Is Colonic Propionate Delivery a Novel Solution to Improve Metabolism and Inflammation in Overweight Or Obese Subjects?

Commentary

in IgG levels in IPE-treated subjects versus Is colonic propionate delivery a novel those receiving cellulose supplementation. This interesting discovery is the Gut: first published as 10.1136/gutjnl-2019-318776 on 26 April 2019. Downloaded from solution to improve metabolism and first evidence in humans that promoting the delivery of propionate in the colon inflammation in overweight or may affect adaptive immunity. It is worth noting that previous preclinical and clin- obese subjects? ical data have shown that supplementation with inulin-type fructans was associated 1,2 with a lower inflammatory tone and a Patrice D Cani reinforcement of the gut barrier.7 8 Never- theless, it remains unknown if these effects Increased intake of dietary fibre has been was the lack of evidence that the observed are directly linked with the production of linked to beneficial impacts on health for effects were due to the presence of inulin propionate, changes in the proportion of decades. Strikingly, the exact mechanisms itself on IPE or the delivery of propionate the overall levels of SCFAs, or the pres- of action are not yet fully understood. into the colon. ence of any other bacterial metabolites. Among the different families of fibres, In GUT, Chambers and colleagues Alongside the changes in the levels prebiotics have gained attention mainly addressed this gap of knowledge and of SCFAs, plasma metabolome analysis because of their capacity to selectively expanded on their previous findings.6 For revealed that each of the supplementa- modulate the gut microbiota composition 42 days, they investigated the impact of tion periods was correlated with different 1 and promote health benefits. Prebiotics dietary supplementation with either 20 g/ profiles and that specific metabolites were are fermented by gut bacteria into short- day IPE versus inulin as a positive control positively or negatively associated with chain fatty acids (SCFA) such as acetate, and used a low-fermentable fibre cellulose fasting insulin according to the dietary butyrate and propionate, but multiple as a negative control. In this randomised treatment (eg, tyrosine, glutamine, N-acetyl other metabolites have also been cross-over trial performed in adults with glycoproteins). However, whether these 2 described. SCFAs have been connected overweight and obesity, the authors found metabolites are causally linked with the regulation of glucose homeostasis remains with different physiological processes that both IPE and inulin similarly improved to be demonstrated. Interestingly, Koh et al including the regulation of glucose and insulin sensitivity compared with the recently described a precise mechanism by lipid metabolism but also energy, immu- low-fermentable fibre control cellulose. which a specific microbial metabolite called nity and inflammation. Therefore, the gut This observation is of great importance imidazole propionate, which is derived microbiota has been suggested as a poten- and strongly suggests that inulin fermen- from an amino acid (ie, histidine) other tial target to mitigate cardiometabolic tation per se is sufficient to improve than those observed in the present study, disorders associated with obesity (for glucose homeostasis without the require- review, see ref 3). could contribute to the onset of insulin ment of targeted propionate delivery in 9 resistance. Indeed, the authors found that http://gut.bmj.com/ Among the different SCFAs, propionate the colon using IPE. Another interesting imidazole propionate directly contributes has attracted the most attention because of finding is that the apparent improvement to the development of insulin resistance and its capacity to bind to specific receptors and in glucose metabolism was independent of trigger the secretion of gut peptides such diabetes by blocking the insulin receptor any significant differences in body weight, 9 signalling pathway. Of note, this metabo- as glucagon-like peptide-1 and peptide food intake or GI side effects compared YY which are involved in the regulation lite was apparently not affected in the study with the low-fermentable fibre cellulose. of appetite and glucose metabolism.3 In by Chambers and colleagues.

This finding also strongly suggests that the on October 2, 2021 by guest. Protected copyright. addition, propionate has been found to In conclusion, beyond the interesting fermentation of fibres (ie, inulin or IPE) enhance the development of regulatory T finding that IPE was not superior to and their metabolites can contribute to cells and to reduce the expansion of classical inulin fibre for the improve- the beneficial effects observed on glucose proinflammatory Th17 cells.4 Therefore, ment of insulin sensitivity, there were metabolism. increasing the endogenous production of specific effects on both the gut micro- However, despite showing a similar propionate or its delivery in the colon is biota composition and immune factor impact on metabolism, inulin and IPE an attractive solution to improve meta- modulation. This is an attractive finding, differentially affected the gut microbiota bolic disorders. although none of the data or any of the composition and immune parameters. Pioneering work by Chambers and correlations with metabolites or bacteria Indeed, in their study, Chambers et al colleagues has shown that inulin-propio- indicated any specific novel mechanistic discovered that IPE supplementation was nate ester (IPE) can target the delivery of insights. Nevertheless, this very inter- propionate to the colon and ameliorate accompanied by a reduction in circulating esting paper is one of the first in the field body weight gain, glycaemia and the accu- interleukin (IL)-8, a proinflammatory to appropriately compare the impact of mulation of abdominal fat.5 However, one chemokine. By using in vitro analysis, they two fermentable fibres (ie, inulin or IPE) of the major caveats in this seminal study demonstrated the proof of concept that versus a less fermentable fibre (cellu- propionate can directly reduce the secre- lose). In addition, as discussed earlier 1Louvain Drug Research Institute, Université catholique tion of IL-8 by peripheral blood mononu- in this commentary, the researchers de Louvain (UCLouvain), Brussels, Belgium 2 clear cells isolated from healthy humans. provide a range of data and clearly Walloon Excellence in Life Sciences and BIOtechnology Although this set of data is interesting, it (WELBIO), Brussels, Belgium show that targeting the microbiota by is difficult to ascertain whether a similar using prebiotics offers the ability to Correspondence to Professor Patrice D Cani, Louvain propionate-dependent mechanism also induce many metabolic improvements, Drug Research Institute, Universite catholique de Louvain (UCLouvain), Brussels 1200, Belgium; occurs in vivo in humans. The authors including changes at the level of immu- patrice. cani@uclouvain. be also found a small but significant increase nity. However, evidence that metabolites

Cani PD. Gut Month 2019 Vol 0 No 0 1 Commentary and a bacterial IPE signature are linked different terms, provided the original work is properly 2 Louis P, Flint HJ. Formation of propionate and butyrate with the observed metabolic and immune cited, appropriate credit is given, any changes made by the human colonic microbiota. Environ Microbiol 2017;19:29–41. effects remains lacking. indicated, and the use is non-commercial. See: http:// creativecommons.org/ licenses/by- nc/4. 0/. 3 Cani PD, Van Hul M, Lefort C, et al. Microbial regulation Gut: first published as 10.1136/gutjnl-2019-318776 on 26 April 2019. Downloaded from of organismal energy homeostasis. Nat Metab Contributors PDC has written the commentary. © Author(s) (or their employer(s)) 2019. Re-use 2019;1:34–46. permitted under CC BY-NC. No commercial re-use. See Funding PDC is a senior research associate at FRS- 4 Arpaia N, Campbell C, Fan X, et al. Metabolites rights and permissions. Published by BMJ. FNRS (Fonds de la Recherche Scientifique), recipient produced by commensal bacteria promote peripheral of grants from FNRS (FRFS-WELBIO-WELBIO-CR- regulatory T-cell generation. Nature 2013;504:451–5. 2017C-02), The Excellence Of Science (EOS-30770923) 5 Chambers ES, Viardot A, Psichas A, et al. Effects of and the Funds Baillet Latour (Grant for Medical targeted delivery of propionate to the human colon Research 2015), SPW-DGO6 (NUTRIMICROBIOTA To cite Cani PD. Gut Epub ahead of print: [please on appetite regulation, body weight maintenance and C-7906). include Day Month Year]. doi:10.1136/ adiposity in overweight adults. Gut 2015;64:1744–54. gutjnl-2019-318776 Competing interests PDC is an inventor on patent 6 Chambers ES, Byrne CS, Morrison DJ, et al. Dietary applications dealing with the use of A. muciniphila and Received 25 March 2019 supplementation with inulin-propionate ester or inulin its components for the treatment of obesity and related Revised 15 April 2019 improves insulin sensitivity in adults with overweight disorders. PDC is a co-founder of A-Mansia Biotech. Accepted 17 April 2019 and obesity with distinct effects on the gut microbiota, plasma metabolome and systemic inflammatory Patient consent for publication Not required. responses: a randomised cross-over trial. Gut 2019. doi: Provenance and peer review Commissioned; 10.1136/gutjnl-2019-318424. [Epub ahead of print 10 internally peer reviewed. Apr 2019]. 7 Cani PD, Possemiers S, Van de Wiele T, et al. ►► http://dx. doi. org/ 10. 1136/ gutjnl- 2019- 318424 Changes in gut microbiota control inflammation Gut 2019;0:1–2. in obese mice through a mechanism involving doi:10.1136/gutjnl-2019-318776 GLP-2-driven improvement of gut permeability. Gut 2009;58:1091–103. 8 Dewulf EM, Cani PD, Claus SP, et al. Insight into the References prebiotic concept: lessons from an exploratory, double Open access This is an open access article distributed 1 Gibson GR, Hutkins R, Sanders ME, et al. Expert blind intervention study with inulin-type fructans in in accordance with the Creative Commons Attribution consensus document: the International Scientific obese women. Gut 2013;62:1112–21. Non Commercial (CC BY-NC 4.0) license, which permits Association for Probiotics and Prebiotics (ISAPP) 9 Koh A, Molinaro A, Ståhlman M, et al. Microbially others to distribute, remix, adapt, build upon this work consensus statement on the definition and scope produced imidazole propionate impairs insulin signaling non-commercially, and license their derivative works on of prebiotics. Nat Rev Gastroenterol Hepatol through mTORC1. Cell 2018;175:947–61. 2017;14:491–502. http://gut.bmj.com/ on October 2, 2021 by guest. Protected copyright.

2 Cani PD. Gut Month 2019 Vol 0 No 0