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expert reaction to study on ALS and the gut microbiome

Research, published in Nature, reports a connection between the gut microbiome and Amyotrophic Lateral Sclerosis (ALS).

 

Dr Luis Emiliano Pena Altamira, Post-doctoral research associate, Kings College London, said:

“The research in this paper is high quality research. The researchers used genetically modified mice that develop ALS (ALS SOD mice). The authors suggest that 11 strains of bacteria seem to influence ALS severity in the mice. Interestingly, these differences are not observed in another set of ALS SOD mice and normal mice that were held in a less clean mouse facility. However, this less clean facility could represent more a real-life setting compared to the cleaner facility, considering the gut starts being populated by microorganisms right after birth. One strain, Akkermansia muciniphila, which is reduced in ALS SOD mice with disease progression, increased survival of ALS mice. To discover this, the gut resident bacteria were removed from the ALS SOD mice and normal mice, so the individual bacteria strains were allowed to populate the whole gut. This approach is valuable to understand the effects a single strain can have on the gut and overall health, but care also should be taken when interpreting these results in the real world since the resident microorganisms of the gut are varied and influence each other and even in disease, there is not only one bacterial strain residing in the gut.

“ALS SOD mice were the first model used for ALS research and while it has contributed to the understanding of ALS, it has also shown to not represent fully what happens during the disease. It would be worth performing the same experiments in a more “real” ALS mouse model, such as a knock-in model, such as the TDP-43 knock-in model in which only the human equivalent gene in the mouse DNA is mutated to cause disease. While the disease outcome is milder, it provides information that is otherwise lost when using an aggressive model such as ALS SOD mice.

“In the last part of the study, the authors studied patients with ALS and their healthy relatives, looking at differences in resident gut microorganisms and molecules in the blood. The authors found some strain differences between patients and healthy relatives and suggest one strain could be associated with the production of nicotinamide. Also, the authors found reduced levels of nicotinamide in the blood of some patients with ALS. However, these results need further investigation given the complexity of the microorganisms that reside in the human gut and as the authors state, they are not a treatment recommendation.”

Further information on Akkermansia muciniphila:

“Akkermansia muciniphila was detected in the human gut in 2007 by Collado and colleagues. It has very recently gained attention for its potential role in obesity in humans. Depommier and colleagues (2019) showed that administration of Akkermansia muciniphila for 3 months to overweight/obese volunteers reduced blood markers associated with liver dysfunction and inflammation. But the bacterium may also play a specific role in the function of the immune system, at least in mice. Ansaldo and colleagues (2019) showed that Akkermansia muciniphila is able to activate and induce the expansion of a specific type of T-cells in the immune system, at least in mice.  Thus Akkermansia muciniphila may be exerting other effects besides the production of nicotinamide. Moreover, reduced numbers of Akkermansia muciniphila have been reported in the elderly by Collado and colleagues (2007), the same was observed in ALS SOD mice with disease progression. Could there be a link between aging, ALS and reduced numbers of this bacterium?

 

Interestingly, a recent clinical trial by de la Rubia and colleagues (2019) focused on the administration of EH301, a combination of nicotinamide riboside (another form of vitamin B3) and pterostilbene (a molecule contained in blueberries) to patients with ALS. After 4 months of administration, patients showed some improvement. While these results are encouraging, the clinical trial was too small and will need larger/deeper investigation yet it still casts light on the role nicotinamide could have in ALS. Gut bacteria can transform niacin (vitamin B3) in foods into nicotinamide. Digestive problems can also decrease the absorption of nicotinamide. Should we also consider the administration of nicotinamide (vitamin B3) in patients with ALS given the evidence of potential benefit of nicotinamide administration in patients with other neurodegenerative diseases such as Parkinson’s disease?

What about nutritional strategies that could increase Akkermansia muciniphila abundance in the gut? While there are no human studies, animal studies show that rats fed a common prebiotic (Reid and colleagues, 2016) such as oligofructose showed increased abundance of Akkermansia muciniphila in feces compared to rats that were not fed the prebiotic. Also, mice fed rhubarb extract showed increased abundance of Akkermansia muciniphila compared to mice not fed the extract (Neyrinck and colleagues, 2017). On this note, David and colleagues (2014) showed that short-term consumption (5 days) of diets composed entirely of animal or plant products changed the population of microorganisms that reside in the gut. Particularly, the animal-based diet promoted the growth of bacteria able to trigger inflammatory bowel disease. What was the diet of patients with ALS and their relatives like in this study? 

 

Dr Nikhil Sharma, Honorary Consultant Neurologist, UCL Queen Square Institute of Neurology, said:

“In recent years, it has become clear that the gut microbiome plays an important role in several neurological conditions such as multiple sclerosis and Parkinson’s disease. We are only beginning to understand the relationship between the gut microbiome and MND. Humans and the gut microbiome ‘evolved’ together; therefore, the relationship is likely to be complex with several layers of interaction. As such, there are many unknowns. For instance, the gut microbiome is extremely variable between individuals and therefore establishing the ‘normal’ microbiome is far from clear. The current study highlights the role of certain bacterial strains in mice that effects how the microbiome works via metabolites, but given the range and variability in the gut microbiome this is unlikely to be specific to those strains. Therefore, while the emerging evidence in MND is encouraging, caution is required.

“This study is thorough and comprehensive, given their experimental approach. The authors are cautious in not over speculating their results. The gut microbiome is part of a complex microbial system that is influenced by the immediate and broader environment. There are several fundamental steps still required in this research space. For example, this study examines the microbiome from a single mouse model within one facility. As the authors report, the gut microbiome at a different mouse facility did not include the majority of bacterial strains reported. Further work is required to understand the variation in the microbiome within different facilities and how it may alter the model phenotype.

“Like in many disease areas, the translation from a mouse model to humans is challenging. Of the several experiments that have positively affected the SOD1 mouse, none have resulted in successful treatment for human MND. Additionally, in humans the SOD1 gene is only responsible for approximately 3% of cases. 

“There is a great deal of work required across several areas to fully understand the relationship between the gut microbiome and the brain. Examining the connection between the gut microbiome and brain in ‘real world’ people living with MND is now feasible. My lab at UCL is about to start an interventional trial called BIOMAX-ALS. The first of its kind in the world, BIOMAX-ALS combines state of the art assessments of brain structure and function with a faecal microbiota transplant (FMT) in real world people living with MND (funded by the Reta Lila Weston trust; thesharmalab.com).”

 

Dr Brian Dickie, Director of Research Development, Motor Neurone Disease Association, said:

Does the press release accurately reflect the science?  Is there any overspeculation? 

“Overall, the press release is quite balanced. It does not try to sensationalise the findings. In the final discussion section of the paper itself, the authors carefully state the limitations of the study and the follow-up work that need to be carried out.”

How does this work fit with the existing evidence on MND?

“There is increasing evidence from a wide variety of sources that the bacteria in our gut can play a role in a wide-range of neurological conditions, though ALS has not been as widely studied as other conditions such as multiple sclerosis, Parkinson’s disease, Alzheimer’s disease and stroke. These are important new findings, which support the theory that certain bacteria may play a disease-modifying role in ALS and that this may occur though changes in a particular metabolic pathway. This adds to an emerging, but still fuzzy, picture of a different metabolism that seems to occur in people with ALS. Diet and exercise are also being studied as potential factors associated with the disease.

“These current findings may also start to address a ‘technical’ question that arises with mouse models. It is known that when ALS mouse models are moved from one institute to another, their disease characteristics, such as symptom onset and rate of progression, can change, which points to environmental factors at play. This study indicates that changes in their microbiome may be a reason why this is happening. It would be helpful to independently replicate the SOD1 mouse findings in another institute, where the environmental conditions may be different.

Is this good quality research?  Are the conclusions backed up by solid data? Are there important limitations to be aware of? What research needs to be done next to test this association?

“Key experiments in the mice have been replicated, which strengthens the findings. The paper and its supplementary sections certainly provide an avalanche of data, though the findings are not definitive and probably raise as many questions as answers, especially when extending them to the human disease. 

“One of the key issues (acknowledged by the authors) is that the basic research has been carried out in a single model of ALS, the SOD1 transgenic mouse. The SOD1 mouse develops an ALS-like disease in a highly predictable fashion, which makes it incredibly useful for many studies. However, this mouse model represents around 3% of all cases of human ALS cases (patients who carry a SOD1 genetic mutation) and some of the key cellular events that occur in the SOD1 version of ALS are different from the other 97% of cases.  A clear next step for the research team is to show the same effect occurs in other mouse models of ALS.

“The SOD1 mouse is also known to undergo major neuroinflammatory changes as the disease progresses. The evidence for other neurological diseases suggests that the microbiome applies its influence on the brain by controlling inflammation, it’s surprising that the researchers have carried out so little analysis of inflammation in the mouse brain and spinal cord.

“Another key experiment to perform would be to see whether a ‘transplant’ of the human species of the bacteria into the mice alters their disease progression. This would provide an important link between mouse and human studies.

“The authors stress that their human data is preliminary. In the context of disease symptoms and progression, humans are a lot ‘messier’ than mice, so I completely agree that small ‘snapshot-based’ studies such as this must be treated with caution. The next step in establishing the human disease relevance is to carry out a larger longitudinal study, examining changes in gut bacteria over time to see if changes are associated with speed of progression. Do people with very rapidly progressing disease have a different microbiome to those with very slow disease? Do people with specific inherited forms of ALS (where there is a strong genetic component) have a different composition to those with ‘sporadic’ disease (where there is no known family history of ALS)?

How often is success in mouse models replicated in human trials? What are the implications in the real world? 

“Many compounds have been shown to limit disease progression in the SOD1 mouse model, but none have yet shown the same effectiveness in ALS patients, so researchers will be cautious when extending these findings to the human disease. There is no currently no evidence that nicotinamide has an effect on ALS progression in humans.”

“There are ongoing clinical studies looking at whether high calorie nutritional supplementation may alter the disease course in ALS patients (eg the UK HighCALS trial: https://www.fundingawards.nihr.ac.uk/award/RP-PG-1016-20006) so it does raise the question of whether analysis of microbiome changes should be included in these trials.”

 

* ‘Potential roles of gut microbiome and metabolites in modulating ALS in mice’ by Blacher et al. was published in Nature at 16:00 UK time on Monday 22nd July.  

DOI: 10.1038/s41586-019-1443-5

 

Declared interests

Dr Luis Emiliano Pena Altamira: “I have no interests to declare that could create conflict with this story.”

Dr Nikhil Sharma: “I’m a principal investigator & neurologist with a programme of research at the ION, UCL that examines the gut microbiome in real-world people living with MND.  In addition to longitudinal observational aspect, this programme involves a trial of faecal microbiota transplant (FMT). The work is funded by the Reta Lila Weston Trust and the MND Assoc.  I am also a trustee of the MND Assoc.”

Dr Brian Dickie: “The MND Association is co-funding a study looking at the microbiota/microbiome composition in ALS patient and whether this can influence disease progression and neuroinflammation, but I personally have no CoI.” 

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