RESEARCH & PRACTICE edited by ESNM

GUT MICROBIOTA & SHORT CHAIN FATTY ACIDS A selection of content from the Gut Microbiota for Health 2016

March 2017

www.gutmicrobiotaforhealth.com TABLE OF CONTENT

EDITORIAL 3 SELECTED CONTENT FROM GUTMICROBIOTAFORHEALTH.COM

• Dietary fibre/short-chain fatty acids and vitamin A may protect mice against peanut allergy via gut microbiota 6

• Fitness may predict a diverse gut microbiota in healthy people 8

• An update on the link between short-chain fatty acids, diet, and human health 10

• The role of gut microbiota composition and microbial metabolites in fat partitioning and metabolism in youth 12

• The role of short-chain fatty acids in driving : Should we blame acetate? 14

• Conserving and restoring the human gut microbiome by increasing consumption of dietary fibre 16

• Mice study shows low-fibre diet may decimate gut diversity over generations 18

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In searching for the molecular SCFAs (in particular, butyrate) mechanisms connecting dietary regulate the AP-1 signaling path- fibre to positive gastrointestinal way (Nepelska et al., 2012). and metabolic effects and lower body weight (Slavin, 2013), Butyrate indeed stands out as an research in the past several important SCFA for regulating decades has centred around a gene expression in the intestine. group of molecules called short- Our group previously found that chain fatty acids (SCFAs), which MUC gene expression and mucin are produced by bacteria when secretion were regulated by they ferment non-digestible carbo- butyrate: its effects on different hydrates. As a young cell biologist MUC genes could influence the recruited to the French National characteristics of mucus gel and, Institute for Agriculture and Food thus, its protective ability. Further, Research (INRA) in the early nine- we discovered that this upregula- ties to study how dietary fibre tion of colonic mucins was impacts human health, I rapidly enhanced when butyrate was the focused my research on these major energy source of the colono- SCFAs, especially on butyrate. The cytes (Gaudier et al., 2004). study of these molecules has revealed local, intermediary, and SCFAs have further effects in the peripheral effects on host tissues, intestine: they also appear to showing how they may influence influence gastrointestinal motility different aspects of host health (Cherbut et al., 1997) in a com- through complex mechanisms. plex manner that has been noted in humans and investigated in Effects in many animal models.

The main role of SCFAs is as an Effects on energy metabolism energy source for host colono- cytes through β-oxidation. SCFAs SCFAs provide around 10% of regulate cell proliferation through daily energy for a human host but the release of growth factors or their role in metabolism is not fully gastrointestinal peptides (e.g. understood. These molecules gastrin), or through modulation of appear to have beneficial effects mucosal blood flow (Blottiere et on host energy metabolism, al., 2003). SCFAs are also known to including a role in reducing influence genes that regulate cell plasma concentrations of free proliferation and cell cycle fatty acids (Ge et al., 2008) and (Siavoshian et al., 2000). For (Fushimi et al., 2006), example, the transcription factor and/or decreasing plasma glucose AP-1 (activator protein-1) is impli- levels (Sakakibara et al., 2006). cated in cellular proliferation, Work from our laboratory in transformation and death—and in collaboration with the Karolinska 2012 our group demonstrated that Institute in Stockholm had to do

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with ANGPTL4 (angiopoietin-like regulatory T cells has been perhaps by altering the intestinal 4), a metabolism-altering protein revealed (Furusawa et al., 2015). environment or by modulating the produced by human intestinal Through their known activation of local immune system in a way that epithelial cells. In an experiment G protein-coupled receptors and reduces cancer risk (Keku et al., with germ-free mice, we found that their influences on the activity of 2015). In the years ahead, more butyrate induced intestinal particular enzymes (namely research is needed on dietary fibre ANGPTL4 gene expression; this lysine/histone deacetylase) and and SCFAs as they relate to CRC occurred with direct oral adminis- transcription factors, SCFAs influ- risk. tration of butyrate, or with coloni- ence the development, survival, zation with the SCFA-producing and function of intestinal epithelial Conclusions bacteria Clostridium tyrobutyricum cells and leukocytes (Corrêa- (Korecka et al., 2013). The molecu- Oliveira et al., 2016). Very recent SCFAs are emerging as important lar mechanisms of how SCFAs work showed that dietary fibre and molecules for host health. SCFA regulate metabolism, however, are SCFAs induced expression of the production is influenced by food not fully understood, and despite RALDH1 enzyme (a vitamin A intake and diet-induced changes in the observation that SCFAs may converting enzyme) in intestinal the gut microbiota (Ríos-Covián et ultimately protect against obesity, epithelial cells, and that the al., 2016), leading some to hypoth- they also provide calories that RALDH1 expression levels in small esize that SCFAs constitute a key could contribute to obesity intestinal epithelial cells correlated link between diet, microbiome, and (Morrison & Preston, 2016). with a number of immune cell health. There is still much to learn changes: altered dendritic cell about the extent of SCFAs’ effects Effects on immune system activity, increased regulatory T on the human body, and probably cells, and higher luminal IgA even the brain. By combining In the late nineties, we and others production (Goverse et al., 2017). mechanistic research with well- reported that SCFAs, especially designed clinical studies we will butyrate, display anti- Effects on cancer advance knowledge of human inflammatory effects with poten- SCFA production, uptake, and tial applications to inflammatory Several links exist between SCFAs excretion, and the pathways by bowel disease (Segain et al., and cancer—in particular, colorec- which these affect overall health. 2000). More recently, their role in tal cancer (CRC). SCFAs may play the generation of differentiation of a role in protection against CRC,

Dr. Hervé M. Blottière Dr. Hervé M. Blottière is Director of Research at MICALIS Institute, in the French National Institute for Agricultural Research (INRA). He is also Scientific Director at MetagenoPolis. A tumor immunologist by training, his activities include a broad range of research projects related to digestive tract physiology. He developed, together with Joël Doré, a functional metagenomics approach for studying host-microbiota cross-talk, and also set up the robotic platform METAFUN for high throughput screenings.

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References

Blottiere, H.M. et al., 2003. Molecular Ge, H. et al., 2008. Activation of G AP-1 Response in Human Intestinal analysis of the effect of short-chain Protein-Coupled Receptor 43 in Epithelial Cells F. Blachier, ed. PLoS fatty acids on intestinal cell Adipocytes Leads to Inhibition of ONE, 7(12), p.e52869. Available at: proliferation. Proceedings of the Lipolysis and Suppression of Plasma http://www.ncbi.nlm.nih.gov/pubmed/ Nutrition Society, 62(1), pp.101–106. Free Fatty Acids. Endocrinology, 23300800 [Accessed February 9, Available at: 149(9), pp.4519–4526. Available at: 2017]. http://www.journals.cambridge.org/abs http://www.ncbi.nlm.nih.gov/pubmed/1 tract_S002966510300017X [Accessed 8499755 [Accessed February 13, 2017]. Ríos-Covián, D. et al., 2016. Intestinal February 10, 2017]. Short Chain Fatty Acids and their Link Goverse, G. et al., 2017. Diet-Derived with Diet and Human Health. Frontiers Cherbut, C. et al., 1997. Effects of Short Chain Fatty Acids Stimulate in microbiology, 7, p.185. Available at: Short-Chain Fatty Acids on Intestinal Epithelial Cells To Induce http://www.ncbi.nlm.nih.gov/pubmed/ Gastrointestinal Motility. Scandinavian Mucosal Tolerogenic Dendritic Cells. 26925050 [Accessed February 12, Journal of Gastroenterology, The Journal of Immunology. 2017]. 32(sup222), pp.58–61. Available at: http://www.ncbi.nlm.nih.gov/pubmed/ Keku, T.O. et al., 2015. The Sakakibara, S. et al., 2006. Acetic acid 9145449 [Accessed February 12, 2017]. gastrointestinal microbiota and activates hepatic AMPK and reduces . American journal of hyperglycemia in diabetic KK-A(y) Corrêa-Oliveira, R. et al., 2016. physiology. Gastrointestinal and liver mice. Biochemical and Biophysical Regulation of immune cell function by physiology, 308(5), pp.G351-63. Research Communications, 344(2), short-chain fatty acids. Clinical & Available at: pp.597–604. translational immunology, 5(4), p.e73. http://www.ncbi.nlm.nih.gov/pubmed/ Available at: 25540232 [Accessed February 13, Segain JP, et al., 2000. Butyrate http://www.ncbi.nlm.nih.gov/pubmed/2 2017]. inhibits inflammatory responses 7195116 [Accessed February 10, 2017]. through NF-κB inhibition: implications Korecka, A. et al., 2013. ANGPTL4 for Crohn’s disease. Gut, 47:397-403. Furusawa Y, Obata Y, Hase K. (2015). expression induced by butyrate and Commensal microbiota regulates T rosiglitazone in human intestinal Siavoshian S, et al., 2000. Butyrate cell fate decision in the gut. Semin epithelial cells utilizes independent and trichostatin A effects on the Immunopathol. 37(1):17-25. doi: pathways. AJP: Gastrointestinal and proliferation/ differentiation of 10.1007/s00281-014-0455-3. Liver Physiology, 304(11), human intestinal epithelial cells: pp.G1025–G1037. Available at: induction of cyclin D3 and p21 Fushimi, T. et al., 2006. Dietary acetic http://www.ncbi.nlm.nih.gov/pubmed/ expression. Gut, 46:507-514. acid reduces serum cholesterol and 23518684 [Accessed February 9, triacylglycerols in rats fed a 2017]. Slavin, J., 2013. Fiber and prebiotics: cholesterol-rich diet. The British mechanisms and health benefits. journal of nutrition, 95(5), pp.916–24. Morrison, D.J. & Preston, T., 2016. , 5(4), pp.1417–35. Available Available at: Formation of short chain fatty acids at: http://www.ncbi.nlm.nih.gov/pubmed/1 by the gut microbiota and their http://www.ncbi.nlm.nih.gov/pubmed/ 6611381 [Accessed February 13, 2017]. impact on human metabolism. Gut 23609775 [Accessed February 13, microbes, 7(3), pp.189–200. Available 2017]. Gaudier, E. et al., 2004. Butyrate at: specifically modulates MUC gene http://www.ncbi.nlm.nih.gov/pubmed/ expression in intestinal epithelial 26963409 [Accessed February 12, goblet cells deprived of glucose. AJP: 2017]. Gastrointestinal and Liver Physiology, 287(6), pp.G1168–G1174. Available at: Nepelska, M. et al., 2012. Butyrate http://www.ncbi.nlm.nih.gov/pubmed/1 Produced by Commensal Bacteria 5308471 [Accessed February 9, 2017]. Potentiates Phorbol Esters Induced

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Dietary fibre/short-chain fatty acids and vitamin A may protect mice against peanut allergy via gut microbiota

ALLERGIES, FOOD & INTOLERANCES, GUT MICROBIOTA, RESEARCH & PRACTICE Published on September 21, 2016 by Andreu Prados

The incidence of food allergies has increased dramatically in Western countries over the past 20 years and the gut microbiota seems to be a promising target for preventing and treating them. However, mechanisms by which gut microbiota is involved in the loss of oral tolerance remain unclear.

A recent study, led by Dr. Charles Mackay from the Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology at Monash University in Clayton (Australia), has found that the development of food allergies in mice could be linked to dietary elements Andreu Prados holds a including fibre and vitamin A. Bachelor of Science Degree in Pharmacy & The researchers examined the ance involving multiple challenges Human Nutrition and beneficial roles of dietary fibre in with peanut extract. Antigen- Dietetics. Science writer peanut allergy using mice. Mice challenged high-fibre-diet-fed mice specialised in gut micro- were fed on diets either depleted or contained a greater proportion of biota and probiotics, enriched in fibre for at least 2 CD103+ DC and Treg cells in the working also as lecturer weeks. High-fibre feeding enhanced MLN 3 days after tolerance induc- and consultant in nutri- the activity of mucosal CD103+ tion. Besides this, total cell numbers tion and healthcare. dendritic cells (DCs), which are the in the MLN of high-fibre-fed mice main regulators of immune tole- were also significantly lower, which rance through promoting the diffe- indicates a reduced inflammatory rentiation of naïve T cells into regu- response. latory T (Treg) cells in the mesen- teric lymph nodes (MLN). The fibre Zero-fibre- and high-fibre-diet-fed achieved this effect by upregulating mice had an induced food allergy in retinoic acid-synthesizing (RALDH) an experimental model of peanut enzyme activity and enhancing allergy. Protection from food allergy antigen-specific Treg cell under the high-fibre diet was asso- responses. ciated with reduced clinical symp- toms of anaphylaxis on day To study the effects of dietary fibre 28-which correlated with lower on oral tolerance in vivo, zero-fibre- levels of serum immunoglobulin E and high-fibre-diet-fed mice were (IgE)-and an increased proportion subjected to a model of oral toler- of both CD103+ DCs and Treg cells

Zero-fibre- and high-fibre-diet-fed mice had an induced food allergy in an experimental model of peanut allergy.

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Dietary fibre/short-chain fatty acids and vitamin A may protect mice against peanut allergy via gut microbiota in the MLN (correlated with lower tigated whether short-chain fatty total cell numbers in the MLN). acids (SCFAs), the end products of Other improved features observed fermentation of dietary fibres by in high-fibre-diet-fed mice were the anaerobic intestinal microbiota, decreased production of T helper could mediate the beneficial effects (Th)-2 cytokines IL-4, IL-5, and IL-13 of dietary fibre in the experimental from lymphocytes from the MLN model of food allergy. Mice were and preserved gut epithelial perme- fed with acetate, butyrate, or pro- ability. High-fibre-mediated protec- pionate for 3 weeks prior to initial tion against food allergy relied on sensitization and throughout the vitamin A metabolism and took experiment. Mice fed with acetate place via promoting immunoglobu- and butyrate showed a reduction in lin A (IgA) and T follicular helper anaphylaxis clinical scores and total and mucosal germinal centre serum IgE levels, which correlated CREDIT: TAN ET AL./CELL REP 2016 responses. Altogether, these results with the induction of CD103+ DCs suggest that high-fibre feeding may and Treg cell responses and a lower enhance oral tolerance and protect total cell numbers in the MLN. How- To sum up, dietary fibre/SCFAs mice against peanut allergy. ever, SCFAs did not protect mice together with vitamin A and a against food allergy in the absence healthy gut microbiota play key In order to study the role of gut of a gut microbiota. Besides SCFAs, roles in protecting mice against microbiota composition in the another pathway by which gut peanut allergy. According to the protective role of high-fibre feeding microbiota can protect against researchers: “These findings in food allergy, germ-free mice food allergy involves commensal support the notion that diets inoculated with zero-fibre or high- bacteria-induced MyD88 signalling. deficient in fibre, typical of many fibre microbiota had a food allergy The authors also found that the Western countries, could underlie induced. Mice reconstituted with beneficial effect of dietary fibre in the rise of food allergies in recent high-fibre microbiota had signifi- mouse peanut allergy involved decades”. cantly better clinical anaphylaxis activity of SCFA receptors GPR43 scores and a greater proportion of and GPR109a, by influencing Treg cells compared to mice recon- CD103+ DC responses and gut stituted with zero-fibre microbiota. epithelial integrity. Furthermore, the researchers inves-

Dietary fibre/SCFAs together with vitamin A and a healthy gut microbiota play key roles in protecting mice against peanut allergy.

References: Tan J, McKenzie C, Vuillermin PJ, et al., and bacterial SCFA enhance oral tolerance and protect against food allergy through diverse cellular pathways. Cell Rep. 2016; 15(12):2809-24. doi: 10.1016/j.celrep.2016.05.047.

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GUT MICROBIOTA RESEARCH & PRACTICE edited by ESNM 7 SELECTED CONTENT Fitness may predict a diverse gut microbiota in healthy people

GUT MICROBIOTA, MOOD & WELLBEING, RESEARCH & PRACTICE Published on September 14, 2016 by Andreu Prados

It has been previously found that exercise may play an important role in the overall health of the host by contributing to the diversity of gut micro- biota. However, extreme dietary differences, especially high protein intakes, amongst the elite athletes studied may confound interpretations about the specific role of exercise in determining gut bacterial richness. How physical fitness contributes to intestinal microbial diversity is currently not known.

A recent study, led by Dr. Deanna L. Diet was not a confounding factor Gibson from the Department of across fitness groups, as there was Biology at the University of British a lack of distinct dietary patterns Andreu Prados holds a Columbia (Canada), has found that amongst all fitness groups (low Bachelor of Science cardiorespiratory fitness is corre- fitness, n=14; average fitness, n=12 Degree in Pharmacy & lated with increased microbial and high fitness, n=13). It was Human Nutrition and diversity and increased production shown that VO2peak, an indicator Dietetics. Science writer of faecal butyrate in healthy of physical fitness, accounted for specialised in gut micro- humans. more than 20% of the variation in biota and probiotics, taxonomic richness, after accoun- working also as lecturer The researchers used high- ting for all other factors such as and consultant in nutri- throughput sequencing to analyse diet. Although VO2peak was not tion and healthcare. faecal microbiota of 39 healthy associated with specific bacterial participants with similar age, body taxa, it was correlated with distinct mass index, and diet, but with vary- microbiome functions including ing cardiorespiratory fitness (CRF) chemotaxis, motility, and fatty acid levels, as assessed by the peak biosynthesis. oxygen uptake (VO2peak). Faecal short-chain fatty acids (SCFAs) VO2peak was strongly correlated were also analysed using gas chro- with faecal butyric acid, which was matography. represented primarily across high and average fitness participants.

Diet was not a confounding factor across fitness groups, as there was a lack of distinct dietary patterns amongst all fitness groups.

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Increased butyrate levels were explained by increased abundances of key butyrate-producing taxa (Clostridiales, Roseburia, Lachno- spiraceae, and Erysipelotrichaceae) among physically fit participants.

In conclusion, CRF, independent of diet, is correlated with increased microbial diversity and production of faecal butyrate. These findings support the use of exercise as an adjuvant therapy in combating those conditions associated with reduced microbial diversity such as diabetes, colorectal cancer, and CREDIT: ESTAKI ET AL./MICROBIOME 2016 inflammatory bowel disease.

These findings support the use of exercise as an adjuvant therapy in combating those conditions associated with reduced microbial diversity.

References: Estaki M, Pither J, Baumeister P, et al., Cardiorespiratory fitness as a predictor of intestinal microbial diversity and distinct metagenomic functions. Microbiome. 2016; 4(1):42. doi: 10.1186/s40168-016-0189-7.

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GUT MICROBIOTA RESEARCH & PRACTICE edited by ESNM 9 SELECTED CONTENT An update on the link between short-chain fatty acids, diet, and human health

DIET, RESEARCH & PRACTICE, SCFA Published on March 18, 2016 by Andreu Prados

A recent review, led by Dr Nuria Salazar from the Institute of Dairy Prod- ucts of Asturias (Spain), belonging to the Spanish National Research Council, summarizes the up-to-date scientific evidence regarding the role of short-chain fatty acids (SCFAs) in host health and the impact of diet on their production.

SCFAs are the end products of butyrate- and propionate- fermentation of non-digestible producing bacteria have been (CHO) and proteins linked to inflammatory disorders, in the large intestine by the such as ulcerative colitis and Andreu Prados holds a anaerobic intestinal microbiota. asthma. Bachelor of Science Acetate, propionate and butyrate Degree in Pharmacy & represent 90-95% of the SCFAs There is a high inter-individual gut Human Nutrition and present in the colon, whereas microbiota variation, even among Dietetics. Science writer branched-chain SCFAs produced healthy individuals, both in orga- specialised in gut micro- from dietary protein that is unab- nismal composition and in meta- biota and probiotics, sorbed in the only bolic function. Diet impacts the gut working also as lecturer represent 5% of total SCFAs microbiota composition and activ- and consultant in nutri- production. Lactate is also ity and, as a result, SCFA produc- tion and healthcare. produced by some members of the tion may be affected. For instance, microbiota and is recycled into it has been found that high dietary different SCFAs in order to avoid fibre intake from fruit, vegetables, metabolic acidosis in the host. and legumes is linked to a rise in health-promoting SCFAs. Indeed, SCFAs are produced by colonic SCFA levels may be considered as microbiota through several meta- a biomarker of a healthy status. bolic pathways. Acetate is the Both epidemiological and inter- most abundant one in the colon. It vention studies carried out with is noticeable that low levels of different populations have shown

It is noticeable that low levels of butyrate- and propionate- producing bacteria have been linked to inflammatory disorders, such as ulcerative colitis and asthma.

GUT MICROBIOTA RESEARCH & PRACTICE edited by ESNM 10 SELECTED CONTENT An update on the link between short-chain fatty acids, diet, and human health that dietary components have an of colorectal cancer and to control impact on microbial composition intestinal inflammation. Butyrate and can modulate the synthesis of and propionate serve a number of SCFAs. The profile of SCFAs epigenetic functions such as synthesized and their presence in balancing histone acetylation and faecal content may one day help us deacetylation activity, which can to distinguish populations with explain in part their biological diseases such as obesity and irrita- effects. In addition, a new field of Knowing the SCFA ble bowel syndrome. Knowing the research shows that SCFAs may profile in a person might SCFA profile in a person might have a critical role in appetite regu- shed light on how shed light on how bacteria contri- lation and energy homeostasis. bacteria contribute to bute to gut microbiota dysbiosis, which perhaps could be modu- In conclusion, although it can be gut microbiota dysbiosis, lated by appropriate probiotics. hypothesized that high levels of which perhaps could be SCFAs are beneficial for host modulated by SCFAs have several effects on health, their role in the interplay appropriate probiotics. human health. They play an impor- between diet, gut, microbiota, and tant role in the maintenance of the host energy metabolism is likely gut barrier function by reducing more complex. Further studies are luminal pH and inhibiting some needed in order to elucidate the pathogenic microorganisms. Besides role of SCFAs in mammalian this, during intestinal absorption, energy metabolism and develop SCFAs (mainly butyrate) are used personalized strategies to mitigate as a source of energy by colono- disease risk through modulating cytes and bacterial communities. SCFA production. SCFAs have also been reported to protect against the development

References: Ríos-Covián D, Ruas-Madiedo P, Margolles A, Gueimonde M, de los Reyes-Gavilán CG, Salazar N. Intestinal short-chain fatty acids and their link with diet and human health. Front Microbiol. 2016. doi:10.3389/fmicb.2016.00185.

De Filippis F, Pellegrini N, Vannini L, et al. High-level adherence to a Mediterranean diet beneficially impacts the gut microbiota and associated metabolome. Gut. 2015. doi:10.1136/gutjnl-2015-309957.

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The role of gut microbiota composition and microbial metabolites in fat partitioning and carbohydrate metabolism in youth

GUT MICROBIOTA, GUT MICROBIOTA COMPOSITION, OBESITY, RESEARCH & PRACTICE, SCFA Published on November 14, 2016 by Andreu Prados

A previous study by Reijnders et al. has added to the body of research calling into question some direct and simple associations found between the gut microbiota and metabolic disorders.

Now a recent study, led by Dr. Nicola Santoro from the Department of Paediatrics at Yale University in New Haven, Connecticut (USA), has found that the gut microbiota of obese youth may drive a higher accumulation of energy than that of lean adolescents through an elevated production of short-chain fatty acids (SCFAs) and a higher capability to oxidize carbohydrates.

Andreu Prados holds a The researchers analysed the gut ratio, and the abundance of Bacte- Bachelor of Science microbiota of 84 children and roidetes and Actinobacteria, with Degree in Pharmacy & teenagers (7-20 years old; the body mass index (BMI), visceral Human Nutrition and participants included 27 youth and subcutaneous fat. These data Dietetics. Science writer who were obese, 35 who were show that children and teenagers specialised in gut micro- severely obese, 7 who were over- who are obese have different gut biota and probiotics, weight and 15 who were normal microorganisms than their lean working also as lecturer weight); in these individuals, body counterparts. and consultant in nutri- fat distribution was measured by tion and healthcare. fast-magnetic resonance imaging, In addition, plasma levels of de novo lipogenesis (DNL) was acetate, propionate, and butyrate quantitated using deuterated were associated with weight gain water, and the capability of gut (expressed as changes of microbiota to ferment carbohy- BMI/year) over a 2-year period drates (CHO) was assessed by independent of age, gender, and 13C-fructose treatment in vitro in ethnicity (84 subjects were faecal material. The participants analysed at baseline and 72 also provided blood samples and subjects were analysed at follow- kept a three-day food diary. up). Strikingly, plasma SCFA Researchers measured plasma concentrations were also linked to SCFAs but not faecal SCFAs. hepatic DNL in obese adolescents. Besides this, the rate of CHO The composition of the gut micro- fermentation from the gut micro- biota was associated with the biota was higher in obese than in degree of obesity and the distribu- lean subjects. tion across body fat depots. Specifically, researchers found a In conclusion, this study has shown significant association between for the first time that for simi- the Firmicutes to Bacteroidetes lar amounts o f die tary ene rgy,

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The role of gut microbiota composition and microbial metabolites in fat partitioning and carbohydrate metabolism in youth

in children and adolescents the turn could enhance hepatic DNL both microbial metabolites and composition of the gut microbiota causing lipid accumulation in all host metabolism. Although this is associated with increased fat the fat depots. study showed levels of plasma deposits. The gut microbiota of SCFAs were linked to obesity, obese youth may drive a higher This trial has highlighted the need other work tends to show SCFAs accumulation of energy than that for more follow-up studies to more are beneficial for health. of lean counterparts through an deeply investigate the relationship elevated production of SCFAs as between changes in gut micro- measured in the plasma, which in biota composition and activity and

CREDIT: GOFFREDO ET AL./J CLIN ENDOCRINOL METAB 2016

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The role of short-chain fatty acids in driving obesity: Should we blame acetate?

FIBERS, GUT MICROBIOTA COMPOSITION, METABOLIC CONDITIONS, OBESITY, PREBIOTICS, RESEARCH & PRACTICE, SCFA Published on August 5, 2016 by Patrice D. Cani

In a recent paper by Perry et al., researchers describe an investigation into the putative mechanisms by which gut microbiota alterations may lead to obesity, insulin resistance, and metabolic syndrome. Authors describe increased production of acetate by altered gut microbiota in rats. They link this to activation of the parasympathetic nervous system, increased glucose-stimulated insulin secretion, higher ghrelin secretion, hyperphagia, and obesity. Thus, they point to increased acetate production as a driver of metabolic syndrome.

Those in the field have known for Attributing all of the observed Professor Patrice D. Cani decades that microbes produces effects to changes in acetate, is researcher from the acetate (see here, for example) and however, is likely premature. Belgian Fund for that this acetate may contribute to Among the short-chain fatty acids Scientific Research changes in liver lipid metabolism as (SCFAs), acetate is probably the (FRS-FNRS), group well as glucose metabolism and most debated in terms of its benefi- leader in the Metabolism food intake. Thus, it is well known cial or detrimental metabolic and Nutrition research that chronically increasing acetate effects. group at the Louvain abundance can drive lipogenesis. A Drug Research Institute link between acetate and diabetes In the paper by Perry, et al., authors (LDRI) from the has been also shown in the past, did not discuss another key body of Université catholique de although it is still debated. work showing that prebiotic Louvain (UCL), Brussels, fermentation by the gut microbiota Belgium, and WELBIO The association between microbes can increase the abundance of (Walloon Excellence in and neuronal routes, in addition, SCFAs, including (in some studies) Lifesciences and has been well described: for exam- the overall pool of SCFAs. For BIOtechnology) ple, here. example, it has been shown that investigator. acetate is increased with prebiotic The key contribution of this paper fructooligosaccharides (FOS) (see by Perry et al. is the discovery that here), and that this is associated in vivo turnover of acetate is with reduced body weight and fat specifically influenced by the gut. In mass, decreased diabetes, and a addition, they used a collection of lower food intake. Another related interesting and sophisticated tools paper by Gary Frost and colleagues to demonstrate that acetate can showed that prebiotics such as directly increase glucose- inulin (C13 labeled) increased stimulated insulin release, affecting acetate that reached the brains of both the gut-brain axis and periph- rats and reduced ghrelin produc- eral sites. tion, leading to a reduction in food

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The role of short-chain fatty acids in driving obesity: Should we blame acetate?

intestine/stomach) or blood-driven mechanisms is not yet resolved.

In the Perry, et al. study, acetate probably did strongly contribute to the changes observed in the rodents, but unfortunately the authors did not put their findings into the general picture of the important literature showing that fermentation of specific dietary fibres may have an impact on SCFAs (including acetate) and on metabolism. As an ultimate exam- ple, the recent paper by De Vadder CREDIT: SCIENCEDIRECT et al. elegantly shows that, in response to dietary fibres, another intake, body weight, and fat mass abundance of acetate can be product of microbiota fermentation through mechanisms involving increased. So here it remains (succinate) can be a precursor of neuronal activity. The effects of unclear whether the observed glucose production in the gut but acetate in this context, therefore, effects are attributable to the can improve glucose homeostasis seem to be contrary to those in the acetate itself or to products of the by a mechanism depending on current study Perry and colleagues. cross-feeding. intestinal neoglucogenesis.

Another complexity not explored in A key question about these mecha- Thus, addressing the central idea of the Perry, et al. work is that the nisms is what drives the secretion the Perry, et al. paper when it microbiota rapidly transform of specific hormones. The authors comes to humans, acetate may or acetate into other SCFAs. The 10 used a protocol of acetate adminis- may not be the driver of obesity; days of intragastric infusion of tration for 10 days, and the intra- most likely, it is dependent on the SCFA probably changed both the gastric route means it would be microbiota and the dietary fibres microbiota and the overall SCFA rapidly absorbed—but this may also used (e.g. resistant starches, prebi- profile in the gut. Ratios of SCFAs change hormonal routes. Thus, the otics). Overall, it seems the story of are also important to consider: if question of whether changes in how the gut microbiota drive the ratio of acetate to propionate is secretion of specific hormones is obesity is not yet complete. changed, for example, the real due to luminal mechanisms (in the

References: Frost G, Sleeth ML, Sahuri-Arisoylu M. The short-chain fatty acid acetate reduces appetite via a central homeostatic mechanism. Nature Communications. 2014;5 doi:10.1038/ncomms4611

Perry RJ, Peng L, Barry NA. Acetate mediates a microbiome–brain–β-cell axis to promote metabolic syndrome. Nature. 2016;534(213-217). doi:10.1038/nature18309

Read the original post online at: http://www.gutmicrobiotaforhealth.com/en/role-short-chain-fatty-acids-driving-obesity-blame-acetate/

GUT MICROBIOTA RESEARCH & PRACTICE edited by ESNM 15 SELECTED CONTENT

Conserving and restoring the human gut microbiome by increasing consumption of dietary fibre

DIET, FIBERS, RESEARCH & PRACTICE Published on MAY 9, 2016 by Andreu Prados

Modern lifestyle and Western diet have led to a substantial depletion of gut microbial diversity, which is linked to many non-communicable diseases (NCDs). In a recent commentary published in Trends in Endocrinology & Metabolism by researchers from the University of Alberta (Canada), it has been argued that we need to reconsider nutritional recommendations to focus on fibre in an attempt to restore proper composition and function of the ‘disappearing’ gut microbiome.

Recent research in this area a more diverse gut microbiota, as it suggests that dietary fibre recom- prioritizes at the first level the mendations should be refigured in consumption of vegetables, fruits Andreu Prados holds a future. Although dietary fibre and legumes, which are known to Bachelor of Science intake recommendations for adults be rich sources of dietary fibre; the Degree in Pharmacy & range from 18-38 g/d (see table current Western diet is high in fat Human Nutrition and below), this seems not to be and simple carbohydrates and low Dietetics. Science writer enough to prevent NCDs. Benefi- in fibre. A second step may be fibre specialised in gut micro- cial effects of dietary fibre have supplementation of widely biota and probiotics, been broadly studied, but only in consumed foods (fortified foods) working also as lecturer recent years have researchers or even taking fibre supplements if and consultant in nutri- investigated to what extent they healthy eating habits are achieved. tion and healthcare. are mediated by changes in both composition and function of the Although revised recommenda- gut microbiota. Microbiota- tions should move in the direction accessible carbohydrates (MACs) of increased dietary fibre, there is found in plant-derived fibre are the still no consensus about the ideal primary substrates for certain gut daily amount. A recent study, led bacteria in humans. In fact, rural by Dr. Kishore Vipperla from the human communities from South Division of General Internal Medi- America and Africa have a low cine at the University of Pittsburgh prevalence of NCDs and this fact (USA), showed that moving has been related to a higher gut African Americans to a traditional microbiota diversity, driven by a South African diet with a daily market economy based on vegeta- dose of 55 g of dietary fibre- bles, fruits, wild game meat and mainly in the form of resistant fish for sustenance without inclu- starch-and reduced fat and protein ding flour-like products and improved mucosal biomarkers of processed food. This suggests that colon cancer risk within just 2 following a plant-based diet is a weeks. Together, these results nice step forward in order to keep suggest that current guidelines

GUT MICROBIOTA RESEARCH & PRACTICE edited by ESNM 16 SELECTED CONTENT

Conserving and restoring the human gut microbiome by increasing consumption of dietary fibre

has been referred as the “fibre gap”. A study in mice showed that loss of gut bacteria diversity related to low-fibre diet may be inherited and irreversible over generations. Thus, enriching the food supply with dietary fibre might have an essential role in preventing lost of certain benefi- cial bacterial species. Beyond boosting the consumption of dietary MACs, the researchers suggest reintroducing missing taxa that were lost through moderniza- tion, which can be achieved either by administering probiotics (food) CREDIT: JONES/ NUTR J 2014 or live biotherapeutics (drugs).

for the consumption of fibre rich fibre diets in the Mediterranean, In conclusion, it’s time to change foods are too low and increasing Africa and China. nutritional recommendations to the fibre recommendation to more focus on fibre, as it is the primary than 50 g/d in African Americans, Even now, dietary fibre intake in substrate for nourishing gut micro- and perhaps in all populations most countries around the world is bial communities. Concomitantly, consuming a Western diet, is likely far below recommended levels. people should be encouraged to to have an immediate effect on The gap between dietary fibre consume quantities of fibre that colon cancer risk. This level of recommendations and intakes is so more closely match the recom- fermentable fibre intake in human extreme in Western countries, as mendations. Enriching the food subjects correlates well with most Westerners only consume supply with dietary fibre seems a estimates of dietary fibre intake for half of the amount of dietary fibre plausible approach. ancient diets and traditional high- recommended by guidelines; this

References: Deehan EC, Walter J. The fiber gap and the disappearing gut microbiome: Implications for human nutrition. Trends Endocrinol Metab. 2016. doi:10.1016/j.tem.2016.03.001.

Jones JM. CODEX-aligned dietary fiber definitions help to bridge the ‘fiber gap’. Nutr J. 2014;13:34.

Sonnenburg ED, Smits SA, Tikhonov M, et al. Diet-induced extinctions in the gut microbiota compound over generations. Nature. 2016;529(7585):212-5.

Tuohy KM, Fava F, Viola R. ‘The way to a man’s heart is through his gut microbiota’ – dietary pro- and prebiotics for the management of cardiovascular risk. Proc Nutr Soc. 2014;73(2):172-85.

Read the original post online at: http://www.gutmicrobiotaforhealth.com/en/conserving-restoring-human-gut-microbiome-increasing-consumption-dietary-fibre/

GUT MICROBIOTA RESEARCH & PRACTICE edited by ESNM 17 SELECTED CONTENT Mice study shows low-fibre diet may decimate gut bacteria diversity over generations

DIET, FIBERS, RESEARCH & PRACTICE Published on March 9, 2016 by Andreu Prados

According to a recent study by Stanford University School of Medicine researchers, gut microbe deterioration from low-fibre diets may be inherited and irreversible over generations.

Microbiota-accessible carbohy- in the mice that had consumed a drates (MACs) found in plant- low-fibre diet partly recovered, derived fibre have a beneficial one-third of the original species did impact on gut microbiota. In the not see their gut microbiota fully study, mice colonised with human restored despite their return to a gut microbes were fed a diet rich in high-fibre diet. dietary fibre (high-MAC) for 6 Andreu Prados holds a weeks and divided into two groups. To study the influence of the differ- Bachelor of Science One group was fed a low-MAC diet ent diets on subsequent genera- Degree in Pharmacy & for 7 weeks, after which they tions, the researchers bred mice Human Nutrition and returned to the high-MAC diet for a from the two groups and weaned Dietetics. Science writer further 6 weeks. The control group their pups over four generations. By specialised in gut micro- was fed a high-MAC diet through- generation four of fibre deprivation, biota and probiotics, out the experiment. In both groups, there was an irreversible disappea- working also as lecturer diets were identical in terms of rance of more than two-thirds of and consultant in nutri- protein, fat and calorie content. the bacterial species identified in tion and healthcare. After the first 7-week period, 60% the first-generation’s gut micro- of the bacterial species in the low- biota. This result was driven by the fibre group showed a dramatic low-MAC diet and switching low- decline in abundance compared MAC-diet mice to the high-MAC with only 11% of the control group. diet did not influence the outcome. When these mice were returned to Although high dietary fibre was a high-MAC diet, 33% showed a insufficient in restoring microbiota lower rate of abundance. The composition or diversity to control control group did not change levels, faecal transplantation significantly. Although gut bacteria together with a high-MAC diet did

Adopting a high-fibre diet may be beneficial for the gut microbial ecosystem of both the person consuming the diet and their future generations.

GUT MICROBIOTA RESEARCH & PRACTICE edited by ESNM 18 SELECTED CONTENT Mice study shows low-fibre diet may decimate gut bacteria diversity over generations

result in microbiota diversity and for the less diverse microbiota microbial ecosystem of both the composition restoration in the observed in the industrialised world person consuming the diet and fourth-generation low-fibre mice. compared with the diet among their future generations. In short, hunter-gatherers and rural agrarian these results suggest that gut These results support a model in populations. microbiota diversity is a key regula- which consuming a modern diet tor of host health. low in fibre could contribute to In conclusion, according to the bacteria loss in the intestine over model used, adopting a high-fibre generations and may be responsible diet may be beneficial for the gut

References: Sonnenburg ED, Smits SA, Tikhonov M, Higginbottom SK, Wingreen NS, Sonnenburg JL. Diet-induced extinctions in the gut microbiota compound over generations. Nature. 2016;529(7585):212-215.

Read the original post online at: http://www.gutmicrobiotaforhealth.com/en/mice-study-shows-low-fibre-diet-may-decimate-gut-bacteria-diversity-genera tions/

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