The gut microbiota and psychiatric illness

How strong is the evidence on which decisions to take prebiotic or probiotic preparations are being made?

How strong is the evidence? In brief, not as strong as it needs to be. Animal studies consistently report that behaviour and the function of the nervous system are modulated by gut microbiota (see the reviews by Dinan and Cryan,2 Foster3 and Anglin and colleagues4). Perturbing the gut microbiota in mice with antibiotics is associated with altered brain-derived neurotrophic factor in the hippocampus and amygdala and an increase in mouse exploratory behaviour, considered a surrogate for decreased anxiety.5 Chronic administration of Lactobacillus rhamnosus str. JB1 also increased exploratory behaviour,6 and this effect was associated with brain region–specific changes in the γ-aminobutyric acid (GABA) system and was dependent on vagal integrity.6 Bifidobacterium longum NCC3001 normalized anxiety in mice with chemically induced low-grade inflammation.7 In contrast, other bacteria can induce anxiety-like behaviour in rodents, and this is effect also appears to be mediated by the vagus nerve.8,9 Social disruption in rodent models is associated with reduced richness and diversity of the gut microbial community, along with shifts at the level of operational taxonomic units (OTUs; groups of micro-organisms clustered by DNA sequence similarity), suggesting a bidirectional component to brain–gut–microbiota relations.10,11 Diet may also play a role.12 Animal studies, therefore, provide strong support to the notion that altering the gut microbiota might result in altered behaviour.

Despite these persuasive animal data, relevant data from humans are extremely limited. Rather, the literature is mostly populated by reviews describing the potential of pre- and probiotics to treat psychiatric conditions. A search of PubMed in January 2017 yielded almost 400 results from a search limited to reviews of “brain microbiome.” Searching for “depression microbiome” alone yielded more than 100 reviews, and “anxiety microbiome” and “autism microbiome” yielded slightly fewer.

In contrast, running the same searches requesting clinical trials rather than reviews will yield only a few articles, and even fewer are actually clinical trials relevant to the condition. The human clinical data supporting a role of pre- or probiotics in other diseases, such as GI conditions, is stronger, but still limited. Systematic reviews suggest that probiotics are effective for symptoms of irritable bowel syndrome, for example, although a particular probiotic could not be recommended because studies used various species and strains.13

Although the paucity of data confirming the ability of the microbiome to enhance nervous system function is striking, there are a few recent studies that have yielded preliminary data supporting the notion that the intestinal microbiota can influence human behaviour. Steenbergen and colleagues14 had 20 healthy participants consume either a multispecies probiotic or identical placebo for 4 weeks and found that the probiotic group had reduced cognitive reactivity to sad mood. These findings are consistent with those of a study in which healthy volunteers who took 1 of 2 prebiotics for 3 weeks had decreased attentional vigilance to negative versus positive information in a dot-probe task.15 In that study, however, there were more measures (anxiety, perceived stress, memory) that did not change with either of the prebiotic products, making it hard to evaluate the significance of change on the dot-probe only.15 A small study reported that women who consumed fermented milk product with probiotics had changes in midbrain connectivity during an emotional attention task compared with women who did not consume the product with probiotics.16

There have been a small number of case–control studies comparing gut microbiota of patients with psychiatric disorders to healthy controls. For example, Jiang and colleagues17 noted that despite “profound interindividual variability,” Bacteroidetes, Proteobacteria and Actinobacteria were increased in 46 people with active or treated major depressive disorder (MDD), whereas Firmicutes were reduced compared with 30 healthy controls.17 Another recent study noted alterations in the phyla Firmicutes, Actinobacteria and Bacteroidetes in patients with MDD.18 Whether alterations in the microbiome contributed to the onset of MDD or emerged as a result of the illness or pharmacological treatment is unknown. One recent study found that there was no significant difference in species richness between depressed and nondepressed participants,19 although another study reported that depression was associated with decreased gut microbiota richness and diversity20 and another reported lower Bifidobacterium counts in patients with MDD.21

Fecal microbiota transfer from patients with MDD to microbiota-deficient animals can induce behavioural changes in the recipient animal that are considered analogues of depression or anxiety.18,19

There are few reports of randomized controlled trials evaluating the effect of probiotics in psychiatric patients. Tomasik and colleagues22 randomized 58 people with schizophrenia to 14 weeks of adjunctive Lactobacillus rhamnosus strain GG and Bifidobacterium animalis subsp. lactis strain Bb12 or placebo. Probiotic treatment reduced levels of immunomodulatory proteins, but the clinical implications are unclear as there were no psychiatric outcomes measured in the trial. In another study, 40 people with major depression received either a capsule containing Lactobacillus acidophilus, Lactobacillus casei and Bifidobacterium bifidum or placebo for 8 weeks.23 Those treated with the probiotic preparation had a significantly greater degree of improvement on the Beck Depression Inventory than those taking placebo.

There are clinical trials of probiotics for depression and/or anxiety in various stages of planning and running according to clinicaltrials.gov. However, many have small sample sizes and most have only 1 probiotic preparation. Given the large number of probiotics on the market containing single strains and combinations of organisms, the uncertainty as to which patient might benefit and what dose and what route to administer the probiotic, it is unlikely that these trials will provide clarity on the efficacy of probiotics in psychiatric disorders in the near future.

Furthermore, probiotics are just 1 approach to change the gut microbiome. There are even fewer data on diet, antibiotics and fecal microbiota transplant therapy, some or all of which may have a role in modulating the gut microbiome to improve psychiatric illness.

What are the barriers to microbiome research in people with psychiatric illnesses?

There are substantial challenges to elucidating the role of the microbiome in human health and disease. A basic challenge is that there is no definition of what constitutes a healthy gut microbiota.24

The term “dysbiosis” is widely used, but is a concept rather than a defined entity, and no researcher can confidently state that an individual has an “unhealthy” gut microbiome. There is large variability among individuals in the composition of the microbiome, superimposed on variation in genetic and epigenetic susceptibilities to disease and dietary and environmental exposures. Thousands of microbial species inhabit human populations, and there is no universal definition of a microbial “species” or OTUs across studies. The distributions of microbes across hosts vary greatly, providing challenges to statistical descriptions of human microbiome data. As noted above, there is little consensus in the literature regarding what species are most likely to have therapeutic properties, and it may be the case that a balance of organisms, supported by a specific diet, provides the most benefit for any particular health condition. Trials of single or a few species may not represent an adequate approach to manipulating an individual’s microbiome.

Finally, describing alteration in the microbiota of people with psychiatric illness requires a multidisciplinary team, including disciplines such as psychiatry, neurobiology, informatics, microbiology, gastroenterology and epidemiology. Such a team would be difficult to assemble and coordinate.