On gut bacteria and depression

I'm kinda standing on the shoulders of giants with this post talking about the findings reported by Mireia Valles-Colomer and colleagues [1]. An editorial published in Nature [2] to coincide with the publication of the Valles-Colomer paper says just about everything that needs to be said on this research, which observed that: "Gut–brain module analysis of faecal metagenomes identified the microbial synthesis potential of the dopamine metabolite 3,4-dihydroxyphenylacetic acid as correlating positively with mental quality of life and indicated a potential role of microbial γ-aminobutyric acid production in depression." Yes folks, the idea that "microorganisms in the human gut could influence the brain" is moving from 'wild idea' to "wise pursuit".

The sequencing of DNA from donor stool samples as part of the Flemish Gut Flora Project ('You too are a walking bacteria colony' is the strap line) was the starting point for the Valles-Colomer study; stool samples provided by over 1000 participants. Researchers also accessed data on both self-reported and "physician-diagnosed depression" and set to work looking for any potentially important correlates between bacteria and psychology. The words "with validation in independent data sets (ntotal = 1,070)" are also (importantly) mentioned in the Valles-Colomer paper. Oh, and they also "mined the data to generate a catalogue describing the microbiota’s capacity to produce or degrade molecules that can interact with the human nervous system."

Results: "Butyrate-producing Faecalibacterium and Coprococcus bacteria were consistently associated with higher quality of life indicators." There's that word again: butyrate and yet more positive publicity for this compound (see here) and it's standing reaching almost 'bacterial sainthood'. Researchers also observed that two groups of bacteria were also reduced in those with depression: Coprococcus and Dialister alongside observing that this finding held "even after correcting for the confounding effects of antidepressants [use]." And then there was that 3,4-dihydroxyphenylacetic acid, also called DOPAC, finding, a metabolite of the neurotransmitter dopamine. I have actually mentioned DOPAC before on this blog (see here) in relation to what happens when rats are subjected to 'early immune stimulation' [2]. I don't think there is much overlap between that rat study and the Valles-Colomer paper (that rat paper was looking at DOPAC levels in brain tissue for example) but the suggestion from the authors that DOPAC levels were "correlating positively with mental quality of life" requires quite a bit more investigation.

Caveats? Well, out of their initial 1054 participant cohort, only 121 participants had "GP-reported depression." About half of these participants were taking antidepressants for their depression, the others weren't. The participant numbers aren't exactly tremendous for this portion of the study. Similar to something mentioned in other research (see here), I'm also minded to suggest that future research might perhaps consider looking at multiple stool samples taken over different occasions for the same person. This would perhaps establish whether gut bacterial populations are stable and whether that stability translates into stability of something like depressive symptoms too. I am likewise cautious that we don't jump ahead of ourselves here in terms of important issues like cause-and-effect and for example; whether there may be other important 'influencers' of gut bacteria when it comes to depression (see here and see here).

Lots more study is required on the suggestion of a gut bacterial *link* to depression [3], including that focused on the mechanics of any relationship (e.g. any involvement of the vagus nerve). If the link is further established, there are a number of potentially important implications: the possibility of a 'bacterial transferability hypothesis of [some] depression' (see here), intervention options focused on redressing balance in bacterial colonies (see here) and what such findings might do for the whole 'gut-brain axis' idea.

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[1] Valles-Colomer M. et al. The neuroactive potential of the human gut microbiota in quality of life and depression. Nature Microbiology. 2019. Feb 4.

[2] Editorial. Links between gut microbes and depression strengthened. Nature. 2019. Feb 4.

[3] Cheung SG. et al. Systematic Review of Gut Microbiota and Major Depression. Front Psychiatry. 2019;10:34.

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"abnormalities in mitochondrial activity in the lower GI tract of children with ASD"

The findings reported by Shannon Rose and colleagues [1] (open-access) continue a research theme by [some of] this authorship group looking at how mitochondrial dysfunction seems to be part and parcel of at least some autism (see here). Indeed, how when one talks about mitochondrial issues potentially accompanying [some] autism, one really needs to look at it in the context of other issues potentially also 'over-represented' in relation to autism (see here).

This time around, Rose et al set out to "determine whether mitochondrial dysfunction may contribute to GI [gastrointestinal] symptoms in children with ASD [autism spectrum disorder]" on the basis that GI symptoms (whether functional or more pathological) are no stranger to autism (see here). With this in mind, I note the name Tim Buie is included as part of the Rose paper authorship team and so should reference some of the sterling work he and his team have done on the topic of GI issues and autism and its importance down the years.

Researchers analysed mitochondrial function(s) in rectal and cecum mucosal biopsies in a small sample of children diagnosed with ASD (n=10) and compared results with those from "10 children with Crohn’s disease and 10 neurotypical children with nonspecific GI complaints." There are two points for me to make here: first, although it is an invasive procedure to collect them, those biopsies used for study were extracted on a clinical basis as part of "elective diagnostic colonoscopy." This was not a case of 'experimenting' on children for the sake of an experiment; rather that children were already undergoing investigations for their significant bowel issues, save any health inequalities appearing "just 'cos they were autistic" for example. Second, although the authors have chosen to use the term 'neurotypical' to reflect not-autism, I myself still find this terminology to be scientifically problematic (see here) in the context that no brain is seemingly typical or atypical according to current scientific evidence. Not least also on the basis that immune-based conditions such as inflammatory bowel diseases do seem to carry an increased 'risk' of psychiatric issues (see here) and what that might [eventually] mean for those children diagnosed with Crohn's disease (an inflammatory bowel disease) for example. Anyhow, two approaches are described in connection with the study of mitochondria in those biopsy samples looking at both the quantity and activity of various electron transport chain (ETC) complexes. Yet again, I can profess no serious expertise on the various elements of mitochondria but there is some good reading out there in the peer-reviewed science domain on the topic.

Results: "Differences in mitochondrial function were found in children with ASD as compared to the other control groups across several ETC complexes suggesting a difference in overall mitochondrial function rather than a change in one specific mitochondrial enzyme." Accepting the small participant numbers included for study, these are potentially important results. Not least because other work looking at such mitochondrial issues in relation to [some] autism has been predominantly based on activity in muscle; now it appears extending "this observation to altered ETC complex activity in the GI mucosa" too.

Then to some speculation: "The fact that increased ETC complex protein content was primarily seen in the cecum, an area where enteric microbiome fermentation products such as PPA [propionic acid] and BUT [butyrate] are abundant, suggests a role for the enteric microbiome in the evolution of mitochondrial abnormalities in children with ASD." An interesting perspective indeed and in need of some further investigation. Butyrate has, in recent years, been elevated to almost scientific sainthood (see here for example) so one has to perhaps be a little cautious about sweeping statements in the context of autism or any other label. I say this with particular relevance to an 'autism colon' discussed by the authors (see here) which I also think is perhaps a little premature to speculate on.

No mind, the results are what they are and add to the growing literature discussing mitochondria in the context of [some] autism. The implication once again is to screen for such issues within the context that a diagnosis of autism should represent a starting point for further investigations not the finishing line.

And finally, to another author on the Rose paper, I'm still waiting to read about some of your results...

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[1] Rose S. et al. Mitochondrial dysfunction in the gastrointestinal mucosa of children with autism: A blinded case-control study. PLoS One. 2017 Oct 13;12(10):e0186377.

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The prebiotic galactooligosaccharide (B-GOS) and autism: just add to poo(p)

Yes, it is childish but...

With all the continued chatter on a possible role for the collected gut microbiota - those wee beasties that inhabit our deepest, darkest recesses - in relation to some autism (see here for example), the paper by Roberta Grimaldi and colleagues [1] (open-access available here) provides yet more potentially important information.

So, poo(p) samples were the starring material in the paper - "obtained from three non-autistic children and three autistic child donors"- and specifically what happened when something called B-GOS "a prebiotic galactooligosaccharide" was added to samples following their journey through a "Three stage continuous culture gut model system" otherwise known as an artificial gut. Said gut model based at Reading University has already been the topic of other news (see here).

As well as looking at the initial bacterial profile of those stool samples, researchers plotted the changes to the stool's inhabitants (or what was left of the stool) over the course of B-GOS addition, as well as looking at things like the "production of SCFAs [short-chain fatty acids] in the fermentations" and other metabolites via the gold-standard chemical analytical technique called 1H-NMR (see here for more details).

Results: "Consistent with previous studies, the microbiota of ASD [autism spectrum disorder] children contained a higher number of Clostridium spp. and a lower number of bifidobacteria compared to non-autistic children." With the addition of B-GOS to the 'mixture', researchers reported on a significant increase in bifidobacterial populations at the different stages of their gut model and in samples from both those with autism and those without autism. Such "bifidogenic properties of B-GOS" are not unheard of.

As to the metabolites of those bacteria present in the poo(p) samples, there were some interesting knock-on effects noted in both raw and B-GOS supplemented samples. "Our data show a lower concentration of butyrate and propionate in autistic models, compared to non-autistic models, but no
differences in acetate before adding B-GOS into the system." Propionic acid (propionate) has some research history with autism in mind (see here). Butyric acid (butyrate) is something of a rising star in quite a few domains, having also been mentioned in the context of autism too (see here). Indeed it's interesting to note that B-GOS administration "mediated significant production of... butyrate... simulating the transverse and distal colon respectively. There was no effect on propionate." The findings of lower starting levels of butyrate in samples from children with autism were also substantiated by the NMR analyses undertaken. Increases in butyrate and changes to various other metabolites ("increasing ethanol, lactate, acetate and butyrate and decreasing propionate and trimethylamine") were also noted via this analytical method for this group.

A long quote coming up: "This in vitro study showed promising and positive results in that supplementing the microbiota of ASD children with 65%B-GOS may manipulate the gut bacterial population and alter metabolic activity towards a configuration that might represent a health benefit to the host. However, further work will be required to assess such changes in an in vivo human intervention study."

Just before anyone makes a run on B-GOS or any similar product however, I do need to stress a few important points. First, this was a study of poo(p) samples from 3 autistic children compared with samples from 3 non-autistic children. Aside from the small participant numbers, we don't know anything about participants' various comorbidities (although we know they were "free of any metabolic and gastrointestinal diseases") and only limited information on their dietary habits and medication history. Second, poo(p) was the target material included for analysis and what happened when B-GOS was supplemented during the journey through the artificial gut model. This study said nothing about what happens when real people with autism take B-GOS orally for example, and how it might affect gut bacterial populations and metabolites as it progresses down a real gastrointestinal (GI) tract. This also includes a lack of information on any potential side-effects in a real-world situation. We are also assuming that any supplement survives the stomach. There is quite a bit more to do in this area.

But for now, I stick to the idea that the Grimaldi paper provides some potentially important information and certainly, some new routes/methods for further study of the link between prebiotics, probiotics and synbiotics in the context of the gut microbiota and autism...

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[1] Grimaldi R. et al. In vitro fermentation of B-GOS: Impact on faecal bacterial populations and metabolic activity in autistic and non-autistic children. FEMS Microbiol Ecol. 2016 Nov 16. pii: fiw233.

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Grimaldi R, Cela D, Swann JR, Vulevic J, Gibson GR, Tzortzis G, & Costabile A (2016). In vitro fermentation of B-GOS: Impact on faecal bacterial populations and metabolic activity in autistic and non-autistic children. FEMS microbiology ecology PMID: 27856622