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Long-term effects Do psychobiotics produce long-term changes in the central nervous system? Both probiotics 22 , 25 and prebiotics 30 , 31 have been shown to induce effects that outlast the period of ingestion, and have implications for the longevity of treatment outcomes. Systematic tracking of psychological, neural, and systemic changes both during long-term psychobiotic ingestion and after cessation of the regime.

Zero-sum effects Are changes in one brain region broadly offset by changes in the opposing direction elsewhere? Very preliminary evidence for a zero-sum effect demonstrating an increase in both GABA and glutamate expression [25] , which control neural inhibition and excitation, respectively.

Earlier research [21] found that probiotics increased GABA representation in some areas but decreased it in others. Overall, this pair of results suggests that changes in excitation—inhibition balance in one brain region may be offset by those in another. Studies focussed specifically on this type of change e.

Research should also follow up the functional implications of these alterations, which may be fundamental in predicting detriments and enhancements. Cognitive enhancement Can psychobiotics confer cognitive benefits?

There is yet no evidence of psychobiotic-induced cognitive enhancements in humans. Numerous rodent studies discussed here show evidence of improvement in learning and memory following psychobiotic ingestion 21 , 22 , 29 , Measurement of memory and learning performance in humans alongside physiological measures.

Lack of evidence of enhancement may be due to the tasks themselves not having the sensitivity to detect subtle changes in performance. Detrimental effects Are psychobiotic benefits accompanied by undetected costs? One study found reduced performance on memory tasks following psychobiotic consumption in humans [32] but this impairment has not been replicated [34]. Careful assessment of side-effects in other areas of cognitive or physiological function. Detrimental effects are difficult to predict a priori , but should not be overlooked.

Joint effects of probiotics and prebiotics What are the independent and interactive effects of prebiotics and probiotics? This would also reveal whether prebiotics and probiotics differentially alter microbiome composition. Strain specificity Why do some strains of probiotic or prebiotic produce effects but not others?

Some psychobiotic strains produce effects while others produce partial or no effects 27 , 38 , Furthermore, strains from the same family may differentially affect anxiety. For example, Bifidobacterium longum B. In another case, Bifidobacterium longum B. In studies that show effects of mixtures of probiotics 35 , 42 , , it is unclear whether the outcome emerges from additive or synergistic interactions between bacterial families, or whether only some of the probiotics in the mixture are truly exerting effects.

Rigorous comparison of the effects of different strains, and efforts to replicate findings of strain-level differences from earlier studies.

The development of a theoretical account of how and why certain different species and strains exert differing effects would enable specific predictions of which strains exert which effects under which conditions. Such a framework is currently lacking. Role of moderators What factors moderate psychobiotic effects? Effects of Lactobacillus helveticus R on inflammation and anxiety depend on diet and genotype [].

Other potential moderators include age and sex. Systematic efforts to identify and assess individual differences and other moderators that could have an effect on psychobiotic outcomes. Drug interactions How do psychobiotics interact with other psychotropic substances? Clinical trials of the adjuvant therapeutic properties of psychobiotics alongside mainstream anxiolytics and antidepressants.

Outstanding Questions What are the dose-response functions associated with psychobiotics? Does the brain adapt to long-term psychobiotic ingestion?

Are there ceiling effects on psychobiotic benefits? What is the direction of causality between systemic and central changes? Acknowledgements The authors thank Arjun Dutta for helpful suggestions on an earlier draft of the manuscript. Glossary Colonisation bacterial colonisation is believed to begin during parturition.

Infant gut bacteria carry a maternal signature, though the mode of delivery substantially influences the composition of the early microbiota. The human infant’s microbiome comes to resemble the adult microbiome in complexity and richness in the first 1 to 3 years.

Commensal gut bacteria communities of indigenous bacteria residing in the intestinal tracts that share symbiotic relationships with the host. Bacteria comprise the vast majority of the microbiome, including at least distinct species and strains. Alongside bacteria reside smaller numbers of archaea, bacteria, fungi, protozoa, and viruses. Cytokine proteins that facilitate cell—cell signalling.

They serve an essential role in the organism’s immune activity, and balance inflammation in response to pathogenic or infectious entities. Pro-inflammatory cytokines enhance inflammation, while anti-inflammatory cytokines suppress inflammation.

Healthy immune function requires balanced pro- and anti-inflammatory cytokines. Depression and anxiety have both been associated with excessive pro-inflammatory cytokines. Enteric nervous system a subdivision of the nervous system embedded throughout the entire gastrointestinal tract, regulating all gastrointestinal function e. Glucocorticoid stress response a hormonal end-product of activity in the hypothalamic-pituitary-adrenal HPA axis.

Glucocorticoids such as cortisol and corticosterone are well-validated biomarkers of stress. In particular, circulating glucocorticoid concentrations increase in response to psychological and physical stress. Their secretion alters glucose metabolism and inhibits immunological activity. They also increase threat sensitivity and negative mood, and impair memory and other cognitive functions. In humans, cortisol is the glucocorticoid that performs these functions.

In rats and mice, corticosterone exerts these effects. Overall, though cortisol and corticosterone have somewhat different molecular structures, they are functionally similar in their physiological and psychological effects.

While glucocorticoids prepare the organism to deal with stressful or uncertain situations, dysregulated HPA-activity and glucocorticoid levels are associated with anxiety and depression.

Gut—brain axis a network comprising the gastrointestinal tract, the enteric nervous system, and the brain. Bidirectional communications between these entities regulate several important functions, including immunity, digestion, metabolism, satiety, and stress reactions. Messenger ribonucleic acid mRNA carries genetic information for the coding of particular proteins from the deoxyribonucleic acid DNA within the cell’s nuclear envelope into the cytoplasm, where protein synthesis occurs.

Inflammation an adaptive response to noxious stimuli or experiences, most notably infection or injury. The response involves coordinated activity across a range of biological actors, including cytokines.

These processes are targeted at protecting tissue from further damage and repairing or clearing affected tissue. Rodent behavioural tests in animal models, psychological states such as anxiety and depression must be inferred from behavioural profiles. Various tests allow for the systematic observation of certain behaviours that correspond closely to the psychological state of interest.

These tests have also been shown to accurately capture anxiolytic and antidepressant effects. In maze-learning tasks, rodents are exposed to novel environments. Over time, they develop spatial representations for the maze through attempts to navigate it.

Anxiety impairs this learning process. The Morris water maze, in which rodents swimming in pools of water must find a submerged platform which allows them to stop swimming, tests similar processes by exploiting the evolutionary fear of drowning. In the elevated plus maze, an evolutionary tendency to prefer closed to open spaces is exploited on a maze with walled-in and no-wall components maintained at a substantial elevation from the ground, with anxious behaviour measured as preference for, and time spent in, the walled sections.

In the open field test, rodents are placed in a novel and open area that they subsequently explore, with anxious behaviour marked by tendencies such as time spent away from the centre of the space. The forced swim test measures depressive behaviour by assessing the vigour with which rodents swim in an enclosed area, with periods of immobility or poor performance reflecting depressive behaviour. In the tail suspension test, rodents are suspended by their tails, and periods of immobility or other signs of insufficient struggle to escape the suspension are taken as markers of depression.

Rodent stress inductions stress can be induced in rodents through exposure to noxious stimuli. These stressors enable experimental analysis of subsequent behavioural and physiological reactions. Restraint stress physically confines the rodent such that it is impossible to move.

Water avoidance stress entails surrounding the rodent with water, which triggers the fear of drowning. A developmental approximation of anxiety and depression is achieved through maternal separation, in which infants are separated from their mothers shortly after birth. This exerts negative emotional and physiological effects throughout the rodent’s developmental trajectory.

The precise purpose of this response is still unknown. It serves as a biomarker of HPA-reactivity, and is exaggerated in depression and anxiety. References 1. Sudo N. Postnatal microbial colonization programs the hypothalamic—pituitary—adrenal system for stress response in mice. Hooper L.

Interactions between the microbiota and the immune system. Kau A. Human nutrition, the gut microbiome and the immune system. Le Chatelier E. Richness of human gut microbiome correlates with metabolic markers. Turnbaugh P. An obesity-associated gut microbiome with increased capacity for energy harvest. Bravo J. Communication between gastrointestinal bacteria and the nervous system. Foster J. Gut—brain axis: how the microbiome influences anxiety and depression. Dinan T. Psychobiotics: a novel class of psychotropic.

Mayer E. Gut microbes and the brain: paradigm shift in neuroscience. Burnet P. Psychobiotics highlight the pathways to happiness. Sansonetti P. Learning tolerance while fighting ignorance. Gibson G. Dietary prebiotics: current status and new definition. Food Sci. Dowlati Y. A meta-analysis of cytokines in major depression. Udina M. Interferon-induced depression in chronic hepatitis C: a systematic review and meta-analysis.

McNutt M. Heldt S. Hippocampus-specific deletion of BDNF in adult mice impairs spatial memory and extinction of aversive memories. Martinowich K. Interaction between BDNF and serotonin: role in mood disorders. Desbonnet L. Effects of the probiotic Bifidobacterium infantis in the maternal separation model of depression.

Gareau M. Probiotic treatment of rat pups normalises corticosterone release and ameliorates colonic dysfunction induced by maternal separation. Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Matthews D. Ingestion of Mycobacterium vaccae decreases anxiety-related behavior and improves learning in mice. The probiotic Bifidobacteria infantis : an assessment of potential antidepressant properties in the rat.

Liang S. Administration of Lactobacillus helveticus NS8 improves behavioral, cognitive, and biochemical aberrations caused by chronic restraint stress. Janik R. Magnetic resonance spectroscopy reveals oral Lactobacillus promotion of increases in brain GABA, N -acetyl aspartate and glutamate.

Alander M. Persistence of colonization of human colonic mucosa by a probiotic strain, Lactobacillus rhamnosus GG, after oral consumption.

Savignac H. Prebiotic feeding elevates central brain derived neurotrophic factor, N -methyl- d -aspartate receptor subunits and d -serine. Memory and the NMDA receptors. Williams S. Oliveros E. Benton D. Impact of consuming a milk drink containing a probiotic on mood and cognition. Messaoudi M. Assessment of psychotropic-like properties of a probiotic formulation Lactobacillus helveticus R and Bifidobacterium longum R in rats and human subjects.

Beneficial psychological effects of a probiotic formulation Lactobacillus helveticus R and Bifidobacterium longum R in healthy human volunteers.

Gut Microbes. Steenbergen L. A randomized controlled trial to test the effect of multispecies probiotics on cognitive reactivity to sad mood. Brain Behav. Kato-Kataoka A. Fermented milk containing Lactobacillus casei strain Shirota preserves the diversity of the gut microbiota and relieves abdominal dysfunction in healthy medical students exposed to academic stress.

Sashihara T. Lactobacillus and bifidobacterium in irritable bowel syndrome: symptom responses and relationship to cytokine profiles. The brain—gut axis in abdominal pain syndromes. Kassinen A. The fecal microbiota of irritable bowel syndrome patients differs significantly from that of healthy subjects. Clarke G. Irritable bowel syndrome: towards biomarker identification. Trends Mol. Tillisch K. Consumption of fermented milk product with probiotic modulates brain activity.

Britton J. Facial expressions and complex IAPS pictures: common and differential networks. Schmidt K. Prebiotic intake reduces the waking cortisol response and alters emotional bias in healthy volunteers. Psychopharmacology Berl ; — Bhagwagar Z. Increased salivary cortisol after waking in depression.

Mannie Z. Increased waking salivary cortisol levels in young people at familial risk of depression. Beck A. Penguin; Cognitive Therapy and the Emotional Disorders. Ironside M. Frontal cortex stimulation reduces vigilance to threat: implications for the treatment of depression and anxiety. Bercik P. The anxiolytic effect of Bifidobacterium longum NCC involves vagal pathways for gut—brain communication.

Kunze W. Lactobacillus reuteri enhances excitability of colonic AH neurons by inhibiting calcium-dependent potassium channel opening. Lactobacillus reuteri ingestion prevents hyperexcitability of colonic DRG neurons induced by noxious stimuli. Liver Physiol. Cryan J. Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. McVey Neufeld The microbiome is essential for normal gut intrinsic primary afferent neuron excitability in the mouse.

Collins J. Intestinal microbiota influence the early postnatal development of the enteric nervous system. Lomasney K. Selective influence of host microbiota on cAMP-mediated ion transport in mouse colon.

Kabouridis P. Microbiota controls the homeostasis of glial cells in the gut lamina propria. Barrett E. Collective unconscious: how gut microbes shape human behavior. Lyte M. Probiotics function mechanistically as delivery vehicles for neuroactive compounds: microbial endocrinology in the design and use of probiotics. Thayer J. Neural concomitants of immunity: focus on the vagus nerve.

Lipid-rich enteral nutrition regulates mucosal mast cell activation via the vagal anti-inflammatory reflex. Mezzacappa E. Vagal rebound and recovery from psychological stress. Spalding T. Vagal and cardiac reactivity to psychological stressors in trained and untrained men. Sports Exerc. Borovikova L. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin.

Kirchner A. Left vagus nerve stimulation suppresses experimentally induced pain. Morris G. Long-term treatment with vagus nerve stimulation in patients with refractory epilepsy. Sackeim H. Rush A. Vagus nerve stimulation for treatment-resistant depression: a randomized, controlled acute phase trial. Adinoff B. Vagal tone decreases following intravenous diazepam.

Psychiatry Res. Salam O. Fluoxetine and sertraline stimulate gastric acid secretion via a vagal pathway in anaesthetised rats. Smith R. Increased association over time between regional frontal lobe BOLD change magnitude and cardiac vagal control with sertraline treatment for major depression. De Lartigue G. Vagal afferent neurons in high fat diet-induced obesity; intestinal microflora, gut inflammation and cholecystokinin.

The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice. Qin J. A human gut microbial gene catalogue established by metagenomic sequencing. Horn T. Neuroprotective effects of lactate in brain ischemia: dependence on anesthetic drugs. Moretti M. Behavioral and neurochemical effects of sodium butyrate in an animal model of mania. Overduin J. Future investigations are likely to reveal many more shared DAMPs.

This observation suggests that efforts to elucidate the pathway s through which innate immunity is activated will likely identify additional signaling components that are shared by these three classes of inducers.

All the data supporting our review is contained within the manuscript. Both authors read and approved the final manuscript. Hyong Woo Choi, Email: ude. Daniel F. Klessig, Email: ude. BMC Plant Biol. Published online Oct Hyong Woo Choi and Daniel F. Author information Article notes Copyright and License information Disclaimer.

Corresponding author. Received Sep 15; Accepted Oct This article has been cited by other articles in PMC. Associated Data Data Availability Statement All the data supporting our review is contained within the manuscript.

Background All living organisms have evolved ways to protect themselves against abiotic and biotic assaults. Open in a separate window. NAMPs Nematodes, one of the most abundant animals in nature, parasitize both plants and animals. Hydroxyproline-rich systemin n. At HMGB3 d n. Klessig c Unpublished data — M. Conclusions Only during the past two decades has the importance of DAMPs for the survival of multicellular organisms emerged; this finding has fostered an active area of investigation.

Availability of data and materials All the data supporting our review is contained within the manuscript. Competing interests The authors declare that they have are no competing interests. Consent for publication Not applicable. Ethics approval and consent to participate Not applicable. References 1. Boller T, Felix G. A renaissance of elicitors: perception of microbe-associated molecular patterns and danger signals by pattern-recognition receptors. Annu Rev Plant Biol.

Pathogen recognition by the innate immune system. Int Rev Immunol. Immunol Rev. Macho AP, Zipfel C. Plant PRRs and the activation of innate immune signaling. Mol Cell. Bianchi ME. J Leukoc Biol. Conserved nematode signalling molecules elicit plant defenses and pathogen resistance.

Nat Commun. Seong SY, Matzinger P. Hydrophobicity: an ancient damage-associated molecular pattern that initiates innate immune responses. Nat Rev Immunol. High-mobility group box 1 protein HMGB1 : nuclear weapon in the immune arsenal. Tail-mediated collapse of HMGB1 is dynamic and occurs via differential binding of the acidic tail to the A and B domains. J Mol Biol. Substantial histone reduction modulates genomewide nucleosomal occupancy and global transcriptional output.

PLoS Biol. Andersson U, Tracey KJ. HMGB1 is a therapeutic target for sterile inflammation and infection. Annu Rev Immunol. HMGB1 as biomarker and drug target. Pharmacol Res. Mutually exclusive redox forms of HMGB1 promote cell recruitment or proinflammatory cytokine release.

J Exp Med. Mol Med. Production of multiple plant hormones from a single polyprotein precursor. A polypeptide from tomato leaves induces wound-inducible proteinase inhibitor proteins. The cellular localization of prosystemin: a functional role for phloem parenchyma in systemic wound signaling. Distinct roles for jasmonate synthesis and action in the systemic wound response of tomato.

Enzymes of jasmonate biosynthesis occur in tomato sieve elements. Plant Cell Physiol. Prosystemin from potato, black nightshade, and bell pepper: primary structure and biological activity of predicted systemin polypeptides.

Plant Mol Biol. An endogenous peptide signal in Arabidopsis activates components of the innate immune response. The cell surface leucine-rich repeat receptor for AtPep1, an endogenous peptide elicitor in Arabidopsis, is functional in transgenic tobacco cells. Plant Cell. Danger peptide receptor signaling in plants ensures basal immunity upon pathogen-induced depletion of BAK1.

EMBO J. ZmPep1, an ortholog of Arabidopsis elicitor peptide 1, regulates maize innate immunity and enhances disease resistance. Plant Physiol. Yamaguchi Y, Huffaker A. Endogenous peptide elicitors in higher plants. Curr Opin Plant Biol. Hyaluronan in tissue injury and repair. Annu Rev Cell Dev Biol. Hyaluronan fragments act as an endogenous danger signal by engaging TLR2.

J Immunol. Activation of defense response pathways by OGs and Flg22 elicitors in Arabidopsis seedlings. Mol Plant. J Biol Chem. A domain swap approach reveals a role of the plant wall-associated kinase 1 WAK1 as a receptor of oligogalacturonides. Decreux A, Messiaen J. Wall-associated kinase WAK1 interacts with cell wall pectins in a calcium-induced conformation.

Burnstock G. Discovery of purinergic signalling, the initial resistance and current explosion of interest. Br J Pharmacol.

Front Plant Sci. Identification of a plant receptor for extracellular ATP. Evidence of a novel cell signaling role for extracellular adenosine triphosphates and diphosphates in Arabidopsis. Activation of plant innate immunity by extracellular high mobility group box 3 and its inhibition by salicylic acid.

PLoS Pathog. Merkle T, Grasser KD. Unexpected mobility of plant chromatin-associated HMGB proteins. Plant Signal Behav. It’s designed this way because the web server only reacts to visits and doesn’t have any active threads running.

To make scheduled builds more accurate: Move the scheduled time to a time when your site normally has visitors.

This lessens the impact to site responsiveness but slows the backup a bit. Schedule Accuracy To guarantee a schedule runs on the time a user sets up the schedule; users can use a third party service to help.

This can also be especially helpful in the event the “Client Side Kickoff” setting has been enabled. This process involves setting up an entry in cron-job. To use this service please follow these steps: Goto cron-job.

Even though the request will be coming in every minute even when no build job is running, it would require very little processing so the simple request will not impact your site performance. Custom Crons: Plugin users should not use custom WP-Crons or plugins like WP Control Cron Manager to setup custom cron jobs because they are all limited by the same thing that Duplicator is limited by. Since WordPress has no active threads it requires traffic to start the execution of any logic, which is why the remote request is the best route to take.

Issue A Package Downloads How to resolve package files archive or installer that will not download or show errors? The browser may block requests to non SSL assets based on server mime types.

Solution 3 Disable. Then try to download the installer or archive file from the main menu or the package details screen. Solution 4 Adjust Mime-Type: If you have issues downloading the these file types. Check with your server administrator on how to make sure the correct MIME types are configured for download. A quick setting for Apache web servers is to create or edit the. Add the following text to your. Other web servers will have similar configurations.

Please check with your server administrator for your proper setup. If you can not download the installer. Solution 5 Browser Settings: Check your browser settings to make sure that the save as dialog is designed to pop up for the the following mime types. Also consider switching browsers for any kind of download issue, even if you are only getting a partial download. Solution 6 WordPress URL Settings: On some servers trying to access https port when you are on http port 80 or vice versa can cause issues.

To fix this issue we recommend using SSL on all parts of your site. Before making this change please read through all the steps in order to be aware of how to back-out of the change if needed. We recommend that you test these steps in a staging environment before trying on a production one.

For a full overview on how to change these values back see this article. Solution 1 Backup Installer: In the event you can download the archive but not the installer, you can always obtain a copy of the installer from within the archive. Inside of the archive file at the root is a backup copy of the installer named installer-backup. If you need to extract an archive. Solution 2 Rename Installer: Some hosting providers very few will not allow php files to be downloaded or created directly from their servers.

In this case you can rename the installer file that is created during the build process. When the installer file is created it will create it as “installer. This will allow you to download the file, but it will need to then be changed to installer. There are several common reasons for a slow build: Unnecessarily Files: Look for large file warnings during the scan report step. Problem When creating a package or exporting plugin settings the results of malformed utf-8 characters notice is present.

After that, rebuild the package to see if the issue goes away. Note: This setting is only available in Duplicator Pro. Option 2 Setting Migration: If you are using the settings migration export tool and see this error then data stored in the settings, templates, storage or schedule area has become corrupted. Check the data in the failed area to make sure the data is correct.

If the data looks correct consider re-saving the data in that respective area. If the problem persists consider removing the items one by one to isolate the setting that is causing the issue. Install Backup The installer process can be ran in the following modes. Pre-Install Before the install process starts. Import Install This Duplicator Pro only feature is the easiest way to install a packaged Duplicator archive. Users can either Drag-n-Drop or Link an archive file for rapid installs.

Overwrite Install This process is very similar to the “Classic Install” except that it depends on an existing WordPress site content to be present vs and empty directory.

This process requires that you upload both the installer and archive files to the destination server with WordPress already installed. For full step-by-step instructions see Overwrite Install section of the the Quick Start guide. The “Classic Install” process requires that both the installer and archive files are uploaded to the destination host in an empty directory. For step-by-step instructions see the Classic Install section of the the Quick Start guide.

Database Only Install Running the installer in “Database Only Mode” is useful when you only have database changes or a large site where all the files were moved manually. The full details of the Database Only Install can be found in the quick start guide. Solution 1 Self Discovery: You can easily find the domain to server path location by simply following these easy steps: Create a file called test.

FTP the test. Keep moving the file around in the various directories on your server until you can locate the test. Solution 2 Contact Host: This is by far the fastest way to locate the proper path.

The physical path on a web server will map to a domain name and inside of your hosts control panel will be various ways to manage this process. Could you please point me to the full path for where this domain name points to on the server?

Thanks Once you have received the path from the host, place the installer and archive in the path they have provided. With this many options Duplicator has chosen to keep the process simple and allow users to safely update their own configuration files vs trying to parse millions of different combinations. Below is a quick outline for how.

Build Process: When an archive. Installer Step 1: When archive file is extracted in Step 1 it will extract the file in this. This is by design so that the. Trying to run the. This allows for the advanced options in step 1 to considered if needed.

Installer Step 4: After step 3 is ran either the. If the advanced option is chosen then the. Installer Step 1: When the installer extracts the archive. Installer Step 3: In step 3 on the options WP-Config file tab there are optional parameters to add to the wp-config. Installer Step 4: This process will generate the wp-config. Workflow Database Workflow Below is an overview of the database workflow that takes place when a database is created and then re-deployed to its new location.

The below outline covers the installer when used in advanced mode which contains four steps vs the two steps found in basic mode. Installer Step 2: The process will execute the SQL data file and install an exact copy of how it was built into the specified database choose in the installer step 1 Installer Step 3: This step is where the database data is updated to support its new environment. The update engine runs through every cell in the database looking for the old URL of the source site old site replacing it with the destination site new site.

Emails When you migrate a site to a new domain, by default the emails associated with the source domain are not touched.

For example if a. There is an option that lets you change this behavior, so the email domain is switched as well. To enable this option in advanced mode see step 3 of the installer. Workflow When installing the archive to a new location, nothing should happen to the old domain where the archive was created. However there can be a few scenarios that play out that make users feel like the old domain was updated.

If your on the same server and setting up the database for Site B you accidentally connected it to Site A database. A WordPress redirect plugin if you have one installed may have not properly gotten updated during the install and is pointing to the URL on Site A.

A web server configuration file such as a. This option is really rare but its always a good idea to double check the files. This is an uncommon scenario but can happen if you’re moving sites on the same server and do not pay attention to the database or even the location where you’re installing the archive.

Please be sure you know the exact name of the database and the exact location of were you place the archive and installer files Forum Thread: Below is a forum thread that lays out this issue with several different users, and should address most of these scenarios. What is happening to the site on the old domain? During the Classic Install process on Step 1 Pro and Step 2 Lite of the installer you will need to connect to a database.

You have several options when it comes to setting up the database: Option 1 Hosts Control Panel: Create a database and user with your host’s control panel. Then assign the user full rights to the database. Here are the basic steps: Login to your hosts control panel and find the section to create a new database Create the new database and copy down the database name Create a new or assign an existing database user to the database and write down the database user name Open the Duplicator installer.

This mode will allow you to overwrite an existing site and reuse that site’s database and existing wp-config.

During this process you will be notified of the existing database and database user of the site you are about to overwrite.

Check the values and click “apply” and the existing database settings will be used. Note: This option will wipe out your current site and database data. Option 4 Change the install process to use the Import Install Mode.

This process will use the database settings of the currently installed WordPress site where the import is taking place. Option 5 Within Duplicator Open the the installer step 1 Pro or step 2 Lite From the database action drop-down choose the ‘Create New Database’ option In the Database input type the name of the database you want to create Type in the name of an existing database user. Duplicator does not create a new user. On most hosting providers the database action option to ‘Create New Database’ is not supported, this is a restriction of your host not Duplicator.

To watch the database process checkout these two videos: Follow Along Step-By-Step starting of How to setup database in cPanel. In the event you no longer have a copy of the installer. Follow these steps to get the installer file. Download the archive. Inside of the archive will be an exact copy of the original installer file in the root of the archive file.

This can be helpful if you are experiencing timeouts, slowness or general extraction issues. Transfer both the installer. This mode will simply skip the installers extraction process. Solution 1 It’s highly desirable to have little to no downtime when moving a site – but how exactly can you install the new site while the DNS is still pointing to the old site?

Below is a table of what is currently supported. If issues arise with a specific host try the download directly from your browser and if issues arise then contact your host.

Dropbox Dropbox is currently supported. AWS This is currently not supported. Google Drive This is currently not supported. OneDrive This is currently not supported. If Imunify is not installed its possible you might have a. In this case we recommend letting your host know or just trying Solution 2 or 5. Solution 2 Manual Upload If the file or link upload of the archive.

Copy the archive. Note: The WordPress root is normally where your wp-config. Solution 2 PHP Execution There are several items you check if the location where the import installer file is trying to run does not allow PHP execution. For example an. Solution: Temporarily rename the htaccess file Security Plugin: Some plugins like Wordfence “might” try to block the request.

If this is the case try to temporarily disable the plugin to see if it resolves the issue. Host or Software If the hosting has set the block via server setting the only solution is to ask the hosting to deactivate the block or change hosting On other systems software like Secure have the ability to prevent the execution of PHP files via cPanel settings.

Solution 3 Install Modes In the event your host does not allow for PHP execution in the directories where Duplicator is trying to run the import then you may need to switch to a different Install Mode. After that, just proceed with the install. Patched: Duplicator Pro Version 4. Please update to 4. In general if you cannot run a PHP file it is always a good thing to ask your host.

If it is not possible to solve the situation there then the standard install modes are still available. Remember that if the package you try to install was created in the same place where you install it, the backup restore installation is activated by default, which is practically identical to the recovery point. Issue A I need to restore my site from a crash or other major issue.

Before doing so consider that purpose of your restore. For example if your site has been hacked, has crashed or something has gone wrong, what are your options? Solution 1 Recovery Point Restore This option which is only available in Duplicator Pro and allows users to restore from a specific recovery point or simply a URL link.

Solution 2 Manual Restore If you choose to restore a site here are some recommended steps to take. We recommend cleaning out the directory and starting with a brand new database, this way you can be sure the issue you where having before will not show back up due to a corrupted file or database table. Starting with a clean environment always helps to lower your risk for issues.

Follow these steps to restore a site. Clean out Directory: Delete all the exiting files of your WordPress site. If your not sure contact your host. Its not required but having your host backup all the current files and database is a good idea. Copy Package: Place the archive. Solution 3 Professional Restore Depending on the severity of your site going down there are alternatives you can take before trying to restoring a previous backup.

It is recommended to take these approaches first because you won’t loose any data that may have been added to your site since the previous backup. In some cases if you do restore of a previous backup that may not fix the issue permanently. For example in the case of a hacked site if the security patch was not applied to the back up you want to restore then the security breach can easily happen after the site is restored if the threat is not properly identified.

Below are some options to consider before trying to restore a site. Hire a professional developer to troubleshoot your issue.

Have your site cleaned by a service like WordFence If your in a hurry or not familiar with Duplicator, consider hiring a professional developer. Issue A Forbidden When browsing to the installer. Solution 2 If you would like to try and fix the issue yourself there are many different techniques you can try, but remember every host is setup differently so some of these options may not properly work on your hosts and others will. Solution 1 Contact Host: This error indicates that your web server is not setup to serve up web pages.

If your not familiar with setting up web servers such as Apache, then the quickest way to fix this issue is to work with your hosting provider and tell them you get a at “XYZ” URL. They should be able to get you up and running in minutes. This is not something the plugin will be able to handle or fix as its a web server configuration issue. Then try to browse out to both of them via a web browser. If neither work then your site is not setup to server from the location at which they are placed.

If only the test. If your not sure about how to configure your web server to server from the proper path or serve up PHP files then contact your hosting admin as these are not issues the plugin will be able to fix. Option 1 Contact Host: The Method Not Allowed is an HTTP response status code indicating that the specified request HTTP method was received and recognized by the server but the server has rejected that particular method for the requested resource.

The bulk of responses have to do with how the web server is configured. The fastest way to resolve this issue is to work with the hosting companies technical support team. Typically what needs to be adjusted is how the web server excepts requests. The server error log on your hosts platform should help the system admin locate the specific request and adjust the server accordingly. Option 2 Troubleshoot Server If you are familiar with troubleshooting web server issues you might have a look at this detailed troubleshooting guide.

Options Web Server: Check to make sure the web server is setup properly. Create a new file named test. Inside the test. Server Logs: Examine the server error log as explained here. If you don’t have direct access to the server logs ask your host support to look for any errors in the logs for you.

Permissions: Check the permissions on installer. On most hosts it should be and files should be Be sure to double check with your hosting provider or server admin as to how they want permissions setup on their servers. Change Browsers: Open another web browser and check for the white screen.

If it works in the new browser then it may be a browser cache issue. Config Files: Backup and remove hidden configuration files such as. These files under certain circumstances have have configurations that prevent the installer from running.

Simply remove them from the same directory that the installer. In this case try to rename the file to something else.

Using the ‘installer. To get around this setup add the following to the top of the installer. Issue A Lost Password When loading the installer there is a password or archive file input that you don’t know or have lost. For the archive file name see the General section. Solution 2 To override the password screen simply do the following: Contact support to help modify the code to fix. Solution 1 Installer Location: The installer.

Solution 2 Browser Restarts: These quick solutions can resolve most issues with this notice: Close your browser and browse to the installer. Clear your browser’s cache and cookies restart the browser and try to browse to the installer again. Try a different browser An attempt was made to access the main-installer.

Be sure to always start the install wizard by first going to the installer. Once extracted you can browse to the installer-backup. Note: You can rename this file to whatever you want but be sure to delete it after the install process is completed.

Instructions on how to manually extract a DAF file can be found here. Also, make sure the archive has been fully downloaded and then uploaded. The size of the archive on your local machine needs to match the size of the archive shown on the packages screen – if it doesn’t try to re-download. If you are running your sites behind a proxy consider temporarily turning off the proxy then flush your dns cache. If you are running a VPN or firewall software, consider turning off those features temporarily to see if that resolves the issue.

Option 1 On some web servers the server auto-inserts an. After doing that browse to the installer. In some cases you may need to clear your web browsers cache. This will cause issues with the Duplicator because the installer looks for a. Attempt to download the plugin again – it should come down as a single file.

The archive should have files such wp-config. To get a raw copy of the archive. When opening a web browser and browsing to the installer. If you see a bunch of text and code then the web server you placed the installer file on is not setup correctly or the installer file was corrupted when the web server served it up as part of the download process. Below outlines a few different scenarios you might run into when trying to run the installer. For example a similar question using MAMP was found here.

For instruction on how to setup your own WordPress server see this article. There may be others issues you run into. The file at this point should be a normal PHP file. Use backup installer: Another option is to open the archive. Solution 3 Download Prompts: If you browse to the installer and get a download prompt then you may have a.

To validate this simply create a blank file called test. If you also get download prompt when browsing to it via a web browser then your web configuration setup is not correct. Here are a few options: Non-Technical Route: If your not technical or just don’t have time to mess around with server setups contact your host and tell them your site is not properly processing PHP files.

They should be able to get you going quickly. Below area few options: In many cases the transfer of the file from one server to another can cause the installer to get corrupted. Change from ANSI to UTF-8 try to convert from one format to the other and then save the file and then re-upload the installer file to the server to see which version works.

Install-Time While the install wizard is being ran. There can be several different causes for the error. Below are some common fixes when using Duplicator. This simply means the host your on is blocking your IP from doing certain operations. Solution 3 DYI During the install process it is possible that your host might automatically lay-down a. Typically Duplicator works best if no. If your wanting to try and resolve the issue your-self without your hosts assistance then check out the article below: How to Fix Gateway Timeout Error in WordPress Solution 4 Permissions A error in Step 1 processing on Duplicator Lite can sometimes be due to a timeout during zip extraction or on Duplicator Lite or Pro when file permissions are being set.

To get around this, first do a Manual Extraction then uncheck the Files and Directory permissions boxes on Step 1 of the installer. Solution 1 In the event the host you are on has issues with AJAX callbacks the best solution is run a manual install.

Notice: The quickest way to isolate this error is contact your hosting provider or server admin. They will be able to monitor the web server logs for clues much quicker that our support staff can with logs only generated by PHP. Issue A Extraction Issues During archive extraction the process fails or does not work. To quickly determine if the archive is valid try to extract it on your local computer a program such as winzip, winrar, 7zip etc.

If the client program errors during extraction then the archive. Proceed to option 2 if the client side program also errors. If the client side program works without issues then proceed to option 3. Option 2 Validate Download Process: If you transferred via FTP make sure that the FTP client is in binary mode when transferring down to your local box and then also when it’s transferring back up to your host or destination server. If you downloaded straight from the plugin interface then try the download one more time to make sure that the http transfer is clean.

Solution 3 These problems usually indicate the web server it not allowing files to be written to the directory. A common solution is to edit the Apache virtual hosts file and include the “AllowOverride All” instruction. On some hosting providers you will have the ability to use multiple extraction engines. By default almost every server will support “ZipArchive”, however some hosts also support “Shell Exec Unzip”. If you run into issues during the extraction process try to switch the archive engine from one format to the other.

Option 5 Manual Extraction: If for some reason the client side program works fine see step 1 and neither of the archive engines work from step 3 then you may want to try a manual extraction of the archive file. Option 6 Imunify If your server or host runs Imunify then its possible the software might cause issues with the extraction process.

If so consider checking out this FAQ titled How to fix installer validation checks? Option 1 This behavior should NOT happen and is usually caused by either a corrupted zip file or a zip file that was created with filenames that are too long. Fix 2: Flush the cache in the plugin settings or remove all files from cache directory. Fix 3: Temporarily remove and delete the plugin then create a new package set from the Duplicator. To validate files are not correctly extracting. Download the package to your desktop and try to manually extract with a desktop program like winrar, winzip or any other zip extracting software.

During extraction you will receive and error message if there is a corrupt file in the archive. Overview On step 1 of the installer a set of validation routines are ran to help discover any possible issues that might arise.

The following statues will show based on the state of the issue, with the various color codes. Status Details Pass The check passed and there are no issues detected Notice An issue has been detected however the risk is very low.

Continue with the install process and if you run into issues then consider getting the notice fixed. Warn An issue has been detected and the risk of install issues is high. You may continue with the install, however it is recommended that you address the issue if possible. Fail A critical issue has been detected and the install will be halted, until the issue is resolved General All checks in this section are detailed in the installer, no additional information is currently needed from the FAQ.

File System This section covers all checks related to the file system. If you continue with the install process you may see one of the items listed below in the logs. Imunify has a feature called “Proactive Defense” which is set to “Kill” by default – it incorrectly views an installer file as malicious so Imunify ends up trashing package installations. After this you should be able to install without an issue.

If you want Proactive Defense on your website after the install, you can re-enable after installation is complete. For additional instructions on how to control this service see this article Disable Imunify cPanel. Note: In the event you don’t see an option for Imunify on your host panel please contact your host support and ask them to at least temporarily disable the Proactive Defense part of Imunify Option 1 During step 1 of the installer if a. A new. This behavior can be skipped by check the option to skip config file updates under Step 1 options section or you can follow these steps: You can try to do this: Perform a manual extraction.

At the end of the installation, check the wp-config. If database connection or timeout issues occur during the install process consider the solutions below. Make sure the database user has the correct permissions. For example: a read only privilege can’t add data to the database. Check the following list to validate permissions. Be sure the database and database user have been created Be sure the password matches the database user being used Be sure the database user is assigned to the database with the correct permissions Temporarly change the database user password to ‘test’ to validate character input Contact your hosting provider for the exact required parameters Solution 2 Hostname Validation: The host input ‘localhost’ works in most cases however it may not on your host so double check with your hosting provider for the exact settings.

Often it’s something like mysql. Sometimes it may even have a port number like “mysql. Please see this site for other various combinations. Please see this forum thread for an example of how to locate the correct hostname. Quickest Fix: If you’re on a hosted server contact your provider to make sure your using the exact credentials they need for their servers.

Many hosting providers have different ways for how to connect to their databases. Solution 1 In order for the database connection to properly take place a database user but be assigned to the database and granted ‘full privileges’ to the database. Below are some resources that cover this process: The quickest way to validate full level of permissions is to contact your hosting provider. This codex covers creating a Database and User. Continue with the install. If Option 1 does not work or the SQL chunking option is not available then try option 2.

Solution 2 Manual SQL Execution Pro Only This process allow you to skip the database insertion process, but still run the database update step 3 process. Quick Steps Advanced Steps Extract the database. Go to phpAdmin or the equivalent. Remove existing database tables.

The phpMyAdmin procedure is described here Import the database. If you believe all the parameters your entering in the installer are correct, you can validate them by creating a simple file in the same directory as the installer called db-test. This will help isolate if your params are in-deed correct, if you’re unsure of how to use the script send it to your host and ask them for help.

Incorrect information in file: ‘. Try these in the order they are presented. Continue with and complete the install process. Solution 1 “Unable to create database In this case you will need to create a database through the tools they provide. On most hosts you can do this through the cpanel.

Please contact your host for how to create a new database. Duplicator Pro users should be able to use the cPanel connection tab to login to there cPanel accounts and create the database through the cPanel installer interface. Alternatively you can use the Import or Overwrite modes. It is best to make sure the server where the installer is running has the same or higher version number than where it was built.

If the major and minor version are the same or close for example [5. A version pair of [5. If the versions are too far apart work with your hosting provider to upgrade the MySQL engine on this server. The utf8mb4 format is only supported in MySQL server 5.

It is highly recommended to upgrade your version of MySQL server on this server to be more compatible with recent releases of WordPress and avoid issues with install errors. This issue can be resolved by updating the MySQL my. This value may just need to be uncommented. While the distributions are very close there are some subtle differences.

Some operating systems will report the version such as “5. Please note some messages are simply notices. It is highly recommended to continue with the install process and closely monitor the installer-log. If any issues are found please visit the FAQ pages and see the question How to resolve database errors or general warnings on the install report?

The current fix is to remove the offending table options from the DB dump by doing a manual search-and-replace on the file. There are 4 ways to solve this issue. Option 1 is the quickest, easiest and safest way to resolve this issue Unknown Collation Overview: An ‘Unknown collation’ error means the MySQL server being installed on target server is older than the MySQL engine you created the package on.

You can view the MySQL server version comparison by clicking on the ‘Test Connection’ button in the installer or by viewing the installer-log. Best Fix: The best and easiest way to solve this issue is to ask you’re host to move your account to a MySQL server that supports the collation type you need see example above. Simply give them the error message your getting and they can help move you to the correct server. Most host will not upgrade the current server your site is on, however they should be able to easily move your account to a newer server.

This is a very common practice and a good host should be able to help out pretty easily. If you’re running any version lower than 5. We strongly encourage users to work with their hosts to use up-to-date software for improved security and performance and to stay in compliance with updates from WordPress core. Don’t let a crappy host use outdated software on your site. Database Upgrades: Compatibility Mode should only be used as an last resort. The recommended approach to fixing database issues is to make sure that both database servers are up-to date and very close in version numbers see OPTION 1.

For example if the database server where you create the package database is 5. N range.


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Federal government websites often end in. The site is secure. Psychobiotics were previously defined as live bacteria probiotics which, when ingested, confer mental health benefits through interactions with commensal gut bacteria. We expand this definition to encompass prebiotics, which enhance the growth of beneficial gut bacteria. We review probiotic and prebiotic effects on emotional, cognitive, systemic, and neural variables relevant to health and disease.

We discuss gut—brain signalling mechanisms enabling psychobiotic effects, such as metabolite production. Overall, knowledge of how the microbiome responds to exogenous influence remains limited. We tabulate several important research questions and issues, exploration of which will generate both mechanistic insights and facilitate future psychobiotic development. We suggest the definition of psychobiotics be expanded beyond probiotics and prebiotics to include other means of influencing the microbiome.

Psychobiotics are beneficial bacteria probiotics or support for such bacteria prebiotics that influence bacteria—brain relationships.

Psychobiotics exert anxiolytic and antidepressant effects characterised by changes in emotional, cognitive, systemic, and neural indices. Bacteria—brain communication channels through which psychobiotics exert effects include the enteric nervous system and the immune system.

The definition of psychobiotics should be expanded to any exogenous influence whose effect on the brain is bacterially-mediated. The gut microbiome comprises all microorganisms and their genomes inhabiting the intestinal tract.

It is a key node in the bidirectional gut—brain axis see Glossary that develops through early colonisation and through which the brain and gut jointly maintain an organism’s health.

A pivotal study found that mice raised in sterile environments and therefore lacking indigenous bacteria germ-free mice showed exaggerated physiological reactions to stress compared to normal controls. The abnormal reactions were reversible through probiotic-induced bacterial recolonisation [1]. This finding revealed the microbiome’s causal involvement in the development of the hypothalamic—pituitary—adrenal HPA axis.

Gut bacteria have since been found to participate in the regulation of varied and important physiological processes, including immunomodulation, adiposity, and energy balance 2 , 3 , 4 , 5 as well as the electrophysiological activity of the enteric nervous system 6 , 7. Probiotics, beneficial bacteria that yield positive health outcomes, have received particular attention, both in the popular press and from the research community.

Here, we critically evaluate efforts to manipulate commensal gut bacteria with psychobiotics. These psychobiotics were first defined as probiotics that, when ingested in appropriate quantities, yield positive psychiatric effects in psychopathology [8]. The bacteria most frequently exploited as probiotics are the Gram-positive Bifidobacterium and Lactobacillus families 9 , Bifidobacteria and Lactobacilli do not possess pro-inflammatory lipopolysaccharide chains, and so their propagation in the gut does not trigger full-fledged immunological reactions.

With the presence of such bacteria, the immune system learns to distinguish to between pro- and anti-inflammatory entities and develops appropriate immunogenic responses by identifying pro-inflammatory elements as antigenic [11]. It should be noted, however, that Gram-positive bacteria are not always beneficial, and some, such as the Clostridia family, may be pathogenic. We propose that the definition of psychobiotics be expanded along two dimensions: First, research on healthy individuals is demonstrating that psychobiotic benefits need not be restricted to clinical groups.

Second, we include prebiotics in the definition of psychobiotics. Prebiotics are compounds that, when fermented in the gut, produce specific changes in bacterial composition or activity [12].

Prebiotics support the growth of intrinsic commensal bacteria. The majority of prebiotic compounds examined for their neural effects are fructans and oligosaccharides comprising three to nine saccharide units. This review will: i discuss psychobiotic effects on emotional, cognitive, systemic, and central processes in animals and humans, in clinical and healthy populations, and ii assess the microbiome—brain signalling mechanisms enabling these effects. Much psychobiotic research is based on rodent models, which use rodent stress inductions and rodent behavioural tests to assess motivation, anxiety, and depression.

Psychobiotics applied to rodent models of illness, infection, and neurodegeneration also provide early clinical insight into human diseases Table 1. Human investigations represent a very recent trend. The psychophysiological effects of psychobiotics fall into the following three categories: i Psychological effects on emotional and cognitive processes.

Pro-inflammatory cytokines share a strong and well-studied positive association with psychiatric conditions such as depression [13]. Proteins include brain-derived neurotrophic factor BDNF , which plays a crucial role in learning and memory processes, including spatial learning, extinction of conditioned fear, and object recognition 16 , BDNF is reduced in anxiety and depression, a reduction that is reversible through antidepressant action [18].

Psychobiotics affect psychophysiological markers of anxiety and depression. One study employed a maternal-separation model to induce early-life stress in infant male Sprague—Dawley rats [19]. Vehicle rats showed typical psychophysiological patterns associated with maternal separation, including poorer performance on the forced swim test and increased inflammation indexed by heightened peripheral concentrations of the pro-inflammatory cytokine interleukin-6 , decreased presence of the neurohormone noradrenaline in the brain, and elevated concentrations of amygdala corticotrophin-releasing factor messenger ribonucleic acid mRNA.

In comparison, these indices were normalised in probiotic-fed rats. Moreover, these outcomes were comparable to those observed in the citalopram group, suggesting that some probiotic benefits resemble antidepressant effects.

In the case of nonclinical populations, experiments are defined by psychobiotic supplementation in rodents that have unimpaired psychophysiological processes and microbiomes. Compared to mice administered a vehicle, those fed Lactobacillus rhamnosus JB-1 expressed fewer depressive and anxious behaviours in the forced swim and elevated plus maze tasks, respectively.

These changes were accompanied by a blunted corticosterone response to stress, suggesting that the probiotic downregulated HPA-axis activity. In the brain, probiotics differentially altered expression of inhibitory GABA receptors in a region-dependent manner. For instance, in comparison to controls, the probiotic reduced expression of GABA B1b mRNA in the hippocampus and amygdala but increased its expression in prelimbic and cingulate regions.

GABA is the chief inhibitory neurotransmitter in the nervous system. Overall, probiotics may modulate regional excitation—inhibition balance, and these changes may be linked with reductions in anxiety- and depression-related behaviour and associated systemic responses.

Furthermore, performance on the maze task was substantially improved in the probiotic-fed mice, which completed the maze faster and with fewer errors, benefits that persisted at 1 week, but not 3 weeks, post-treatment. These results provide preliminary but important evidence of the potential longevity of effects, an area that has received little consideration in psychobiotic research. While there were no behavioural changes in swim test performance, there were significant increases of tryptophan, the serotonin precursor, in the plasma.

There were also decreased concentrations of 5-hydroxyindoleacetic acid, the serotonin metabolite, in the brain. This was taken as evidence of reduced serotonergic turnover.

These reductions jointly characterise a dampened pro-inflammatory response. This approach highlights the importance of examining physiological variables in psychobiotic research, as physiological changes were noted in the absence of significant behavioural changes.

Probiotic effects during stressful experiences have also been examined [24]. Relative to the control group, the probiotic-fed rats showed lower levels of post-restraint anxiety assessed in the elevated plus maze and the open-field test , as well as enhanced post-restraint object-recognition memory. At the biochemical level, probiotic-supplemented rats displayed lower levels of corticosterone and adrenocorticotropic hormone.

The probiotic group also showed increases in the anti-inflammatory cytokine interleukin, and in hippocampal BDNF mRNA, noradrenaline, and serotonin. Overall, probiotic and antidepressant effects were comparable. Recent work [25] has also studied psychobiotic-induced changes in central neurotransmitter concentrations in vivo using magnetic resonance spectroscopy MRS. The authors interpreted tNAA changes as a marker of alterations in neural metabolism resulting from the intervention.

Glutamate is the chief excitatory neurotransmitter in the central nervous system, and, to the best of our knowledge, this is the first demonstration that it is sensitive to probiotics. The implications of concurrent elevations in both glutamate and GABA for regional excitation-inhibition balance are currently unknown, but are suggestive of an overall metabolic increase.

Furthermore, because GABA and glutamate have opposing effects on neural excitability, it is possible that the total psychobiotic effect may be occurring within a zero-sum framework. The researchers also conducted periodic MRS, finding differential rates of emergence for the effects. For example, NAA increased after 2 weeks of probiotics, an elevation that was sustained for the remainder of the supplementation, and which returned to baseline 4 weeks thereafter. Glutamate and glutamine levels also increased after 2 weeks, and then remained elevated for a further 6 weeks, including 4 weeks after the intervention.

Finally, GABA concentrations were only elevated in the fourth week of the intervention, but not before or after. These results represent a crucial step towards determining emergence and longevity of effects.

While the general consensus is that ingestion of probiotics results in transient, rather than permanent, colonisation of the gut [26] , these findings suggest both that psychobiotics may have some long-term effects, and that the effects have differential longevity.

A much smaller number of studies has examined the psychophysiological effects of prebiotics. These include investigations of galacto-oligosaccharides GOS and fructo-oligosaccharides FOS , which are a source of nutrition for Bifidobacteria and Lactobacilli , and stimulate their activity and propagation in the gut.

These receptors play an essential role in maintaining synaptic plasticity and optimal memory function [28]. Prebiotic supplementation has also been studied in neonatal rats [30]. Crucially, these changes were observed even 26 days after treatment cessation. Relative to vehicle, rats fed the prebiotic during lactation showed substantially enhanced maze-learning and object-recognition one year later.

These findings have important implications for assessing the longevity of prebiotic effects, and are suggestive of very long lasting gains. The rodent-human translation has been surprisingly robust, though many more human studies are necessary. At the end of the 3-week intervention, there were no overall changes in self-reported affect. However, when only participants whose baseline mood scores fell in the lowest third of the total range were analysed, probiotic supplementation resulted in significantly more participants self-rating as happy rather than depressed, relative to placebo.

These results suggest that the emotional benefits of psychobiotics may be subject to ceiling effects. The researchers also found that the probiotic-fed participants performed lower on two assessments of memory function. This may be attributable to chance, as the authors themselves have suggested, but it may also imply possible detrimental effects of psychobiotics. Another well-known study provided evidence of improved mood in a generally healthy sample [33]. Participants also collected urine over 24 hours before and after the intervention, enabling cortisol estimations.

Relative to placebo, probiotic-treated participants showed significant declines in self-reported negative mood and distress. Parallel to these changes was a decrease in urinary free cortisol, which is suggestive of reduced stress.

Interestingly, a follow-up analysis of the individuals with the lowest stress indexed by cortisol concentrations showed similar affective benefits to those with higher cortisol concentrations [34] , to some extent contravening the role of ceiling effects in determining psychobiotic outcomes.

The researchers also investigated potential detrimental effects, including probiotic-induced impairments in learning and memory. However, there was no evidence of dysfunctions in learning and memory, and furthermore, the probiotics did not induce addiction, suggesting a good safety profile without concomitant cognitive impairments.

Similar effects have been observed in other investigations of mood. Relative to placebo, probiotic-treated participants exhibited substantially reduced reactivity to sad mood assessed by the Leiden Index of Depression Sensitivity Scale , an effect that was specifically attributable to reduced rumination and aggressive cognition.


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