RePOOPulating the gut

# # # # The gastrointestinal system is teeming with life – billions and billions of microorganisms that play a critical role in not only your physiological wellbeing, but also your survival. A lot of research has been conducted on how this biosphere changes as we age. Recently researchers published a study indicating that transplantation of the gut bacteria from young mice can improve the brain and immune systems of aged mice. In today’s post, we will explore how the bacteria in our guts affects us, review the new research, and consider the implication for Parkinson’s. # # # #

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Source: Youtube

Today’s post starts with goats.

In the late 1950s, the Australian Division of Tropical Pastures began introducing and evaluating tropical plants for use in the beef industry of Northern Australia. Among the most promising was a shrub from central and South America called Leucaena leucocephala (Leucaena).

Leucaena leucocephala. Source: Wikipedia

It looked like a winner – it grew like a weed and the cattle loved it – but there was just one small problem: Leucaena contains a toxic amino acid called “mimosine” which made the animals very sick.

I can imagine that the scientists involved with the introduction of Leucaena must have been thinking “Struth mate, I’m feeling like a fair dinkum, true blue drongo. What have we done?”

But one researcher – named Dr Raymond Jones – made an interesting observation while at a research meeting in Hawaii – goats on the island were eating Leucaena…. without getting sick.

Dr Raymond Jones. Source: Creation

Long story short, Dr Jones & colleagues worked out that a bacteria in the rumen (a special ‘stomach’ where the food is pre-digested by microbes in cattle, sheep and goats) of the animals in Hawaii was able to breakdown mimosine.

Subsequent transplantation of the bacteria (which was named Synergistes jonesii after Dr Jones) allowed goats and cattle in Australia to eat Leucaena, and they all lived happily ever after:

Title: Successful transfer of DHP-degrading bacteria from Hawaiian goats to Australian ruminants to overcome the toxicity of Leucaena.
Authors: Jones RJ, Megarrity RG.
Journal: Aust Vet J. 1986 Aug;63(8):259-62.
PMID: 3790013

This case represents a powerful example of how transplanting gut bacteria can result in positive outcomes.

Interesting, but what does this have to do with Parkinson’s?

Well, recently some interesting preclinical research was published that may one day lead to another example of how powerful the microorganisms of the gut are.

Here is the publication in question:

Title: Microbiota from young mice counteracts selective age-associated behavioral deficits
Authors: Boehme M, Guzzetta KE, Bastiaanssen TFS, van de Wouw M, Moloney GM, Gual-Grau A, Spichak S, Olavarría-Ramírez L, Fitzgerald P, Morillas E, Ritz NL, Jaggar M, Cowan CSM, Crispie F, Donoso F, Halitzki E, Neto MC, Sichetti M, Golubeva AV, Fitzgerald RS, Claesson MJ, Cotter PD, O’Leary OF, Dinan TG & Cryan JF
Journal: Nature Aging 2021, 1, 666–676.
PMID: N/A             (https://doi.org/10.1038/s43587-021-00093-9)

In this study, the researchers were interested in what impact the gut microbiota of young mice might have on aged mice.

Intriguing, but before we go any further: What exactly is the gut microbiota?

Ours bodies are made up of microbiota – that is,  collections of microbes or microorganisms inhabiting particular environments (or region of our body) and creating “mini-ecosystems”. We are covered (inside and out) with a large number of bacteria, viruses, fungi, and protozoa.

Source: Metode

You should never feel alone, because you are definitely not.

By mass, the microbiota of the human body weighs approximately two to three kilograms in an adult. Collectively, it is one of the heaviest organs.

And whether you like it or not, you definitely need these little passengers. They serve a wide variety of necessary functions.

Source: The conversation

The microorganisms in the human gut, for example, perform all manner of tasks for you to make your life easier. From helping to break down food, to aiding with the production of certain vitamins (in particular B and K) that you do not make yourself.

Ok, but why would the gut microbiota of young mice influence aged mice?

Back in 2012, this landmark paper was published:

Title: Gut microbiota composition correlates with diet and health in the elderly.
Authors: Claesson MJ, Jeffery IB, Conde S, Power SE, O’Connor EM, Cusack S, Harris HM, Coakley M, Lakshminarayanan B, O’Sullivan O, Fitzgerald GF, Deane J, O’Connor M, Harnedy N, O’Connor K, O’Mahony D, van Sinderen D, Wallace M, Brennan L, Stanton C, Marchesi JR, Fitzgerald AP, Shanahan F, Hill C, Ross RP, O’Toole PW.
Journal: Nature. 2012 Aug 9;488(7410):178-84.
PMID: 22797518

In this study, the researchers collected dietary information, and measured a range of clinical and biological features of 178 elderly individuals, and then they analysed the composition of their gut microbiota.

How did they do that?

They collected fecal samples and extracted DNA from them for genomic analysis.

Fecal samples?

Poop. The analysis of which is a crappy task, but the data can be very interesting.

From their analysis, the researchers found that the composition of the elderly gut microbiota correlated significantly with measures of frailty, co-morbidity, nutritional status, and markers of inflammation. They also found that the microbiota of people living in long-stay care was significantly less diverse than the microbiota of elderly people living out in the wider community.

In effect: loss of diversity gut microbiota = increased frailty with aging.

This (and other results) led the researchers behind the report we are reviewing in today’s post to ask what impact the gut microbiota from young individuals could have on aged people. They were particularly interested in understand how the gut microbiota might be impacting the health and immunity of the brain during the aging process.

To address this, they transplanted (on a bi-weekly basis) fecal matter from either young (3-4 months of age) or aged (19-20 months of age). When they analysed the gut microbiota of the mice at the start of the study, the investigators observed significant differences in the composition of the young vs aged microbiota.

After 8 weeks of bi-weekly transplantation, however, many of these differences had disappeared. That is to say, the gut microbiota of the aged mice that had been given young mouse microbes began to resemble the gut microbiota of the younger mice.

In addition to what was occurring in the gut, there were also changes in the brain and the immune system. In the brain, the researchers observed changes in the resident immune cells in the brain – the microglia – of the aged mice transplanted with young microbiota. The microglia in these mice resembled those from a young mouse brain rather than an aged brain. These physical changes were associated with alterations in inflammatory markers as well.

The young microbiota transplant also improved the performance of aged mice in specific cognitive tasks. The aged mice that received transplants of young microbiota learned to solve mazes faster, plus they were better at remembering the maze layout during subsequent test sessions.

Overall, the researchers were excited, but cautious about their results, suggesting that future studies are required to “further elucidate the direct mechanistic underpinnings of how specific gut microbes drive these changes in rejuvenating the aging brain“. It will also be important to determine whether the young microbiota microbes have “moved in” and formed permanent colonies, or if they were unable to imbed and just passed through.

So I should be bi-weekly consuming…young…?

No. That is not recommended.

While these results in mice are exciting and interesting, fecal microbiota transplantation for neurodegenerative conditions is still experimental, and it is not without risks.

One important consideration is exactly what constitutes “healthy, young gut microbiota”? And this is an important issue as there is the potential for infection transmission with this procedure. If you are going to consume fecal matter from another person, you want to be sure of the quality of that material, right? (this is weird to write, so it must be disturbing to read!)

Has anyone ever looked at microbiota transplantation in Parkinson’s?

Yes, there have been both preclinical and clinical investigations of fecal microbiota transplantation in Parkinson’s. The number of studies are rather limited, but on the clinical side, there have been improvements in constipation reported:

Title: Evaluation of fecal microbiota transplantation in Parkinson’s disease patients with constipation.
Authors: Kuai XY, Yao XH, Xu LJ, Zhou YQ, Zhang LP, Liu Y, Pei SF, Zhou CL.
Journal: Microb Cell Fact. 2021 May 13;20(1):98.
PMID: 33985520                 (This report is OPEN ACCESS if you would like to read it)

In this study, the researchers conducted a prospective, single-arm study involving 11 individuals with PD who received fecal microbiota transplantation treatment (40 to 50 ml of frozen fecal microbiota suspended in 200 ml of warm normal saline and transplanted into the intestine via a nasoduodenal tube). This was an evaluation of the safety and effectiveness of a single transplant for individuals with Parkinson’s and constipation.

The researchers found that after half of the participants experienced flatulence and one quarter of them had nausea and abdominal pain. But they also noted that all of the study group had improvements in their episodes of constipation.

Other small pilot studies have reported similar results (Click here and here to read more about this).

Sounds encouraging?

Perhaps, but most of the studies thus far have been open label, safety evaluations, which are difficult to really interpret in terms of any measures of efficacy (given that everyone knows that they are receiving the treatment there is the potential for a placebo effect to occur).

And given the variability between samples of fecal matter, reproducibility between studies will be complicated.

A better approach may be to focus on specific components of the gut microbiota.

What do you mean?

Last year, I wrote a SoPD post on research from a group in Edinburgh that had screened different types of gut bacteria and identified one in particular that had beneficial effects in models of Parkinson’s (Click here to read that post).

A clinical trial is now being set up based on that research (Click here to read more about that).

Another approach is to engineer gut bacteria that do not take up residence in the gut – rather they just pass through – but as they go, they are releasing beneficial factors that could help to alleviate symptoms or slow progression of a condition.

One example of this is being developed by the biotech firm CHAIN biotech:

Another example is the biotech company 4D Pharma:

Both companies are developing bacteria that can be delivered by pill, grow in the gut, produce and release their treatment, and then be excreted after 3-4 days of travelling down the intestinal tract.

By taking 1-2 pills per day, individuals should be able to maintain a continuous administration of treatment. And once the ailment has improved, the treatment can be stopped.

Potential for Parkinson’s?

We shall see. It is interesting to note that 4D Pharma has 2 products ( MRx0029 & MRx0005 ) in their pipeline for “Neurodegeneration” (Click here to read more about this).

So what does it all mean?

There was a tremendous opportunity with this post to have some fun with the title (for example, I could have called it “New poo, new you?“), but I thought better of it and decided to focus on the science rather than the humor. And the research is really interesting. Plus there is an ever increasing amount of it. The gastrointestinal system is a white hot area of investigation!

The gut is a vast microbial universe, that can both positively and negatively impact our lives and sense of wellbeing. Dysbiosis in the gut has been associated with Parkinson’s (Click here to read a previous SoPD post on this), and there is real potential for therapies focused on the gut to impact the condition, not just symptomatically (Click here to read an old SoPD post about this), but also possibly helping to slow the progression of the condition (as we have explored in today’s post).

I am not sure that fecal microbiota transplantation is the answer, but it has provided hints of what could be possible. And more focused approaches, that have defined mechanisms of action, could be entering clinical testing in the not-to-distant future for Parkinson’s.

Call it a gut feeling.

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