Faecal microbiota transplants for depression – Who gives a crapsule?

Interest in the gut microbiome and its role in health has recently exploded. In fact, 80% of all microbiome research published to date has appeared in the last 5 years. The field has been embraced by our colleagues in cardiology, gastroenterology, infectious diseases and endocrinology, and has been the focus of new medical conferences, research groups and journals. The topic has captured the interest of the media and public, with television programmes, books, news stories and even comedy sketches focused on the gut. But is all this attention on the microbiome of any relevance to psychiatry? There are many reasons to think that it is.

What is the evidence for this? To start with, mice bred without commensal microbiota (germ-free mice) have been shown to have altered brain function and perturbations of hypothalamic pituitary responses, as well as differences in risk-taking behaviours. Experiments in animals have also demonstrated that changing the gut microbiota through exposure to antibiotics or probiotics can moderate anxiety- and depression-like behaviours. In humans, several studies demonstrate differences in human gut microbiota between depressed persons and healthy controls (Zheng et al., 2016): biodiversity as well as particular bacterial phyla have been implicated. Intriguingly, new evidence suggests that probiotics might be efficacious in addressing mental disorders (Dickerson et al., 2018).

Importantly, experimental studies suggest that alterations of microbial composition of the gut via faecal transplant can induce changes in behaviour. For example, when germ-free mice with a risk-averse phenotype were colonised with the intestinal microbiota of mice with higher risk-taking behaviour, and vice versa, the behavioural phenotypes were reversed. More remarkably, the transfer of faeces from depressed humans into microbiota-depleted mice induces depression-like behaviours in the mice (Zheng et al., 2016).

The ancient practice of faecal microbiota transplantation (FMT), wherein stools from healthy donors are transferred into another individual with the purpose of treating a disease state, dates back to 4th century in China, where it was used to treat food poisoning and severe diarrhoea. Encouraged by recent advances in our understanding of the role of the intestinal microbiome in moderating health, FMT is now being trailed in a myriad of health conditions that are thought to involve the gut microbiota.

While FMT for depression has not yet (to our knowledge) been trialled in humans, there is a recently published study using FMT in autism spectrum disorder. Following 10 weeks of treatment with FMT, children with autism spectrum disorder showed improvement in scales measuring global functioning, social skills deficits and other autism-related symptoms including irritability, hyperactivity, lethargy, stereotypies and aberrant speech; furthermore, the average developmental age increased by 1.4 years. These changes persisted for 8 weeks following cessation of treatment (Kang et al., 2017). A recent open-label, pilot study evaluating the use of FMT for irritable bowel syndrome (IBS), which is commonly comorbid with major depressive disorder, also yielded preliminary yet encouraging results. Adults with IBS, functional diarrhoea or functional constipation who underwent FMT were shown to have statistically and clinically significant improvements in depression and anxiety symptoms for 4 weeks following the intervention. These improvements were observed irrespective of improvement in gastrointestinal symptoms (Kurokawa et al., 2018).

While there remains much to be understood about the many and interacting mechanisms underpinning the gut–brain relationship, several established hypotheses exist. The aetiology of depression is linked with several biological mechanisms including: (1) inflammation and immune activation; (2) oxidative and nitrosative stress (3) hypothalamic–pituitary–adrenal axis dysregulation; (4) perturbations in cortisol levels; and (5) neurotransmitter/neuropeptide dysregulation. Each of these mechanisms is influenced by the gut microbiome (Zheng et al., 2016). These mechanisms are discussed extensively in other literature and will only be touched on briefly here.

Regarding the immune–inflammatory hypothesis, gut microbiota may theoretically modify these systems in a number of ways. For one, short chain fatty acids are produced in large quantities by certain bacteria in the gut and subsequently absorbed into the blood stream where they have been shown to have immune-modulating properties. Some bacterial species may act to reduce inflammation and enhance immunity, while other microbiota that have been associated with disease states may do the opposite. Immune system cells are central to brain function and changes to immunity may therefore have important implications for mental health. At the same time, various exposures and changes in microbiota composition can result in increased gut permeability or ‘leaky gut’, wherein bacteria and their products pass through the lining of the gut into the blood stream, resulting in increased inflammation. This chronic low-grade inflammation may also impact the permeability of the blood–brain barrier, wherein a ‘leaky gut’ may lead to a ‘leaky brain’ (Marotz and Zarrinpar, 2016).

Neurotransmitters are implicated in the aetiology of depression, and the gut microbiome is known to synthesise large quantities of several neuroactive substances, including gaba-aminobutyric acid, norepinephrine, serotonin and dopamine, and brain-derived neurotrophic factor. It is hypothesised that these substances act locally on the enteric nervous system, influencing brain activity including via the vagus nerve (Marotz and Zarrinpar, 2016).

At the same time, altered mood states are known to have an impact on gut function and the microbiome; hence, the bidirectional relationship or ‘gut–brain axis’. Other factors are also known to have significant impacts on the microbiome, including medications, diet, disease states and many other environmental exposures. However, what constitutes ‘healthy’ gut bacteria or optimal microbial composition remains poorly understood (Zheng et al., 2016).

Critics of FMT point out that treatment with FMT may carry significant risk to the recipient. For instance, if positive characteristics such as antidepressant properties can be transferred through the faeces, could negative characteristics also be transferred? There is a case report of a healthy female recipient becoming obese following the delivery of a FMT from an obese donor. There have also been reports of other mild adverse effects such as fever, long-term food intolerances and diarrhoea (Marotz and Zarrinpar, 2016). However, these reported risks are few, and may be mitigated by careful screening of potential donors. Comprehensive screening protocols have been developed and public stool banks in the United States such as Open Biome are manufacturing FMT on a commercial scale.

Another potential consideration is the regulatory requirements. To date, FMT has been almost exclusively delivered via colonoscopy; however, new protocols involve the production of encapsulated faeces (‘crapsules’) to enhance feasibility and reduce costs. As the treatment is very new, it would appear (as is often the case) that the science is moving faster than the regulators. In Australia, FMT currently sits in a grey zone between a ‘drug’, a probiotic nutraceutical, and a biological product. Thus, it is currently unregulated, but care must be exercised and thorough screening protocols must be utilised. However, due to the promising effects of FMT, there have been many reports of individuals taking matters into their own hands and practising unregulated FMT at home for a variety of indications. Commercially available FMT is also available in some medical and non-medical practices. So, there are risks in not developing this treatment in a safe and regulated way to meet this apparent demand.

It is worth noting too that FMT is already a mainstream and first-line treatment for treatment-resistant Clostridium difficile infection. The treatment, including the use of crapsules, is considered highly effective at modifying the acute dysbiotic state, treating C. difficile with success rates of over 90% and good tolerability. Thus, FMT is already being used on a large scale in medically unwell, potentially immunocompromised individuals with good effect, and few adverse effects have been observed (Marotz and Zarrinpar, 2016).

In addition to its excellent efficacy for C. difficile, FMT has also demonstrated promising results in treating inflammatory bowel disease. It is also currently being trialled in an array of other health conditions which may also be related to the gut microbiome. These include – but are not restricted to – multiple sclerosis, IBS, hepatic disease, obesity and metabolic diseases. Trials of FMT in unipolar and bipolar depression are currently underway in Switzerland and Canada, respectively (see clinicaltrials.gov).

FMT may have several benefits compared with current treatments for depression. Faecal material in the form of ‘crapsules’ is relatively easy to produce, readily available and may offer benefit where other treatments have not worked well before. It may directly target a novel mechanism of disease. Given the burden of depression, anything that may make a difference would be useful. So, should we, as a field, embark on a programme to rigorously test the efficacy of FMT? Certainly, there is reason to think we should.