Kudos
Kunnskapsdokumenter i offentlig sektor

Kunnskapsoppsummering

Scoping review of research on gastrointestinal effects of selected emulsifiers, stabilisers, and thickeners

This scoping review was commissioned by the Norwegian Food Safety Authority. The aim was to map the scientific literature investigating effects on the gastrointestinal (GI) tract after intake of emulsifiers, stabilisers, and thickeners (ESTs). The background for the assignment was that certain published studies indicated that the ESTs carrageenan and sodium carboxymethyl cellulose may have negative effects on the GI tract. Eight ESTs are included in this scoping review: carrageenan (E 407) and sodium carboxymethyl cellulose (E 466), and six ESTs that may be used as their substitutes, namely sodium alginate (E 401), agar (E 406), processed Eucheuma seaweed (E 407a), guar gum (E 412), xanthan gum (E 415), and gellan gum (E 418). Comprehensive literature searches were performed to map the scientific literature investigating GI tract effects after intake of the included ESTs. The eligibility criteria used for the study selection were included in the previously published protocol (VKM, 2023), and are as follows: • Population: Humans, other mammals, as well as ex vivo GI tract model systems. • Exposure: Oral intake of the included ESTs. The substances tested must fulfill the criteria for being used as food additives. • Comparison: Placebo, no treatment, or dose comparison. • Outcomes: Any GI tract effect. • Study design: Controlled human studies, controlled animal studies, ex vivo GI tract model studies, and systematic reviews. • Language: English, Norwegian, Danish, and Swedish. There were no restrictions on publication year or country. Fourteen studies of which one was a study on humans and 13 were studies on animals, fulfilled the eligibility criteria. The studies were conducted between 1977 and 2022. VKM evaluated whether the design and conduct of the included studies prevented bias (systematic errors), as bias may cause misleading results and wrong conclusions. Ten of the included studies had high risk of bias and none had low risk of bias. An additional 214 studies fulfilled all eligibility criteria except the criterion that the substance tested must be in accordance with the regulations for food additives in the EU and Norway. Whenever the same name was used for similar substances having different chemical and biological properties, only the substance(s) approved for use as food additive was included in this scoping review. This applies to e.g. carrageenan, for which the size of the molecule is among the properties contributing to adverse effects caused by the substance. Low molecular weight (weight average of 20–40 kDa) carrageenan, also called degraded carrageenan, may cause e.g. cancer in animals (EFSA et al., 2018c). The degraded carrageenan is not approved as a food additive according to EU regulations. The regulations specify a limitation of no more than 5% of the carrageenan having a molecular weight below 50 kDa. In contrast, no such molecular weight limitation is set for carrageenan in specifications defined by the Joint Scoping review of research on gastrointestinal effects of selected emulsifiers, stabilisers, and thickeners FAO/WHO Expert Committee on Food Additives (JECFA). This lack of specification may explain why the molecular weight of carrageenan often is omitted in reports of toxicological studies performed outside Europe. Nevertheless, in the EU, information about molecular weight of carrageenan tested in studies is crucial for evaluating its use as a food additive (EFSA et al., 2018c). In the 214 studies mentioned above, the substance being tested was not described well enough, and it was unknown whether it was approved as an additive. None of the included studies investigated GI tract effects of sodium alginate (E 401) or gellan gum (E 418). GI tract effects were investigated in one animal study of agar (E 406) and Eucheuma seaweed (E 407a), in one human and one animal study of xanthan gum (E 415), two animal studies of sodium carboxymethyl cellulose (E 466), in four animal studies of guar gum (E 412), and in seven animal studies of carrageenan (E 407). The outcomes addressed in the included studies were as follows (number of studies in parentheses): • Changes in the gut microbiota composition and/or the microbiota numbers (5). • Enzymatic activity (microbial or colonic mucosa; 6). • Faecal or caecal content, weight, colour, consistency, and/or viscosity (8). • Gastric transit time and stool frequency (1). • Inflammation (colon or markers measured in faeces; 4). • Intestinal permeability (markers measured in serum; 2). • Intestinal utilisation and fermentation of nutrients (3). • Macroscopic changes (stomach, small intestine and/or large intestine; 2). • Microscopic changes (stomach, small intestine and/or large intestine; 10). • Mucosal weight and/or protein content (colon; 2). • Presence of mucus or blood in the faeces (1). • Tumour development (small intestine and/or colon; 2). • Weight and/or length (stomach, small intestine and/or large intestine; 6). The number of studies addressing GI tract effects of substitution ESTs for carrageenan was limited, and none of these substances were included in the studies addressing gut inflammation or gut permeability. The outcomes were distributed between studies and substances as follows: • Inflammation (colon or markers measured in the faeces) was investigated in four animal studies of which two were on carrageenan and two on sodium carboxymethyl cellulose. • Intestinal permeability was investigated in two animal studies of which one was on carrageenan and one on sodium carboxymethyl cellulose. • Changes in the gut microbiota composition and/or the microbiota numbers (i.e. the number of bacteria, virus, etc.) were investigated in five animal studies of which one each was on agar, carrageenan, and guar gum, and two were on sodium carboxymethyl cellulose. Chronic exposures were not addressed in the included studies. Five out of the six animal studies on gut inflammation and gut permeability, as well as all five studies on Scoping review of research on gastrointestinal effects of selected emulsifiers, stabilisers, and thickeners microbiota composition and/or numbers, had a high risk of bias. Rodents such as mice and rats are commonly used to study negative health effects in humans. Although the GI tract in rodents and humans are mostly similar, rodents have a forestomach that is absent in humans. Adverse health effects such as inflammation is known to be affected by the microbiome. The microbiome in rodents and humans share only 4% of the genes, indicating that the microbiome is different in rodents and humans and that rodents are not an appropriate model to study inflammation and microbiome changes in humans (Hugenholtz and de Vos, 2018; Ward et al., 2020). Conclusion GI tract effects of ESTs were addressed in 14 eligible studies. GI tract effects were not investigated for two of the ESTs included in the scoping review. GI tract effects were investigated in studies of agar (E 406), sodium alginate (E 401), carrageenan (E 407), processed Eucheuma seaweed (E 407a), sodium carboxymethyl cellulose (E 466), gellan gum (E 418), guar gum (E 412), and xanthan gum (E 415). None of the studies addressed chronic exposures. Animal models were used in 13 of the included studies, and the risk of bias was high in ten studies. Thus, the available research literature on GI tract effects, according to our inclusion criteria, is limited in quantity and has limited relevance for long-term exposure in humans and is encumbered with high risk of bias. These weaknesses limit the use of the results of the scoping review in a future risk assessment.