September 19, 2023

expert reaction to study looking at mouse gut immune cells and dietary emulsifiers

A study published in PLOS Biology looks at mouse gut immune cells and dietary emulsifiers.

Prof Nathalie Juge, Group Leader and Deputy Chief Scientific Officer, Quadram Institute, said:

Are there “usual detrimental effects of ingesting food additive emulsifiers”?

“There is accumulating in vitro and animal evidence that food additive emulsifiers can affect microbiota composition, gut barrier function and chronic inflammation but some level of caution is needed as some of these studies used levels of emulsifiers which may not account to what is consumed by humans, and with the limitations of in vitro models/ disease mouse models which differ from humans, this has been reviewed recently (Bancil et al 2021).  In terms of relevance to humans, there is a current focus on the potential deleterious effects of emulsifiers on patients with chronic inflammation such as IBD but high quality/ sufficiently powered human studies (with CD/UC populations, heathy volunteers etc.) are required to support the findings from in vitro/animal work and to conclude on the effect of food emulsifiers on healthy populations.  I see there is also a recently published prospective cohort study which found positive associations between risk of CVD and intake of five individual and two groups of food additive emulsifiers widely used in industrial foods (Sellem et al., 2023, the corresponding author was one of the authors).

Is this good quality research?  Are the conclusions backed up by solid data?

“The work is based on observations that in mouse models, food emulsifiers lead to a dysbiosis of the microbiota associated by increased penetration of flagellated bacteria in the mucus layer (a phenomena the authors refer to as encroachment), resulting in low level inflammation.  This led to the focus on microbiota-targeted strategies to decrease inflammation, and the experimental design and approaches and data analyses are sound.

“The authors are aware of limitations of the study as reported in the Discussion section as questions remain with regards to which flagellated bacterial populations affected by the food emulsifiers and by the immunisation with purified flagellin, and mechanisms underpinning the effect of immunisation on faecal flagellin levels.  On a technical basis, the use of shotgun metagenomic approaches (rather than 16 rRNA gene sequencing used in this study) may have provided better insights into the microbiota changes (beyond compositional level).  One aspect which has not being investigated/discussed in this work is the direct impact of emulsifiers (and treatment) on mucus structural properties, as increased levels of faecal flagellins may be a direct consequence of altered mucus porosity.

How does this work fit with the existing evidence?

“This work builds from a series of experimental murine studies involving the corresponding author showing that consumption of food emulsifiers in mice alters gut microbiota structure and function (https://pubmed.ncbi.nlm.nih.gov/33752754/; https://pubmed.ncbi.nlm.nih.gov/34774538/)and immune response, colitis (https://pubmed.ncbi.nlm.nih.gov/32942699/ )but also food allergy (https://pubmed.ncbi.nlm.nih.gov/36501013/), small-intestine tumour development (https://pubmed.ncbi.nlm.nih.gov/33807577/), anxiety-like and social-related behaviors (https://pubmed.ncbi.nlm.nih.gov/30655577/).

“In addition, the authors reported earlier (Tran et al 2019)  that such anti-flagellin immunization approach could protect against colitis as well as against diet-induced obesity in experimental models, so this is in the same line.

Have the authors accounted for confounders?  Are there important limitations to be aware of?

“The authors have addressed limitations of the applicability of the treatment to humans in the Discussion: ‘the repeated injection of purified flagellin is not applicable in the clinical setting’.  They also raise potential issues around the possibility of cross-specificity which may affect beneficial members of the gut microbiota.

What are the implications in the real world?  Is there any overspeculation?

“The experimental work is sound.  Relevance to humans is limited by the fact that the study is done in mice, which differ in terms of anatomy, immune make up and physiological responses.  The other issue is that it is difficult to relate the doses of food emulsifiers given to animals (1% in drinking water) to the recommended intake in humans.  There is also no indication on whether the emulsifiers used in this study are food-grade and of the same structures as the ones in food (as far as I can see).

“I have no issue with the description of the press release, apart perhaps the title ‘Training the gut’s immune system to combat detrimental effects of emulsifiers in processed food’ which may imply to the reader that detrimental effects of emulsifiers in processed food has been demonstrated in humans while many questions remain (as mentioned above).”

References:

Sellem L, Srour B, Javaux G, Chazelas E, Chassaing B, Viennois E, Debras C, Salamé C, Druesne-Pecollo N, Esseddik Y, de Edelenyi FS, Agaësse C, De Sa A, Lutchia R, Louveau E, Huybrechts I, Pierre F, Coumoul X, Fezeu LK, Julia C, Kesse-Guyot E, Allès B, Galan P, Hercberg S, Deschasaux-Tanguy M, Touvier M. Food additive emulsifiers and risk of cardiovascular disease in the NutriNet-Santé cohort: prospective cohort study. BMJ. 2023 Sep 6;382:e076058. doi: 10.1136/bmj-2023-076058. PMID: 37673430; PMCID: PMC10480690.

Bancil AS, Sandall AM, Rossi M, Chassaing B, Lindsay JO, Whelan K. Food Additive Emulsifiers and Their Impact on Gut Microbiome, Permeability, and Inflammation: Mechanistic Insights in Inflammatory Bowel Disease. J Crohns Colitis. 2021 Jun 22;15(6):1068-1079. doi: 10.1093/ecco-jcc/jjaa254. PMID: 33336247.

Tran HQ, Ley RE, Gewirtz AT, Chassaing B. Flagellin-elicited adaptive immunity suppresses flagellated microbiota and vaccinates against chronic inflammatory diseases. Nat Commun. 2019 Dec 11;10(1):5650. doi: 10.1038/s41467-019-13538-y. PMID: 31827095; PMCID: PMC6906489.

Prof Gunter Kuhnle, Professor of Nutrition and Food Science, University of Reading, said:

“This study – and the press release – is based on the assumption that emulsifiers as consumed in our diet have damage our health.  However, there are no data that support this statement and all risk assessments have shown them to be safe.  A key limitation of claims that emulsifiers damage the gut microbiome is that most studies were conducted in animals and their intestinal ecosystem is very different from that of humans; for example, mice consume their own faeces and have a very different gut anatomy.  Moreover, most changes in the diet – for example increasing fibre intake – can change the composition of the microbiome, but this cannot easily be translated into health effects in humans.

“The study itself has a number of methodological limitations that make it very difficult to translate results: first, they do not use emulsifiers used in foods but purchase them from a chemical supplier.  While the compounds might be similar, it is impossible to say whether they were food grade and of the same composition.  Second, they provided the emulsifier in drinking water – whereas in food, emulsifier would normally be embedded in a food matrix and therefore exposure to the microbiome would be very different.

“In food for humans, emulsifier use is regulated, although for some foods, there is no upper limit (‘quantum satis’ – as much as needed).  For polysorbate 80, the maximum permitted use (except for food supplements) is 10,000 mg/kg (1% – as used in the study) for certain spreads like margarines, but for most foods it is 0.5% (plant-based drinks, or sauces) or 0.1%, which is much lower than the amount used in the study.  This is different for carboxy-methylcellulose, which can be used in higher amounts (‘quantum satis’) in most foods.  As a type of cellulose, CMC acts very similar to fibre and can be fermented by the microbiome or excreted.

“It is important to investigate the effect of additives on health, and regulators are looking at new data all the time.  However, it is also important to understand the limitations of animal models and non-regulatory studies and ensure that consumers are aware of these limitations.”

Dr Duane Mellor, Registered Dietitian and Senior Lecturer, Aston Medical School, Aston University, said:

“Although this is interesting research, we must be very careful not to stretch the conclusions too far and get ahead of the research data.  This study investigated the effects of a vaccine in mice to see if it reduced inflammation which has been linked to two specific emulsifiers which were given to the animals in their water.  The suggestion that training the immune system with an immunisation against a bacterial protein could reduce the risk of developing type 2 diabetes or inflammatory bowel disease which may be linked to emulsifiers goes way beyond the findings of this study.

“This study only looked at methyl cellulose and polysorbate 80 which are two chemically produced emulsifier used in food production, which in this study were not part of a food, but were simply added to the animals water.  This is important as some emulsifiers naturally occur in foods, such as lecithin found in egg yolks which is used in the kitchen to make mayonnaise – lecithin has not been linked to any health problems and may actually be beneficial as is a source of choline which can is part of the membrane of every cell in our bodies.  So, it is important to note that not all emulsifiers have been associated with health problems, only these two – with the current evidence being largely from mice studies.  Secondly, it is vital to acknowledge that this is not a vaccine against ultra-processed foods – it is an experiment in mice.  And finally the inflammation linked to risk of disease has only partly been seen in animals and does not provide clear evidence of a risk of developing disease in humans.”

‘Vaccination against microbiota motility protects mice from the detrimental impact of dietary emulsifier consumption’ by Melissa C. Kordahi et al. was published in PLOS Biology at 19:00 UK time on Tuesday 19 September 2023.

DOI: 10.1371/journal.pbio.3002289

Declared interests

Prof Nathalie Juge: “No interests to declare.”

Prof Gunter Kuhnle: “Member of EFSA panel that assessed CMC.  Member of the COT (Committee on Toxicity).”

Dr Duane Mellor: “No conflicts of interest.”