whether IBS symptoms are caused by alterations in brain signaling from the intestine to the microbiota or primary disruption of the microbiota, and whether they are involved in altered interactions between the brain and intestine during development. We review the potential mechanisms involved in the pathogenesis of IBS in different groups of patients. Studies are needed to better characterize alterations to the intestinal microbiome in large cohorts of well-phenotyped patients, and to correlate intestinal metabolites with specific abnormalities in gut-brain interactions.
Alterations of the human gut microbiome in multiple sclerosis.
Jangi Sushrut,Gandhi Roopali,Cox Laura M,Li Ning,von Glehn Felipe,Yan Raymond,Patel Bonny,Mazzola Maria Antonietta,Liu Shirong,Glanz Bonnie L,Cook Sandra,Tankou Stephanie,Stuart Fiona,Melo Kirsy,Nejad Parham,Smith Kathleen,Topçuolu Begüm D,Holden James,Kivisäkk Pia,Chitnis Tanuja,De Jager Philip L,Quintana Francisco J,Gerber Georg K,Bry Lynn,Weiner Howard L
The gut microbiome plays an important role in immune function and has been implicated in several autoimmune disorders. Here we use 16S rRNA sequencing to investigate the gut microbiome in subjects with multiple sclerosis (MS, n=60) and healthy controls (n=43). Microbiome alterations in MS include increases in Methanobrevibacter and Akkermansia and decreases in Butyricimonas, and correlate with variations in the expression of genes involved in dendritic cell maturation, interferon signalling and NF-kB signalling pathways in circulating T cells and monocytes. Patients on disease-modifying treatment show increased abundances of Prevotella and Sutterella, and decreased Sarcina, compared with untreated patients. MS patients of a second cohort show elevated breath methane compared with controls, consistent with our observation of increased gut Methanobrevibacter in MS in the first cohort. Further study is required to assess whether the observed alterations in the gut microbiome play a role in, or are a consequence of, MS pathogenesis.
Gut bacterial tyrosine decarboxylases restrict levels of levodopa in the treatment of Parkinson's disease.
van Kessel Sebastiaan P,Frye Alexandra K,El-Gendy Ahmed O,Castejon Maria,Keshavarzian Ali,van Dijk Gertjan,El Aidy Sahar
Human gut microbiota senses its environment and responds by releasing metabolites, some of which are key regulators of human health and disease. In this study, we characterize gut-associated bacteria in their ability to decarboxylate levodopa to dopamine via tyrosine decarboxylases. Bacterial tyrosine decarboxylases efficiently convert levodopa to dopamine, even in the presence of tyrosine, a competitive substrate, or inhibitors of human decarboxylase. In situ levels of levodopa are compromised by high abundance of gut bacterial tyrosine decarboxylase in patients with Parkinson's disease. Finally, the higher relative abundance of bacterial tyrosine decarboxylases at the site of levodopa absorption, proximal small intestine, had a significant impact on levels of levodopa in the plasma of rats. Our results highlight the role of microbial metabolism in drug availability, and specifically, that abundance of bacterial tyrosine decarboxylase in the proximal small intestine can explain the increased dosage regimen of levodopa treatment in Parkinson's disease patients.
Brain Autoimmunity and Intestinal Microbiota: 100 Trillion Game Changers.
Trends in immunology
T cells play a critical role in autoimmune diseases in the brain, particularly in multiple sclerosis (MS). Since T cells are normally prevented from crossing the blood-brain barrier (BBB), autoimmunity requires prior activation of naturally occurring autoreactive T cells in peripheral tissue. Recently, a critical role for the microbiota in this activation process has emerged. Here, we review the role of gut-associated lymphoid tissues (GALT) as a major site for the phenotypic changes that allow the migration of autoreactive T cells to the brain. Additionally, we examine the involvement of the microbiota in clinical MS as well as other brain disorders such as Parkinson's disease (PD), stroke, and psychiatric disorders.
The Central Nervous System and the Gut Microbiome.
Sharon Gil,Sampson Timothy R,Geschwind Daniel H,Mazmanian Sarkis K
Neurodevelopment is a complex process governed by both intrinsic and extrinsic signals. While historically studied by researching the brain, inputs from the periphery impact many neurological conditions. Indeed, emerging data suggest communication between the gut and the brain in anxiety, depression, cognition, and autism spectrum disorder (ASD). The development of a healthy, functional brain depends on key pre- and post-natal events that integrate environmental cues, such as molecular signals from the gut. These cues largely originate from the microbiome, the consortium of symbiotic bacteria that reside within all animals. Research over the past few years reveals that the gut microbiome plays a role in basic neurogenerative processes such as the formation of the blood-brain barrier, myelination, neurogenesis, and microglia maturation and also modulates many aspects of animal behavior. Herein, we discuss the biological intersection of neurodevelopment and the microbiome and explore the hypothesis that gut bacteria are integral contributors to development and function of the nervous system and to the balance between mental health and disease.
Non-conventional features of peripheral serotonin signalling - the gut and beyond.
Spohn Stephanie N,Mawe Gary M
Nature reviews. Gastroenterology & hepatology
Serotonin was first discovered in the gut, and its conventional actions as an intercellular signalling molecule in the intrinsic and extrinsic enteric reflexes are well recognized, as are a number of serotonin signalling pharmacotherapeutic targets for treatment of nausea, diarrhoea or constipation. The latest discoveries have greatly broadened our understanding of non-conventional actions of peripheral serotonin within the gastrointestinal tract and in a number of other tissues. For example, it is now clear that bacteria within the lumen of the bowel influence serotonin synthesis and release by enterochromaffin cells. Also, serotonin can act both as a pro-inflammatory and anti-inflammatory signalling molecule in the intestinal mucosa via activation of serotonin receptors (5-HT or 5-HT receptors, respectively). For decades, serotonin receptors have been known to exist in a variety of tissues other than the gut, but studies have now provided strong evidence for physiological roles of serotonin in several important processes, including haematopoiesis, metabolic homeostasis and bone metabolism. Furthermore, evidence for serotonin synthesis in peripheral tissues outside of the gut is emerging. In this Review, we expand the discussion beyond gastrointestinal functions to highlight the roles of peripheral serotonin in colitis, haematopoiesis, energy and bone metabolism, and how serotonin is influenced by the gut microbiota.
Individual variations in cardiovascular-disease-related protein levels are driven by genetics and gut microbiome.
Zhernakova Daria V,Le Trang H,Kurilshikov Alexander,Atanasovska Biljana,Bonder Marc Jan,Sanna Serena,Claringbould Annique,Võsa Urmo,Deelen Patrick,Franke Lude,de Boer Rudolf A,Kuipers Folkert,Netea Mihai G,Hofker Marten H,Wijmenga Cisca,Zhernakova Alexandra,Fu Jingyuan, ,
Despite a growing body of evidence, the role of the gut microbiome in cardiovascular diseases is still unclear. Here, we present a systems-genome-wide and metagenome-wide association study on plasma concentrations of 92 cardiovascular-disease-related proteins in the population cohort LifeLines-DEEP. We identified genetic components for 73 proteins and microbial associations for 41 proteins, of which 31 were associated to both. The genetic and microbial factors identified mostly exert additive effects and collectively explain up to 76.6% of inter-individual variation (17.5% on average). Genetics contribute most to concentrations of immune-related proteins, while the gut microbiome contributes most to proteins involved in metabolism and intestinal health. We found several host-microbe interactions that impact proteins involved in epithelial function, lipid metabolism, and central nervous system function. This study provides important evidence for a joint genetic and microbial effect in cardiovascular disease and provides directions for future applications in personalized medicine.
The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner.
Clarke G,Grenham S,Scully P,Fitzgerald P,Moloney R D,Shanahan F,Dinan T G,Cryan J F
Bacterial colonisation of the intestine has 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) signalling. Regulation of the microbiome-gut-brain axis is essential for maintaining homeostasis, including that of the CNS. However, there is a paucity of data pertaining to the influence of microbiome on the serotonergic system. Germ-free (GF) animals represent an effective preclinical tool to investigate such phenomena. Here we show that male GF animals have a significant elevation in the hippocampal concentration of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid, its main metabolite, compared with conventionally colonised control animals. Moreover, this alteration is sex specific in contrast with the immunological and neuroendocrine effects which are evident in both sexes. Concentrations of tryptophan, the precursor of serotonin, are increased in the plasma of male GF animals, suggesting a humoral route through which the microbiota can influence CNS serotonergic neurotransmission. Interestingly, colonisation of the GF animals post weaning is insufficient to reverse the CNS neurochemical consequences in adulthood of an absent microbiota in early life despite the peripheral availability of tryptophan being restored to baseline values. In addition, reduced anxiety in GF animals is also normalised following restoration of the intestinal microbiota. These results demonstrate that CNS neurotransmission can be profoundly disturbed by the absence of a normal gut microbiota and that this aberrant neurochemical, but not behavioural, profile is resistant to restoration of a normal gut flora in later life.
Altered bile acid profile associates with cognitive impairment in Alzheimer's disease-An emerging role for gut microbiome.
MahmoudianDehkordi Siamak,Arnold Matthias,Nho Kwangsik,Ahmad Shahzad,Jia Wei,Xie Guoxiang,Louie Gregory,Kueider-Paisley Alexandra,Moseley M Arthur,Thompson J Will,St John Williams Lisa,Tenenbaum Jessica D,Blach Colette,Baillie Rebecca,Han Xianlin,Bhattacharyya Sudeepa,Toledo Jon B,Schafferer Simon,Klein Sebastian,Koal Therese,Risacher Shannon L,Kling Mitchel Allan,Motsinger-Reif Alison,Rotroff Daniel M,Jack John,Hankemeier Thomas,Bennett David A,De Jager Philip L,Trojanowski John Q,Shaw Leslie M,Weiner Michael W,Doraiswamy P Murali,van Duijn Cornelia M,Saykin Andrew J,Kastenmüller Gabi,Kaddurah-Daouk Rima,
Alzheimer's & dementia : the journal of the Alzheimer's Association
INTRODUCTION:Increasing evidence suggests a role for the gut microbiome in central nervous system disorders and a specific role for the gut-brain axis in neurodegeneration. Bile acids (BAs), products of cholesterol metabolism and clearance, are produced in the liver and are further metabolized by gut bacteria. They have major regulatory and signaling functions and seem dysregulated in Alzheimer's disease (AD). METHODS:Serum levels of 15 primary and secondary BAs and their conjugated forms were measured in 1464 subjects including 370 cognitively normal older adults, 284 with early mild cognitive impairment, 505 with late mild cognitive impairment, and 305 AD cases enrolled in the AD Neuroimaging Initiative. We assessed associations of BA profiles including selected ratios with diagnosis, cognition, and AD-related genetic variants, adjusting for confounders and multiple testing. RESULTS:In AD compared to cognitively normal older adults, we observed significantly lower serum concentrations of a primary BA (cholic acid [CA]) and increased levels of the bacterially produced, secondary BA, deoxycholic acid, and its glycine and taurine conjugated forms. An increased ratio of deoxycholic acid:CA, which reflects 7α-dehydroxylation of CA by gut bacteria, strongly associated with cognitive decline, a finding replicated in serum and brain samples in the Rush Religious Orders and Memory and Aging Project. Several genetic variants in immune response-related genes implicated in AD showed associations with BA profiles. DISCUSSION:We report for the first time an association between altered BA profile, genetic variants implicated in AD, and cognitive changes in disease using a large multicenter study. These findings warrant further investigation of gut dysbiosis and possible role of gut-liver-brain axis in the pathogenesis of AD.
Gut microbial molecules in behavioural and neurodegenerative conditions.
Needham Brittany D,Kaddurah-Daouk Rima,Mazmanian Sarkis K
Nature reviews. Neuroscience
Mounting evidence suggests that the gut microbiome impacts brain development and function. Gut-brain connections may be mediated by an assortment of microbial molecules that are produced in the gastrointestinal tract, which can subsequently permeate many organs, including sometimes the brain. Studies in animal models have identified molecular cues propagated from intestinal bacteria to the brain that can affect neurological function and/or neurodevelopmental and neurodegenerative conditions. Herein, we describe bacterial metabolites with known or suspected neuromodulatory activity, define mechanisms of signalling pathways from the gut microbiota to the brain and discuss direct effects that gut bacterial molecules are likely exerting on specific brain cells. Many discoveries are recent, and the findings described in this Perspective are largely novel and yet to be extensively validated. However, expanding research into the dynamic molecular communications between gut microorganisms and the CNS continues to uncover critical and previously unappreciated clues in understanding the pathophysiology of behavioural, psychiatric and neurodegenerative diseases.
Parkinson disease and the gut: new insights into pathogenesis and clinical relevance.
Travagli R Alberto,Browning Kirsteen N,Camilleri Michael
Nature reviews. Gastroenterology & hepatology
The classic view portrays Parkinson disease (PD) as a motor disorder resulting from loss of substantia nigra pars compacta dopaminergic neurons. Multiple studies, however, describe prodromal, non-motor dysfunctions that affect the quality of life of patients who subsequently develop PD. These prodromal dysfunctions comprise a wide array of gastrointestinal motility disorders including dysphagia, delayed gastric emptying and chronic constipation. The histological hallmark of PD - misfolded α-synuclein aggregates that form Lewy bodies and neurites - is detected in the enteric nervous system prior to clinical diagnosis, suggesting that the gastrointestinal tract and its neural (vagal) connection to the central nervous system could have a major role in disease aetiology. This Review provides novel insights on the pathogenesis of PD, including gut-to-brain trafficking of α-synuclein as well as the newly discovered nigro-vagal pathway, and highlights how vagal connections from the gut could be the conduit by which ingested environmental pathogens enter the central nervous system and ultimately induce, or accelerate, PD progression. The pathogenic potential of various environmental neurotoxicants and the suitability and translational potential of experimental animal models of PD will be highlighted and appraised. Finally, the clinical manifestations of gastrointestinal involvement in PD and medications will be discussed briefly.
Neuroimmunophysiology of the gut: advances and emerging concepts focusing on the epithelium.
Sharkey Keith A,Beck Paul L,McKay Derek M
Nature reviews. Gastroenterology & hepatology
The epithelial lining of the gastrointestinal tract serves as the interface for digestion and absorption of nutrients and water and as a defensive barrier. The defensive functions of the intestinal epithelium are remarkable considering that the gut lumen is home to trillions of resident bacteria, fungi and protozoa (collectively, the intestinal microbiota) that must be prevented from translocation across the epithelial barrier. Imbalances in the relationship between the intestinal microbiota and the host lead to the manifestation of diseases that range from disorders of motility and sensation (IBS) and intestinal inflammation (IBD) to behavioural and metabolic disorders, including autism and obesity. The latest discoveries shed light on the sophisticated intracellular, intercellular and interkingdom signalling mechanisms of host defence that involve epithelial and enteroendocrine cells, the enteric nervous system and the immune system. Together, they maintain homeostasis by integrating luminal signals, including those derived from the microbiota, to regulate the physiology of the gastrointestinal tract in health and disease. Therapeutic strategies are being developed that target these signalling systems to improve the resilience of the gut and treat the symptoms of gastrointestinal disease.
Dietary tryptophan links encephalogenicity of autoreactive T cells with gut microbial ecology.
Sonner Jana K,Keil Melanie,Falk-Paulsen Maren,Mishra Neha,Rehman Ateequr,Kramer Magdalena,Deumelandt Katrin,Röwe Julian,Sanghvi Khwab,Wolf Lara,von Landenberg Anna,Wolff Hendrik,Bharti Richa,Oezen Iris,Lanz Tobias V,Wanke Florian,Tang Yilang,Brandao Ines,Mohapatra Soumya R,Epping Lisa,Grill Alexandra,Röth Ralph,Niesler Beate,Meuth Sven G,Opitz Christiane A,Okun Jürgen G,Reinhardt Christoph,Kurschus Florian C,Wick Wolfgang,Bode Helge B,Rosenstiel Philip,Platten Michael
The interaction between the mammalian host and its resident gut microbiota is known to license adaptive immune responses. Nutritional constituents strongly influence composition and functional properties of the intestinal microbial communities. Here, we report that omission of a single essential amino acid - tryptophan - from the diet abrogates CNS autoimmunity in a mouse model of multiple sclerosis. Dietary tryptophan restriction results in impaired encephalitogenic T cell responses and is accompanied by a mild intestinal inflammatory response and a profound phenotypic shift of gut microbiota. Protective effects of dietary tryptophan restriction are abrogated in germ-free mice, but are independent of canonical host sensors of intracellular tryptophan metabolites. We conclude that dietary tryptophan restriction alters metabolic properties of gut microbiota, which in turn have an impact on encephalitogenic T cell responses. This link between gut microbiota, dietary tryptophan and adaptive immunity may help to develop therapeutic strategies for protection from autoimmune neuroinflammation.
Gut/brain axis and the microbiota.
Mayer Emeran A,Tillisch Kirsten,Gupta Arpana
The Journal of clinical investigation
Tremendous progress has been made in characterizing the bidirectional interactions between the central nervous system, the enteric nervous system, and the gastrointestinal tract. A series of provocative preclinical studies have suggested a prominent role for the gut microbiota in these gut-brain interactions. Based on studies using rodents raised in a germ-free environment, the gut microbiota appears to influence the development of emotional behavior, stress- and pain-modulation systems, and brain neurotransmitter systems. Additionally, microbiota perturbations by probiotics and antibiotics exert modulatory effects on some of these measures in adult animals. Current evidence suggests that multiple mechanisms, including endocrine and neurocrine pathways, may be involved in gut microbiota-to-brain signaling and that the brain can in turn alter microbial composition and behavior via the autonomic nervous system. Limited information is available on how these findings may translate to healthy humans or to disease states involving the brain or the gut/brain axis. Future research needs to focus on confirming that the rodent findings are translatable to human physiology and to diseases such as irritable bowel syndrome, autism, anxiety, depression, and Parkinson's disease.
Disorders of the enteric nervous system - a holistic view.
Niesler Beate,Kuerten Stefanie,Demir I Ekin,Schäfer Karl-Herbert
Nature reviews. Gastroenterology & hepatology
The enteric nervous system (ENS) is the largest division of the peripheral nervous system and closely resembles components and functions of the central nervous system. Although the central role of the ENS in congenital enteric neuropathic disorders, including Hirschsprung disease and inflammatory and functional bowel diseases, is well acknowledged, its role in systemic diseases is less understood. Evidence of a disordered ENS has accumulated in neurodegenerative diseases ranging from amyotrophic lateral sclerosis, Alzheimer disease and multiple sclerosis to Parkinson disease as well as neurodevelopmental disorders such as autism. The ENS is a key modulator of gut barrier function and a regulator of enteric homeostasis. A 'leaky gut' represents the gateway for bacterial and toxin translocation that might initiate downstream processes. Data indicate that changes in the gut microbiome acting in concert with the individual genetic background can modify the ENS, central nervous system and the immune system, impair barrier function, and contribute to various disorders such as irritable bowel syndrome, inflammatory bowel disease or neurodegeneration. Here, we summarize the current knowledge on the role of the ENS in gastrointestinal and systemic diseases, highlighting its interaction with various key players involved in shaping the phenotypes. Finally, current flaws and pitfalls related to ENS research in addition to future perspectives are also addressed.
The role of gut dysbiosis in Parkinson's disease: mechanistic insights and therapeutic options.
Wang Qing,Luo Yuqi,Ray Chaudhuri K,Reynolds Richard,Tan Eng-King,Pettersson Sven
Brain : a journal of neurology
Parkinson's disease is a common neurodegenerative disorder in which gastrointestinal symptoms may appear prior to motor symptoms. The gut microbiota of patients with Parkinson's disease shows unique changes, which may be used as early biomarkers of disease. Alterations in the gut microbiota composition may be related to the cause or effect of motor or non-motor symptoms, but the specific pathogenic mechanisms are unclear. The gut microbiota and its metabolites have been suggested to be involved in the pathogenesis of Parkinson's disease by regulating neuroinflammation, barrier function and neurotransmitter activity. There is bidirectional communication between the enteric nervous system and the CNS, and the microbiota-gut-brain axis may provide a pathway for the transmission of α-synuclein. We highlight recent discoveries about alterations to the gut microbiota in Parkinson's disease and focus on current mechanistic insights into the microbiota-gut-brain axis in disease pathophysiology. Moreover, we discuss the interactions between the production and transmission of α-synuclein and gut inflammation and neuroinflammation. In addition, we draw attention to diet modification, the use of probiotics and prebiotics and faecal microbiota transplantation as potential therapeutic approaches that may lead to a new treatment paradigm for Parkinson's disease.
Implications of the Human Gut-Brain and Gut-Cancer Axes for Future Nanomedicine.
Javed Ibrahim,Cui Xuejing,Wang Xiaoyu,Mortimer Monika,Andrikopoulos Nikolaos,Li Yuhuan,Davis Thomas P,Zhao Yuliang,Ke Pu Chun,Chen Chunying
Recent clinical and pathological evidence have implicated the gut microbiota as a nexus for modulating the homeostasis of the human body, impacting conditions from cancer and dementia to obesity and social behavior. The connections between microbiota and human diseases offer numerous opportunities in medicine, most of which have limited or no therapeutic solutions available. In light of this paradigm-setting trend in science, this review aims to provide a comprehensive and timely summary of the mechanistic pathways governing the gut microbiota and their implications for nanomedicines targeting cancer and neurodegenerative diseases. Specifically, we discuss in parallel the beneficial and pathogenic relationship of the gut microbiota along the gut-brain and gut-cancer axes, elaborate on the impact of dysbiosis and the gastrointestinal corona on the efficacy of nanomedicines, and highlight a molecular mimicry that manipulates the universal cross-β backbone of bacterial amyloid to accelerate neurological disorders. This review further offers a forward-looking section on the rational design of cancer and dementia nanomedicines exploiting the gut-brain and gut-cancer axes.
Dietary Fatty Acids Directly Impact Central Nervous System Autoimmunity via the Small Intestine.
Haghikia Aiden,Jörg Stefanie,Duscha Alexander,Berg Johannes,Manzel Arndt,Waschbisch Anne,Hammer Anna,Lee De-Hyung,May Caroline,Wilck Nicola,Balogh Andras,Ostermann Annika I,Schebb Nils Helge,Akkad Denis A,Grohme Diana A,Kleinewietfeld Markus,Kempa Stefan,Thöne Jan,Demir Seray,Müller Dominik N,Gold Ralf,Linker Ralf A
Growing empirical evidence suggests that nutrition and bacterial metabolites might impact the systemic immune response in the context of disease and autoimmunity. We report that long-chain fatty acids (LCFAs) enhanced differentiation and proliferation of T helper 1 (Th1) and/or Th17 cells and impaired their intestinal sequestration via p38-MAPK pathway. Alternatively, dietary short-chain FAs (SCFAs) expanded gut T regulatory (Treg) cells by suppression of the JNK1 and p38 pathway. We used experimental autoimmune encephalomyelitis (EAE) as a model of T cell-mediated autoimmunity to show that LCFAs consistently decreased SCFAs in the gut and exacerbated disease by expanding pathogenic Th1 and/or Th17 cell populations in the small intestine. Treatment with SCFAs ameliorated EAE and reduced axonal damage via long-lasting imprinting on lamina-propria-derived Treg cells. These data demonstrate a direct dietary impact on intestinal-specific, and subsequently central nervous system-specific, Th cell responses in autoimmunity, and thus might have therapeutic implications for autoimmune diseases such as multiple sclerosis.
From gut dysbiosis to altered brain function and mental illness: mechanisms and pathways.
Rogers G B,Keating D J,Young R L,Wong M-L,Licinio J,Wesselingh S
The human body hosts an enormous abundance and diversity of microbes, which perform a range of essential and beneficial functions. Our appreciation of the importance of these microbial communities to many aspects of human physiology has grown dramatically in recent years. We know, for example, that animals raised in a germ-free environment exhibit substantially altered immune and metabolic function, while the disruption of commensal microbiota in humans is associated with the development of a growing number of diseases. Evidence is now emerging that, through interactions with the gut-brain axis, the bidirectional communication system between the central nervous system and the gastrointestinal tract, the gut microbiome can also influence neural development, cognition and behaviour, with recent evidence that changes in behaviour alter gut microbiota composition, while modifications of the microbiome can induce depressive-like behaviours. Although an association between enteropathy and certain psychiatric conditions has long been recognized, it now appears that gut microbes represent direct mediators of psychopathology. Here, we examine roles of gut microbiome in shaping brain development and neurological function, and the mechanisms by which it can contribute to mental illness. Further, we discuss how the insight provided by this new and exciting field of research can inform care and provide a basis for the design of novel, microbiota-targeted, therapies.
The Microbiome and Host Behavior.
Vuong Helen E,Yano Jessica M,Fung Thomas C,Hsiao Elaine Y
Annual review of neuroscience
The microbiota is increasingly recognized for its ability to influence the development and function of the nervous system and several complex host behaviors. In this review, we discuss emerging roles for the gut microbiota in modulating host social and communicative behavior, stressor-induced behavior, and performance in learning and memory tasks. We summarize effects of the microbiota on host neurophysiology, including brain microstructure, gene expression, and neurochemical metabolism across regions of the amygdala, hippocampus, frontal cortex, and hypothalamus. We further assess evidence linking dysbiosis of the gut microbiota to neurobehavioral diseases, such as autism spectrum disorder and major depression, drawing upon findings from animal models and human trials. Finally, based on increasing associations between the microbiota, neurophysiology, and behavior, we consider whether investigating mechanisms underlying the microbiota-gut-brain axis could lead to novel approaches for treating particular neurological conditions.
Impaired Autonomic Nervous System-Microbiome Circuit in Hypertension.
Zubcevic Jasenka,Richards Elaine M,Yang Tao,Kim Seungbum,Sumners Colin,Pepine Carl J,Raizada Mohan K
Hypertension affects an estimated 103 million Americans, yet gaps in knowledge continue to limit its successful management. Rapidly emerging evidence is linking gut dysbiosis to many disorders and diseases including hypertension. The evolution of the -omics techniques has allowed determination of the abundance and potential function of gut bacterial species by next-generation bacterial sequencing, whereas metabolomics techniques report shifts in bacterial metabolites in the systemic circulation of hypertensive patients and rodent models of hypertension. The gut microbiome and host have evolved to exist in balance and cooperation, and there is extensive crosstalk between the 2 to maintain this balance, including during regulation of blood pressure. However, an understanding of the mechanisms of dysfunctional host-microbiome interactions in hypertension is still lacking. Here, we synthesize some of our recent data with published reports and present concepts and a rationale for our emerging hypothesis of a dysfunctional gut-brain axis in hypertension. Hopefully, this new information will improve the understanding of hypertension and help to address some of these knowledge gaps.
Gut microbiome and liver diseases.
Tilg Herbert,Cani Patrice D,Mayer Emeran A
The gut microbiota has recently evolved as a new important player in the pathophysiology of many intestinal and extraintestinal diseases. The liver is the organ which is in closest contact with the intestinal tract, and is exposed to a substantial amount of bacterial components and metabolites. Various liver disorders such as alcoholic liver disease, non-alcoholic liver disease and primary sclerosing cholangitis have been associated with an altered microbiome. This dysbiosis may influence the degree of hepatic steatosis, inflammation and fibrosis through multiple interactions with the host's immune system and other cell types. Whereas few results from clinical metagenomic studies in liver disease are available, evidence is accumulating that in liver cirrhosis an oral microbiome is overrepresented in the lower intestinal tract, potentially contributing to disease process and severity. A major role for the gut microbiota in liver disorders is also supported by the accumulating evidence that several complications of severe liver disease such as hepatic encephalopathy are efficiently treated by various prebiotics, probiotics and antibiotics. A better understanding of the gut microbiota and its components in liver diseases might provide a more complete picture of these complex disorders and also form the basis for novel therapies.
Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor.
Rothhammer Veit,Mascanfroni Ivan D,Bunse Lukas,Takenaka Maisa C,Kenison Jessica E,Mayo Lior,Chao Chun-Cheih,Patel Bonny,Yan Raymond,Blain Manon,Alvarez Jorge I,Kébir Hania,Anandasabapathy Niroshana,Izquierdo Guillermo,Jung Steffen,Obholzer Nikolaus,Pochet Nathalie,Clish Clary B,Prinz Marco,Prat Alexandre,Antel Jack,Quintana Francisco J
Astrocytes have important roles in the central nervous system (CNS) during health and disease. Through genome-wide analyses we detected a transcriptional response to type I interferons (IFN-Is) in astrocytes during experimental CNS autoimmunity and also in CNS lesions from patients with multiple sclerosis (MS). IFN-I signaling in astrocytes reduces inflammation and experimental autoimmune encephalomyelitis (EAE) disease scores via the ligand-activated transcription factor aryl hydrocarbon receptor (AHR) and the suppressor of cytokine signaling 2 (SOCS2). The anti-inflammatory effects of nasally administered interferon (IFN)-β are partly mediated by AHR. Dietary tryptophan is metabolized by the gut microbiota into AHR agonists that have an effect on astrocytes to limit CNS inflammation. EAE scores were increased following ampicillin treatment during the recovery phase, and CNS inflammation was reduced in antibiotic-treated mice by supplementation with the tryptophan metabolites indole, indoxyl-3-sulfate, indole-3-propionic acid and indole-3-aldehyde, or the bacterial enzyme tryptophanase. In individuals with MS, the circulating levels of AHR agonists were decreased. These findings suggest that IFN-Is produced in the CNS function in combination with metabolites derived from dietary tryptophan by the gut flora to activate AHR signaling in astrocytes and suppress CNS inflammation.
Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson's Disease.
Sampson Timothy R,Debelius Justine W,Thron Taren,Janssen Stefan,Shastri Gauri G,Ilhan Zehra Esra,Challis Collin,Schretter Catherine E,Rocha Sandra,Gradinaru Viviana,Chesselet Marie-Francoise,Keshavarzian Ali,Shannon Kathleen M,Krajmalnik-Brown Rosa,Wittung-Stafshede Pernilla,Knight Rob,Mazmanian Sarkis K
The intestinal microbiota influence neurodevelopment, modulate behavior, and contribute to neurological disorders. However, a functional link between gut bacteria and neurodegenerative diseases remains unexplored. Synucleinopathies are characterized by aggregation of the protein α-synuclein (αSyn), often resulting in motor dysfunction as exemplified by Parkinson's disease (PD). Using mice that overexpress αSyn, we report herein that gut microbiota are required for motor deficits, microglia activation, and αSyn pathology. Antibiotic treatment ameliorates, while microbial re-colonization promotes, pathophysiology in adult animals, suggesting that postnatal signaling between the gut and the brain modulates disease. Indeed, oral administration of specific microbial metabolites to germ-free mice promotes neuroinflammation and motor symptoms. Remarkably, colonization of αSyn-overexpressing mice with microbiota from PD-affected patients enhances physical impairments compared to microbiota transplants from healthy human donors. These findings reveal that gut bacteria regulate movement disorders in mice and suggest that alterations in the human microbiome represent a risk factor for PD.
The mucosal immune system: master regulator of bidirectional gut-brain communications.
Powell Nick,Walker Marjorie M,Talley Nicholas J
Nature reviews. Gastroenterology & hepatology
Communication between the brain and gut is not one-way, but a bidirectional highway whereby reciprocal signals between the two organ systems are exchanged to coordinate function. The messengers of this complex dialogue include neural, metabolic, endocrine and immune mediators responsive to diverse environmental cues, including nutrients and components of the intestinal microbiota (microbiota-gut-brain axis). We are now starting to understand how perturbation of these systems affects transition between health and disease. The pathological repercussions of disordered gut-brain dialogue are probably especially pertinent in functional gastrointestinal diseases, including IBS and functional dyspepsia. New insights into these pathways might lead to novel treatment strategies in these common gastrointestinal diseases. In this Review, we consider the role of the immune system as the gatekeeper and master regulator of brain-gut and gut-brain communications. Although adaptive immunity (T cells in particular) participates in this process, there is an emerging role for cells of the innate immune compartment (including innate lymphoid cells and cells of the mononuclear phagocyte system). We will also consider how these key immune cells interact with the specific components of the enteric and central nervous systems, and rapidly respond to environmental variables, including the microbiota, to alter gut homeostasis.
GABA-modulating bacteria of the human gut microbiota.
Strandwitz Philip,Kim Ki Hyun,Terekhova Darya,Liu Joanne K,Sharma Anukriti,Levering Jennifer,McDonald Daniel,Dietrich David,Ramadhar Timothy R,Lekbua Asama,Mroue Nader,Liston Conor,Stewart Eric J,Dubin Marc J,Zengler Karsten,Knight Rob,Gilbert Jack A,Clardy Jon,Lewis Kim
The gut microbiota affects many important host functions, including the immune response and the nervous system. However, while substantial progress has been made in growing diverse microorganisms of the microbiota, 23-65% of species residing in the human gut remain uncultured, which is an obstacle for understanding their biological roles. A likely reason for this unculturability is the absence in artificial media of key growth factors that are provided by neighbouring bacteria in situ. In the present study, we used co-culture to isolate KLE1738, which required the presence of Bacteroides fragilis to grow. Bioassay-driven purification of B. fragilis supernatant led to the isolation of the growth factor, which, surprisingly, is the major inhibitory neurotransmitter GABA (γ-aminobutyric acid). GABA was the only tested nutrient that supported the growth of KLE1738, and a genome analysis supported a GABA-dependent metabolism mechanism. Using growth of KLE1738 as an indicator, we isolated a variety of GABA-producing bacteria, and found that Bacteroides ssp. produced large quantities of GABA. Genome-based metabolic modelling of the human gut microbiota revealed multiple genera with the predicted capability to produce or consume GABA. A transcriptome analysis of human stool samples from healthy individuals showed that GABA-producing pathways are actively expressed by Bacteroides, Parabacteroides and Escherichia species. By coupling 16S ribosmal RNA sequencing with functional magentic resonance imaging in patients with major depressive disorder, a disease associated with an altered GABA-mediated response, we found that the relative abundance levels of faecal Bacteroides are negatively correlated with brain signatures associated with depression.
Gut Microbiota, Bacterial Translocation, and Interactions with Diet: Pathophysiological Links between Major Depressive Disorder and Non-Communicable Medical Comorbidities.
Slyepchenko Anastasiya,Maes Michael,Jacka Felice N,Köhler Cristiano A,Barichello Tatiana,McIntyre Roger S,Berk Michael,Grande Iria,Foster Jane A,Vieta Eduard,Carvalho André F
Psychotherapy and psychosomatics
BACKGROUND:Persistent low-grade immune-inflammatory processes, oxidative and nitrosative stress (O&NS), and hypothalamic-pituitary-adrenal axis activation are integral to the pathophysiology of major depressive disorder (MDD). The microbiome, intestinal compositional changes, and resultant bacterial translocation add a new element to the bidirectional interactions of the gut-brain axis; new evidence implicates these pathways in the patho-aetiology of MDD. In addition, abnormalities in the gut-brain axis are associated with several chronic non-communicable disorders, which frequently co-occur in individuals with MDD, including but not limited to irritable bowel syndrome (IBS), chronic fatigue syndrome (CFS), obesity, and type 2 diabetes mellitus (T2DM). METHODS:We searched the PubMed/MEDLINE database up until May 1, 2016 for studies which investigated intestinal dysbiosis and bacterial translocation (the 'leaky gut') in the pathophysiology of MDD and co-occurring somatic comorbidities with an emphasis on IBS, CFS, obesity, and T2DM. RESULTS:The composition of the gut microbiota is influenced by several genetic and environmental factors (e.g. diet). Several lines of evidence indicate that gut-microbiota-diet interactions play a significant pathophysiological role in MDD and related medical comorbidities. Gut dysbiosis and the leaky gut may influence several pathways implicated in the biology of MDD, including but not limited to immune activation, O&NS, and neuroplasticity cascades. However, methodological inconsistencies and limitations limit comparisons across studies. CONCLUSIONS:Intestinal dysbiosis and the leaky gut may constitute a key pathophysiological link between MDD and its medical comorbidities. This emerging literature opens relevant preventative and therapeutic perspectives.
The gut microbiome in neurological disorders.
Cryan John F,O'Riordan Kenneth J,Sandhu Kiran,Peterson Veronica,Dinan Timothy G
The Lancet. Neurology
Research into the role of the gut microbiome in modulating brain function has rapidly increased over the past 10 years, albeit chiefly in animal models. Increasing clinical and preclinical evidence implicates the microbiome as a possible key susceptibility factor for neurological disorders, including Alzheimer's disease, autism spectrum disorder, multiple sclerosis, Parkinson's disease, and stroke. Cross-sectional clinical studies are bolstering the concept of altered microbial composition contributing to the pathophysiology of such diseases. However, the field is nascent, and interpretation of such data is often difficult given that the composition of the microbiome is influenced by various factors such as diet and exercise. Longitudinal studies and randomised controlled trials in humans are needed to find out if targeting the microbiome can yield novel therapeutic strategies. Systems biology approaches will also be important in integrating such data with genomic and metabolomic datasets from clinical cohorts with neurological disease to help guide individual treatment selection.
Interactions between the microbiota, immune and nervous systems in health and disease.
Fung Thomas C,Olson Christine A,Hsiao Elaine Y
The diverse collection of microorganisms that inhabit the gastrointestinal tract, collectively called the gut microbiota, profoundly influences many aspects of host physiology, including nutrient metabolism, resistance to infection and immune system development. Studies investigating the gut-brain axis demonstrate a critical role for the gut microbiota in orchestrating brain development and behavior, and the immune system is emerging as an important regulator of these interactions. Intestinal microbes modulate the maturation and function of tissue-resident immune cells in the CNS. Microbes also influence the activation of peripheral immune cells, which regulate responses to neuroinflammation, brain injury, autoimmunity and neurogenesis. Accordingly, both the gut microbiota and immune system are implicated in the etiopathogenesis or manifestation of neurodevelopmental, psychiatric and neurodegenerative diseases, such as autism spectrum disorder, depression and Alzheimer's disease. In this review, we discuss the role of CNS-resident and peripheral immune pathways in microbiota-gut-brain communication during health and neurological disease.
Mild cognitive impairment has similar alterations as Alzheimer's disease in gut microbiota.
Li Binyin,He Yixi,Ma Jianfang,Huang Pei,Du Juanjuan,Cao Li,Wang Yan,Xiao Qin,Tang Huidong,Chen Shengdi
Alzheimer's & dementia : the journal of the Alzheimer's Association
OBJECTIVE:Gut microbiota changes before the onset of Alzheimer's disease (AD) and the alterations could be detected in the stage of mild cognitive impairment (MCI). The findings might offer diagnostic biomarkers before the onset of dementia. BACKGROUND:AD is the most common cause of dementia, and MCI is the predementia state. Recent studies suggest the alterations in the gut microbial communities associated with AD, whereas the microbiota in MCI before the onset of dementia has not been discovered and characterized in humans. NEW/UPDATED HYPOTHESIS:We hypothesize that the dysbiosis happens in the MCI stage. Patients with AD and MCI have decreased microbial diversity, and changes in gut microbiota could be detected for early detection of AD. In our preliminary study, we identified differences between AD and normal controls in 11 genera from the feces and 11 genera from the blood. No difference in genera between AD and MCI was detected. Using the diagnostic model from fecal samples with all different genera input, 93% (28 in 30) of patients with MCI could be identified correctly. MAJOR CHALLENGES FOR THE HYPOTHESIS:The diagnosis of MCI and AD in the study was based on symptoms and neuroimaging, and AD biomarkers should be included for precise diagnosis in further validating studies. Besides, as the microbiota changes longitudinally, their relationship with the progress of dementia needs to be studied in the prospective studies. LINKAGE TO OTHER MAJOR THEORIES:Escherichia was observed increased at genus level in both fecal and blood samples from AD and MCI. For AD biomarker, postmortem brain tissue from patients with AD showed lipopolysaccharides and gram-negative Escherichia coli fragments colocalize with amyloid plaque. In this way, the amyloid pathogenesis for AD would be triggered during MCI by gut microbiota shifting. Besides, systemic inflammatory reactions caused by compounds secreted by bacteria may impair the blood-brain barrier and promote neuroinflammation and/or neurodegeneration. Furthermore, abnormal metabolites caused by microbial gene functions have an impact on neurodegeneration.
Sodium oligomannate therapeutically remodels gut microbiota and suppresses gut bacterial amino acids-shaped neuroinflammation to inhibit Alzheimer's disease progression.
Wang Xinyi,Sun Guangqiang,Feng Teng,Zhang Jing,Huang Xun,Wang Tao,Xie Zuoquan,Chu Xingkun,Yang Jun,Wang Huan,Chang Shuaishuai,Gong Yanxue,Ruan Lingfei,Zhang Guanqun,Yan Siyuan,Lian Wen,Du Chen,Yang Dabing,Zhang Qingli,Lin Feifei,Liu Jia,Zhang Haiyan,Ge Changrong,Xiao Shifu,Ding Jian,Geng Meiyu
Recently, increasing evidence has suggested the association between gut dysbiosis and Alzheimer's disease (AD) progression, yet the role of gut microbiota in AD pathogenesis remains obscure. Herein, we provide a potential mechanistic link between gut microbiota dysbiosis and neuroinflammation in AD progression. Using AD mouse models, we discovered that, during AD progression, the alteration of gut microbiota composition leads to the peripheral accumulation of phenylalanine and isoleucine, which stimulates the differentiation and proliferation of pro-inflammatory T helper 1 (Th1) cells. The brain-infiltrated peripheral Th1 immune cells are associated with the M1 microglia activation, contributing to AD-associated neuroinflammation. Importantly, the elevation of phenylalanine and isoleucine concentrations and the increase of Th1 cell frequency in the blood were also observed in two small independent cohorts of patients with mild cognitive impairment (MCI) due to AD. Furthermore, GV-971, a sodium oligomannate that has demonstrated solid and consistent cognition improvement in a phase 3 clinical trial in China, suppresses gut dysbiosis and the associated phenylalanine/isoleucine accumulation, harnesses neuroinflammation and reverses the cognition impairment. Together, our findings highlight the role of gut dysbiosis-promoted neuroinflammation in AD progression and suggest a novel strategy for AD therapy by remodelling the gut microbiota.
The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease.
Yang Tao,Richards Elaine M,Pepine Carl J,Raizada Mohan K
Nature reviews. Nephrology
Crosstalk between the gut microbiota and the host has attracted considerable attention owing to its involvement in diverse diseases. Chronic kidney disease (CKD) is commonly associated with hypertension and is characterized by immune dysregulation, metabolic disorder and sympathetic activation, which are all linked to gut dysbiosis and altered host-microbiota crosstalk. In this Review, we discuss the complex interplay between the brain, the gut, the microbiota and the kidney in CKD and hypertension and explain our brain-gut-kidney axis hypothesis for the pathogenesis of these diseases. Consideration of the role of the brain-gut-kidney axis in the maintenance of normal homeostasis and of dysregulation of this axis in CKD and hypertension could lead to the identification of novel therapeutic targets. In addition, the discovery of unique microbial communities and their associated metabolites and the elucidation of brain-gut-kidney signalling are likely to fill fundamental knowledge gaps leading to innovative research, clinical trials and treatments for CKD and hypertension.
The Microbiota-Gut-Brain Axis.
Cryan John F,O'Riordan Kenneth J,Cowan Caitlin S M,Sandhu Kiran V,Bastiaanssen Thomaz F S,Boehme Marcus,Codagnone Martin G,Cussotto Sofia,Fulling Christine,Golubeva Anna V,Guzzetta Katherine E,Jaggar Minal,Long-Smith Caitriona M,Lyte Joshua M,Martin Jason A,Molinero-Perez Alicia,Moloney Gerard,Morelli Emanuela,Morillas Enrique,O'Connor Rory,Cruz-Pereira Joana S,Peterson Veronica L,Rea Kieran,Ritz Nathaniel L,Sherwin Eoin,Spichak Simon,Teichman Emily M,van de Wouw Marcel,Ventura-Silva Ana Paula,Wallace-Fitzsimons Shauna E,Hyland Niall,Clarke Gerard,Dinan Timothy G
The importance of the gut-brain axis in maintaining homeostasis has long been appreciated. However, the past 15 yr have seen the emergence of the microbiota (the trillions of microorganisms within and on our bodies) as one of the key regulators of gut-brain function and has led to the appreciation of the importance of a distinct microbiota-gut-brain axis. This axis is gaining ever more traction in fields investigating the biological and physiological basis of psychiatric, neurodevelopmental, age-related, and neurodegenerative disorders. The microbiota and the brain communicate with each other via various routes including the immune system, tryptophan metabolism, the vagus nerve and the enteric nervous system, involving microbial metabolites such as short-chain fatty acids, branched chain amino acids, and peptidoglycans. Many factors can influence microbiota composition in early life, including infection, mode of birth delivery, use of antibiotic medications, the nature of nutritional provision, environmental stressors, and host genetics. At the other extreme of life, microbial diversity diminishes with aging. Stress, in particular, can significantly impact the microbiota-gut-brain axis at all stages of life. Much recent work has implicated the gut microbiota in many conditions including autism, anxiety, obesity, schizophrenia, Parkinson's disease, and Alzheimer's disease. Animal models have been paramount in linking the regulation of fundamental neural processes, such as neurogenesis and myelination, to microbiome activation of microglia. Moreover, translational human studies are ongoing and will greatly enhance the field. Future studies will focus on understanding the mechanisms underlying the microbiota-gut-brain axis and attempt to elucidate microbial-based intervention and therapeutic strategies for neuropsychiatric disorders.
Microbiota-Gut-Brain Axis: New Therapeutic Opportunities.
Long-Smith Caitríona,O'Riordan Kenneth J,Clarke Gerard,Stanton Catherine,Dinan Timothy G,Cryan John F
Annual review of pharmacology and toxicology
The traditional fields of pharmacology and toxicology are beginning to consider the substantial impact our gut microbiota has on host physiology. The microbiota-gut-brain axis is emerging as a particular area of interest and a potential new therapeutic target for effective treatment of central nervous system disorders, in addition to being a potential cause of drug side effects. Microbiota-gut-brain axis signaling can occur via several pathways, including via the immune system, recruitment of host neurochemical signaling, direct enteric nervous system routes and the vagus nerve, and the production of bacterial metabolites. Altered gut microbial profiles have been described in several psychiatric and neurological disorders. Psychobiotics, live biotherapeutics or substances whose beneficial effects on the brain are bacterially mediated, are currently being investigated as direct and/or adjunctive therapies for psychiatric and neurodevelopmental disorders and possibly for neurodegenerative disease, and they may emerge as new therapeutic options in the clinical management of brain disorders.
The gut microbiota: A treasure for human health.
Li Daotong,Wang Pan,Wang Pengpu,Hu Xiaosong,Chen Fang
The interplay between the host and host-associated gut microbiota is an area of increasing interest during the recent decade. From young infants to elderly people, from primitive tribes to modern societies, accumulating evidence has suggested the association of critical physiological roles of gut microbiota in the pathogenesis of a variety of human metabolic, immunological and neurological diseases. Importantly, it appears that the relationship between the gut microbiota and disease is bidirectional, instead of causal or consequential. Personalized nutritional and therapeutic strategies targeting the gut microbiota such as prebiotics, probiotics, drugs and fecal microbiota transplantation may create a new era in the human health.
The Effect of Microbiota and the Immune System on the Development and Organization of the Enteric Nervous System.
Obata Yuuki,Pachnis Vassilis
The gastrointestinal (GI) tract is essential for the absorption of nutrients, induction of mucosal and systemic immune responses, and maintenance of a healthy gut microbiota. Key aspects of gastrointestinal physiology are controlled by the enteric nervous system (ENS), which is composed of neurons and glial cells. The ENS is exposed to and interacts with the outer (microbiota, metabolites, and nutrients) and inner (immune cells and stromal cells) microenvironment of the gut. Although the cellular blueprint of the ENS is mostly in place by birth, the functional maturation of intestinal neural networks is completed within the microenvironment of the postnatal gut, under the influence of gut microbiota and the mucosal immune system. Recent studies have shown the importance of molecular interactions among microbiota, enteric neurons, and immune cells for GI homeostasis. In addition to its role in GI physiology, the ENS has been associated with the pathogenesis of neurodegenerative disorders, such as Parkinson's disease, raising the possibility that microbiota-ENS interactions could offer a viable strategy for influencing the course of brain diseases. Here, we discuss recent advances on the role of microbiota and the immune system on the development and homeostasis of the ENS, a key relay station along the gut-brain axis.
Interplay among gut microbiota, intestinal mucosal barrier and enteric neuro-immune system: a common path to neurodegenerative diseases?
Pellegrini Carolina,Antonioli Luca,Colucci Rocchina,Blandizzi Corrado,Fornai Matteo
Neurological diseases, such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS) and multiple sclerosis, are often associated with functional gastrointestinal disorders. These gastrointestinal disturbances may occur at all stages of the neurodegenerative diseases, to such an extent that they are now considered an integral part of their clinical picture. Several lines of evidence support the contention that, in central neurodegenerative diseases, changes in gut microbiota and enteric neuro-immune system alterations could contribute to gastrointesinal dysfunctions as well as initiation and upward spreading of the neurologic disorder. The present review has been intended to provide a comprehensive overview of the available knowledge on the role played by enteric microbiota, mucosal immune system and enteric nervous system, considered as an integrated network, in the pathophysiology of the main neurological diseases known to be associated with intestinal disturbances. In addition, based on current human and pre-clinical evidence, our intent was to critically discuss whether changes in the dynamic interplay between gut microbiota, intestinal epithelial barrier and enteric neuro-immune system are a consequence of the central neurodegeneration or might represent the starting point of the neurodegenerative process. Special attention has been paid also to discuss whether alterations of the enteric bacterial-neuro-immune network could represent a common path driving the onset of the main neurodegenerative diseases, even though each disease displays its own distinct clinical features.
Mechanisms Underlying Microbial-Mediated Changes in Social Behavior in Mouse Models of Autism Spectrum Disorder.
Sgritta Martina,Dooling Sean W,Buffington Shelly A,Momin Eric N,Francis Michael B,Britton Robert A,Costa-Mattioli Mauro
Currently, there are no medications that effectively treat the core symptoms of Autism Spectrum Disorder (ASD). We recently found that the bacterial species Lactobacillus (L.) reuteri reverses social deficits in maternal high-fat-diet offspring. However, whether the effect of L. reuteri on social behavior is generalizable to other ASD models and its mechanism(s) of action remains unknown. Here, we found that treatment with L. reuteri selectively rescues social deficits in genetic, environmental, and idiopathic ASD models. Interestingly, the effects of L. reuteri on social behavior are not mediated by restoring the composition of the host's gut microbiome, which is altered in all of these ASD models. Instead, L. reuteri acts in a vagus nerve-dependent manner and rescues social interaction-induced synaptic plasticity in the ventral tegmental area of ASD mice, but not in oxytocin receptor-deficient mice. Collectively, treatment with L. reuteri emerges as promising non-invasive microbial-based avenue to combat ASD-related social dysfunction.
Role of melatonin in sleep deprivation-induced intestinal barrier dysfunction in mice.
Gao Ting,Wang Zixu,Dong Yulan,Cao Jing,Lin Rutao,Wang Xintong,Yu Zhengquan,Chen Yaoxing
Journal of pineal research
Intestinal diseases caused by sleep deprivation (SD) are severe public health threats worldwide. This study focuses on the effect of melatonin on intestinal mucosal injury and microbiota dysbiosis in sleep-deprived mice. Mice subjected to SD had significantly elevated norepinephrine levels and decreased melatonin content in plasma. Consistent with the decrease in melatonin levels, we observed a decrease of antioxidant ability, down-regulation of anti-inflammatory cytokines and up-regulation of pro-inflammatory cytokines in sleep-deprived mice, which resulted in colonic mucosal injury, including a reduced number of goblet cells, proliferating cell nuclear antigen-positive cells, expression of MUC2 and tight junction proteins and elevated expression of ATG5, Beclin1, p-P65 and p-IκB. High-throughput pyrosequencing of 16S rRNA demonstrated that the diversity and richness of the colonic microbiota were decreased in sleep-deprived mice, especially in probiotics, including Akkermansia, Bacteroides and Faecalibacterium. However, the pathogen Aeromonas was markedly increased. By contrast, supplementation with 20 and 40 mg/kg melatonin reversed these SD-induced changes and improved the mucosal injury and dysbiosis of the microbiota in the colon. Our results suggest that the effect of SD on intestinal barrier dysfunction might be an outcome of melatonin suppression rather than a loss of sleep per se. SD-induced intestinal barrier dysfunction involved the suppression of melatonin production and activation of the NF-κB pathway by oxidative stress.
Interactions Between Commensal Bacteria and Enteric Neurons, via FPR1 Induction of ROS, Increase Gastrointestinal Motility in Mice.
Chandrasekharan Bindu,Saeedi Bejan J,Alam Ashfaqul,Houser Madelyn,Srinivasan Shanthi,Tansey Malu,Jones Rheinallt,Nusrat Asma,Neish Andrew S
BACKGROUND & AIMS:Reduced gastrointestinal (GI) motility is a feature of disorders associated with intestinal dysbiosis and loss of beneficial microbes. It is not clear how consumption of beneficial commensal microbes, marketed as probiotics, affects the enteric nervous system (ENS). We studied the effects of the widely used probiotic and the commensal Lactobacillus rhamnosus GG (LGG) on ENS and GI motility in mice. METHODS:Conventional and germ free C57B6 mice were gavaged with LGG and intestinal tissues were collected; changes in the enteric neuronal subtypes were assessed by real-time polymerase chain reaction, immunoblots, and immunostaining. Production of reactive oxygen species (ROS) in the jejunal myenteric plexi and phosphorylation (p) of mitogen-activated protein kinase 1 (MAPK1) in the enteric ganglia were assessed by immunoblots and immunostaining. Fluorescence in situ hybridization was performed on jejunal cryosections with probes to detect formyl peptide receptor 1 (FPR1). GI motility in conventional mice was assessed after daily gavage of LGG for 1 week. RESULTS:Feeding of LGG to mice stimulated myenteric production of ROS, increased levels of phosphorylated MAPK1, and increased expression of choline acetyl transferase by neurons (P < .001). These effects were not observed in mice given N-acetyl cysteine (a ROS inhibitor) or LGGΩSpaC (an adhesion-mutant strain of LGG) or FPR1-knockout mice. Gavage of mice with LGG for 1 week significantly increased stool frequency, reduced total GI transit time, and increased contractions of ileal circular muscle strips in ex vivo experiments (P < .05). CONCLUSIONS:Using mouse models, we found that LGG-mediated signaling in the ENS requires bacterial adhesion, redox mechanisms, and FPR1. This pathway might be activated to increase GI motility in patients.