Fecal transplants could one day be used as a therapy to restore cognitive function in the elderly – according to new research from the University of East Anglia, the University of Florence and the Quadram Institute.
A new study published today shows how fecal transplants from older to younger mice altered their gut microbiome, which in turn impacted their spatial learning and memory.
The research team hope that reversing the procedure could one day see fecal transplantation used to combat cognitive decline among the elderly.
Dr. David Vauzour, from UEA’s Norwich Medical School, said: “Aging is an inevitable process that starts immediately after birth and ultimately leads to physical health problems as well as a decline in psychological well-being and cognitive function.
“Research has shown that the aging process may be linked with age-related changes in our gut microbiota.
Recently, the existence of two-way communication between the gut and the brain – known as the ‘gut-brain axis’ – has emerged as an important player in shaping aspects of behavior and cognitive function.
We wanted to see whether transferring gut microbes from older to younger mice could affect parts of the central nervous system associated with aging.”
The research team performed fecal transplants from older adult mice to younger adult mice and then assessed the young adults for markers such as anxiety, exploratory behavior and memory.
While the young adults showed no significant changes in markers of anxiety, explorative behavior or locomotor activity, they did show impaired spatial learning and memory as measured in a maze test.
These changes were paralleled by alterations in the expression of proteins associated with synaptic plasticity and neuro transmission, and changes to cells in the hippocampus part of their brains—responsible for learning and memory.
Dr. Vauzour said: “Our research shows that a fecal transplantation from an old donor to a young recipient causes an age-associated shift in the composition of gut microbiota.
The procedure had an impact on the expression of proteins involved in key functions of the hippocampus – an important part of the brain that has a vital role in a variety of functions including memory, learning but also in spatial navigation and emotional behavior and mood.
In short, the young mice began to behave like older mice, in terms of their cognitive function.”
Prof Claudio Nicoletti, from the University of Florence, Italy, said: “While it remains to be seen whether transplantation from very young donors can restore cognitive function in aged recipients, the findings demonstrate that age-related shifts in the gut microbiome can alter components of the central nervous system.”
This work highlights the importance of the gut-brain axis in aging and provides a strong rationale to devise therapies aiming to restore a young-like microbiota to improve cognitive functions and quality of life in the elderly, he added.
“Manipulating the microbiome is increasingly being seen as a way of improving or maintaining human health, and these results are an exciting indication of its potential for helping us age healthily,” said Prof Arjan Narbad from the Quadram Institute.
“We have established an FMT service on the Norwich Research Park to treat serious gut infections and now want to explore in humans its effectiveness in combating a number of age-related conditions, including cognitive decline.”
The research was led by a team at UEA and the University of Florence, in collaboration with colleagues at the University of Milan, the Earlham Institute, University of Siena, the Quadram Institute, and Nottingham Trent University.
Funding: It was funded by the Fondazione Cassa di Risparmio, the University of Florence and the Medical Research Council.
In recent years, there has been a growing appreciation for research in the field of the “gut-brain axis” (GBA). The GBA consists of bidirectional biochemical and neural signalling between the gastrointestinal (GI) tract and the brain. Specifically, the gut microbiota is able to modulate the GBA both directly and indirectly via endocrine, neural, and immune pathways.
In disease- or stress-states these pathways may become compromised resulting in intestinal dysbiosis, changes in mood, behavior, and cognition, and altered inflammatory levels .
The gastrointestinal tract is colonized by over one hundred trillion commensal bacteria that exist symbiotically with our bodies. Colonization of the gut occurs at birth and is largely influenced by mode of delivery (c-section vs. vaginal birth) and through breast feeding. However, bacterial composition of the gut begins to stabilize throughout adulthood .
Detailed analyses of human gut microbiota have shown considerable individual variability in bacterial content as this dynamic system is influenced by a variety of factors, such as genetics, diet, metabolism, age, geography, antibiotic treatment, psychotropics, and stress [3, 4].
Gut microbiota are critical in the normal development of the immune system, central nervous system (CNS) circuitry, GI functioning, and autonomic nervous system (ANS) functioning. This community of bacteria and its genetic material is often referred to as a virtual organ [4–6].
Studies have since shown that gut bacteria play a vital role in regulating important aspects of brain development and function, along with other host physiology [5, 7].
The gut and psychiatric symptoms and disorders
The interaction of the gut with the environmental risk factors of psychiatric illnesses, such as diet and early life stress, suggests that interventions targeting the gut microbiome could prevent and treat psychiatric symptoms . Psychiatric symptoms can manifest in both psychological and physiological ways, often resulting in impaired functioning.
Common physiological symptoms share similarities with symptoms of GI disorders, such as Irritable Bowel Syndrome (IBS). This association may be explained by the close connection between the gut and the brain.
In past studies, individuals with psychiatric illness have also been shown to have a dissimilar microbiota composition compared to healthy individuals, due to decreased diversity and abundance of the healthy gut microbes .
Studies also show that lack of exposure to commensal bacteria, such as in germ-free mice, has significant effects on stress responsiveness in adulthood; it has also been shown that early colonization of the gut with a conventional microbiota, even a single species, can partially reverse these effects .
Some investigations have shown neurochemical changes as a result of gut microbiome dysfunction, such as altered levels of brain-derived neurotropic factor (BDNF), reduced serotonin receptor expression, reduced synaptic plasticity gene expression, and increased striatal monoamine turnover [10–12].
Fecal microbiota transplant
Several methods of examining the influence of the gut microbiome on the gut-brain axis have been explored, including manipulating the microbiome via probiotic and antibiotic administration, the use of germ-free animal models, and perhaps most notably, fecal microbiota transplantation (FMT).
FMT is the transfer of fecal bacteria from a healthy donor to a recipient. FMT was first used in fourth century China for the treatment of severe food poisoning and diarrhea and other related symptoms . However, it is currently only indicated for the treatment of Clostridium difficile (C. difficile.) infections. C. difficile is often contracted by older patients in-hospital following routine pharmacological treatments such as antibiotics.
The use of antibiotics often depletes healthy bacteria in the GI tract which can result in microbial dysfunction. FMT is used to restore healthy status of the microbiome via repopulation of healthy bacteria to the gut. Functioning in a similar manner to probiotics, this treatment method helps to maintain the bacterial balance and function.
FMT are most commonly accomplished via endoscopies, enemas, and oral feeding of freeze-dried material. Aside from GI and psychiatric disorders, this treatment method is also being explored as a potential treatment for metabolic disorders, autism, multiple sclerosis, and Parkinson’s disease [14–17].
Other variations of this treatment, such as Microbial Ecosystem Therapeutics-2 (MET-2) are also currently being explored, in psychiatric indications such as Generalized Anxiety (GAD) and Major Depressive Disorders (MDD).
MET-2 consists of gut bacteria obtained from stool samples of a healthy donor, chosen for its safety profile, that is then purified and lab-grown prior to being lyophilized and ingested orally by patients .
FMT in the context of psychiatric illness
Two of the most prevalent groups of psychiatric disorders include Major Depressive Disorder and anxiety disorders. MDD is characterized by either depressed mood and/or loss of interest or pleasure, as well other psychiatric and physiological symptoms. Anxiety disorders is a category that includes a variety of disorders characterized by intense feelings of anxiety, nervousness, or fear.
These include Generalized Anxiety Disorder, Agoraphobia, Panic Disorder, and specific phobias. Both groups of disorders are characterized by a significant impairment in daily functioning . While there are pharmacological treatments available for both disorders, many people deny treatment due to side effects or stigma-related reasons or are treatment-resistant and unable to find an effective way to improve their symptoms.
By targeting the gut, FMT may be a potential way to overcome these drawbacks. Research on the gut-brain axis indicates that there may be a possibility to improve these symptoms through restoration of the gut microbiome via fecal transplant from a healthy donor. However, as this is a relatively novel area of research, there are few studies on FMT in humans as a treatment method in the context of psychiatric disorders.
This review examines findings from preclinical and clinical studies that have examined the effects of endogenous microbiome transfer on psychiatric symptoms. The studies included in this review assess the effects of FMT and related interventions on symptoms associated with a variety of psychiatric illnesses including MDD, anxiety, and chronic stress. Comorbid disorders associated with poor mental health outcomes such as alcoholism and anorexia were also included in several of the studies.
The findings from reviewing the included studies suggest that FMT can affect symptoms of psychiatric disorders. This was shown for both the relief of psychiatric symptoms resulting from the transfer of microbiota from healthy donors to ill recipients and the transmission of symptoms through the transplantation of microbiota from ill donors to healthy recipients.
This relationship was investigated in a variety of psychiatric disorders including depression, anxiety, anorexia and alcoholism. The transmissible properties of FMT were also well demonstrated in these studies. Notably, regardless of donor species, the transmission of psychiatric symptoms from ill donors to GF mice was consistently found.
This was supported in multiple studies, with observed transference of symptoms from mouse models of depression, anxiety, chronic stress and alcoholism, and from humans with depression, to GF mice.
This provides support for the concept that the gut microbiome may both contribute to the development of psychiatric disorders and be a viable target for treatment for these disorders.
All included clinical studies found improvement in the symptoms of psychiatric disorders related to these disorders following FMT from healthy donors.
The beneficial aspect of FMT from healthy donors was also demonstrated preclinically where healthy transplants resulted in alleviation of depression- and anxiety-like symptoms that appeared in mice subjected to certain conditions. This alleviation of symptoms was found in mice experiencing alcohol withdrawal, as well as stressful living conditions. Though symptom alleviation was consistently observed, the duration of improvement was inconsistent.
Some studies, such as Xie et al., observed an alleviation of symptoms that seemed to last indefinitely, but the majority found this to be transient (Xie et al. 2019 ; H. L. Huang et al. 2019 ; Mazzawi et al. 2018 ; Mizuno et al. 2017 ). The benefits seemed to last for only around 3–6 months, which, if used as a treatment for psychiatric disorders, is a limitation for FMT in clinical practice.
Mechanism of action
The mechanism of action for how this gut microbiome modulation results in the observed symptomatic changes has yet to be fully understood. There are currently a few major hypotheses for how the microbiome affects the nervous system, resulting in symptomatic changes.
The papers included in this study discussed some of these theories, with the majority postulating the mechanism to be through changes in serotonin production, immune response, and metabolism in response to microbiome changes. Serotonin transmission has long been known to be altered in depression, with selective serotonin reuptake inhibitors (SSRIs) being the most prescribed treatment for depression .
An estimated 90% of the body’s serotonin is produced by enterochromaffin (EC) cells in the digestive tract . The functioning of these cells has been known to be affected by gut microbiome changes. One way that microbiome disruption is thought to affect serotonin production is through short chain fatty acids (SCFAs).
SCFAs are produced by the gut microbiome through the fermentation of non-digestible carbohydrates, suggesting that treatments that ameliorate gut health can influence SCFA concentrations. SCFAs, particularly butyrate and propionateinfluence the synthesis of the rate limiting enzyme tryptophan hydroxylase which synthesizes serotonin produced by EC cells [52, 53].
In addition to their role in serotonin production, SCFAs also have the ability to cross gut-blood and blood-brain barriers during immune signaling.
The immune system can be affected by the gut simply by the fact that there are many immune cells located in the gastrointestinal tract, meaning that gut disruption can also disrupt these cells. The SCFAs produced by the gut microbiome have anti-inflammatory properties and can work to regulate the immune response .
In the gut, they influence expression of anti-inflammatory markers, such as interleukin (IL-)10 in macrophages and intestinal dendritic cells . In the central nervous system, SCFAs have additional roles, such as regulating maturity and function of microglia (macrophages in the brain that are part of the brain’s immune response) .
Many psychiatric disorders have been linked to inflammation and an increased immune response, as observed through elevated levels of immune marker cytokines . It is hypothesised that this response is mediated by the NLRP3 inflammasome, a multiprotein intracellular complex that activates pro-inflammatory cytokines .
A more direct way that the microbiota influences the central nervous system is through interaction with the vagus nerve. The vagus nerve is comprised of 80% afferent nerve fibers and 20% efferent fibers. Afferent nerve fibers of the vagus nerve are affected by metabolites of the microbiota that then take that information back to central nervous system .
This is hypothesized to influence central and peripheral changes resulting in alleviation of psychiatric symptoms. More specifically, the vagus nerve is affected by long and short chain fatty acids both directly and indirectly, through cellular production of neurotransmitters, such as serotonin .
These mechanisms may provide insight into the use of FMT as a potential treatment for psychiatric symptoms, such as mood and anxiety. The repopulation of the gut microbiome with healthy bacteria through FMT may have positive neurological, immune, and metabolic effects which in turn may influence the trajectory of the psychiatric indication.
Using FMT as a treatment for psychiatric illnesses in the future is an interesting idea that merits exploration. MDD and anxiety disorders affect millions of people worldwide and have a very large burden to the individual and society as a whole.
The current gold-standard treatment for psychiatric illnesses, MDD and anxiety disorders in particular, are antidepressants medications. Though antidepressants have a relatively high efficacy, a large proportion of individuals with psychiatric illnesses do not respond to these first-line treatments, and thus need to try alternatives .
Further, many antidepressant users also experience side effects such as restlessness, nausea, vomiting, anxiety, insomnia, sexual dysfunction, gastrointestinal cramps and diarrhea, and headaches that can make the arduous process of searching for effective treatments even harder .
Antidepressant medications are also still steeped in stigma further impeding one’s ability to ask for and receive help and treatment. Finally, as is stands, on average antidepressants can be costly, especially without insurance or government-funded healthcare.
There is a great need for new therapeutic targets and treatments in order to provide options and better help individuals suffering from these psychiatric illnesses. When considering the findings demonstrated in this review, FMT appears to be a promising candidate for this.
The ongoing research certainly suggests its efficacy and given the few side effects and adverse events reported in these papers, may even challenge the treatments currently available. Though the treatment effect seems transient, symptoms appeared to improve relatively quickly after treatment.
Another common issue seen in these indications are often to do with treatment adherence.
However, given FMT effects can last up to 6 months, it may be easier to adhere to than a daily medication or a weekly psychotherapy appointment. Assuming one transplant is sufficient for therapeutic benefits lasting up to 6 months, the cost of treatment may be comparable to that of brand-name antidepressants, however not much is known about the costs of FMT (Eisenberg Centre at Oregon Health & Sciences University, 2007).
There is potential, however, for cost of FMT to decrease, as treatment becomes more mainstream and modified.
Though the effectiveness and tolerability of FMT, as seen in these studies, makes it a promising potential treatment, there are some aspects that could limit its adoption into mainstream clinical settings. A potential drawback currently is the procedure itself. Although costs are comparable to antidepressants, it is still relatively expensive and a labor-intensive alternative to other psychiatric treatments.
Additionally, the safety of FMT has also not been sufficiently understood and its associated stigma is still unknown. These points, along with the treatment still being in the early stages of research, make it difficult to fully determine the feasibility of FMT as a treatment for psychiatric illnesses such as depression and anxiety.
Although the studies included in this review were of good quality and contributed to a greater understanding of FMT in the context of mental health and illness, there are considerable limitations.
A significant limitation in any FMT study is the fact that although research on the gut microbiome has been prolific, we still do not know what a ‘healthy microbiome’ is. Some researchers refer to a healthy microbiome as one of an individual with no overt diseases and others, however, even among those who are considered healthy, the variation in taxonomic composition is great [63–65].
The main limitation of the clinical studies were small sample sizes. The lack of large-scale, double blind randomized controlled trails makes it difficult to determine efficacy and safety. The majority of clinical studies also assessed the psychiatric symptoms in individuals with IBS, and not necessarily those exclusively with psychiatric disorders.
This means that, though there was clear improvement if psychiatric symptoms, it cannot conclusively be said that FMT will improve the symptoms of individuals with psychiatric disorders. Additionally, it is possible that the improvement of psychiatric symptoms is secondary to the improvement of gastrointestinal symptoms associated with IBS, thus is not a direct relationship.
For the preclinical studies using human donors, the sex of the mice and donors was a major limitation, given most studies used donors or mice of only male sex.
Given that there are clear sex and gender differences in the prevalence and symptomatology of mental illnesses, further research is warranted to determine if sex and gender have an effect on the efficacy of FMT procedures. Some of these studies also included donors that were taking various medications, including antidepressants, which may have affected the results.
Additionally, the administration of antibiotics to create GF recipient mice and the variability in FMT administration protocol make the findings difficult to translate. For instance, some recipients received multiple FMTs, while others received only one and the justification for choosing donors varied.
The heterogeneity of indications studied also creates difficulty in knowing, with any certainty, how efficacious this procedure will be for a given indication. Without a consensus on a standard procedure for conducting this research, it is difficult to compare results between studies.
With high individual variability in symptomatology and prognosis, high levels of comorbidity with other disorders, genetic and environmental influences, progress in research in treatment of psychiatric disorders has been challenging. Given the huge heterogeneity of psychiatric disorders, finding treatment that works for all patients is not achievable, especially given the range of factors that influence the disorder and treatment response.
While the research in this field is far from complete, the potential of targeting the gut-brain axis using FMT to alleviate symptoms of psychiatric illness is promising. Additionally, given the adaptable nature of the gut microbiome, it may be a good representation of the individual’s history and could explain differences in risk of illness, disease course, and response to treatment.
If these therapies are able to alleviate symptoms of psychiatric disorders, they could be offered to some patients as personalized, alternative, and/or adjunctive treatments to combat specific symptoms that tie together specific gut bacteria strains or the gut, as a whole, to the brain.
reference link : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7294648/
Source:University of East Anglia