Dorgeles Dje-Kouadio

Frank Wieringa

Valérie Greffeuille

Christèle Humblot
email: christèle.humblot@ird.fr

''Bacteria from the gut influence the host micronutrient status''

Keywords:

Micronutrient malnutrition remains a serious public health problem in most low-and middle income countries, with severe consequences for child physical and psychomotor development. Traditional methods of treatment and prevention, such as supplementation and fortification, have not always proven to be effective and may have undesirable side-effects, including increased growth and virulence of pathogenic gut bacteria, resulting in diarrhea and gut inflammation. Commensal bacteria in the gut have demonstrated the ability to increase the bioavailability of certain micronutrients, notably by removing anti-nutritional compounds, such as phytates and polyphenols, or by the synthesis of vitamins or their derivatives. The intestinal microbiota is also, in symbiosis with the gastrointestinal mucosa, the first line of protection of the internal environment against the external environment. It thus contributes to the reinforcement of the integrity of the intestinal epithelium and to a better absorption of micronutrients. They represent a save alternative to prevent micronutrients deficiencies. However, the metabolic characterization of the intestinal microbiota is not yet complete and its role in micronutrient malnutrition is still poorly understood. The bacterial metabolism is also dependent of micronutrients acquired from the gut environment and resident bacteria may compete or collaborate to maintain micronutrient homeostasis. Gut microbiota composition can therefore be modulated by micronutrient availability. This review brings together current knowledge on this two-way relationship between micronutrients and gut microbiota bacteria, with a focus on iron, zinc, vitamin A and folate (vitamin B9), which are respectively minerals and vitamins of interest in a global context.

Introduction

Micronutrients, including minerals and vitamins, are nutrients needed only in small quantities on a daily basis, but who are vital to human metabolic processes [START_REF] Gharibzahedi | The importance of minerals in human nutrition: Bioavailability, food fortification, processing effects and nanoencapsulation[END_REF][START_REF] Shenkin | Micronutrients in health and disease[END_REF]. Vitamin and mineral deficiencies, also called 'Hidden Hunger' to highlight the lack of visibility, is a serious public health problem, encountered in all social strata of the world, but especially affecting vulnerable groups in low-and middle income countries [START_REF] Stein | The Human and Economic Cost of Hidden Hunger[END_REF]. Micronutrient deficiencies are widespread around the world, estimated to affect over 2 billion people, and are implicated in a wide range of adverse health outcomes such as increased prevalence of morbidity and mortality, anaemia, stunting and delayed cognitive development. In a global context, the diets of two-thirds of women and children, mainly from resource-poor households, are deficient in at least one micronutrient [START_REF] Kennedy | The scourge of "hidden hunger": global dimensions of micronutrient deficiencies[END_REF]. The most prevalent micronutrient deficiencies worldwide include iron, zinc, vitamin A and folate (vitamin B9) [START_REF] Kennedy | The scourge of "hidden hunger": global dimensions of micronutrient deficiencies[END_REF][START_REF] Bailey | The epidemiology of global micronutrient deficiencies[END_REF].

Several strategies to improve micronutrient status of individuals or populations exist, with fortification of staple foods being regarded as the most cost-effective intervention to improve micronutrient status of populations [START_REF] Bhutta | What works? Interventions for maternal and child undernutrition and survival[END_REF]. Nevertheless, strategies to fight micronutrients deficiencies are not always efficient. Absorption of micronutrients occurs mainly in the small intestine, through different mechanisms depending on the micronutrient. For example, zinc and iron are mainly absorbed in the duodenum and jejunum through specific transport carriers [START_REF] Frazer | The regulation of iron transport[END_REF][START_REF] Krebs | Overview of Zinc Absorption and Excretion in the Human Gastrointestinal Tract[END_REF], whereas folate is not only absorbed in the small intestine, but also in the colon [START_REF] Visentin | The intestinal absorption of folates[END_REF].

In the digestive tract, there is a complex community of microorganisms with a concentration and diversity that increases from mouth to colon [START_REF] Tremaroli | Functional interactions between the gut microbiota and host metabolism[END_REF]. Although other microorganisms (viruses, fungi) share this niche, most studies have dealt with bacteria, the phyla Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria and Verrucomicrobia being the most represented [START_REF] Tremaroli | Functional interactions between the gut microbiota and host metabolism[END_REF]. The role of the intestinal microbiota in human health is undeniable today [START_REF] Clemente | The Impact of the Gut Microbiota on Human Health: An Integrative View[END_REF]. Indeed, the composition of the gut microbiota have been associated with diseases such as inflammatory bowel disease [START_REF] Gonzalez | Our microbial selves: what ecology can teach us[END_REF], or obesity [START_REF] Turnbaugh | The Human Microbiome Project[END_REF]). And the intestinal microbiome plays an important role in the aetiology of severe acute malnutrition [START_REF] Million | Gut microbiota and malnutrition[END_REF][START_REF] Subramanian | Persistent gut microbiota immaturity in malnourished Bangladeshi children[END_REF]. Faecal bacterial composition strongly vary among individuals, which was found to be dictated by the host's genetics, but also by many environmental factors including diet [START_REF] Subramanian | Cultivating Healthy Growth and Nutrition through the Gut Microbiota[END_REF][START_REF] Voreades | Diet and the development of the human intestinal microbiome[END_REF].

For long, most research on the effect of food on the intestinal microbiota has focused on macronutrients (fats, carbohydrates, proteins) [START_REF] Conlon | The impact of diet and lifestyle on gut microbiota and human health[END_REF][START_REF] Turnbaugh | The core gut microbiome, energy balance and obesity[END_REF]. However, bacteria need micronutrients for their survival. For example, bacteria require iron from external sources, and some of them even have developed specific mechanisms such as transferrin transporters to compete for iron sources [START_REF] Andrews | Bacterial iron homeostasis[END_REF]. In contrast, many bacteria can directly synthesise vitamins such as folate (vitamin B9), thus, not necessarily requiring an external source.

Even though the absorption of most micronutrients by the host is now well described, the role of the intestinal microbiota on micronutrient absorption and/or availability is less clear. Considering the amount and the diversity of the bacteria along the digestive tract, there is a need to sum up the actual knowledge and to underline the gaps and research needed in this field. Absorption of micronutrients generally occurs in the upper part of the digestive tract, usually in the duodenum or jejunum through specific transport mechanisms [START_REF] Basu | Intestinal absorption in health and disease: micronutrients[END_REF]. However, typically only 5%-50% of micronutrients are absorbed, meaning that the most part of the ingested micronutrients reach the colon [START_REF] Welch | Breeding for micronutrients in staple food crops from a human nutrition perspective[END_REF].

Gut microbiota have different modes of action on the micronutrients, which can result in a better or a worse bioavailability for the host. These actions can be direct, targeting directly the micronutrients of interest. For example, bacteria can take up iron and zinc, but in case of excess efflux of these metals is possible. These mechanisms allow pathogenic bacteria to scavenge minerals efficiently and escaped nutritional immunity and develop in presence of commensal bacteria from the gut (Celis 2020).

Similar mechanisms in commensal bacteria are not completely understood, even if it some authors underline that they should be less aggressive than the ones used by pathogens (Celis 2020). Actions can also be indirect, for example through production of short chain fatty acids (SCFA), which will result in a better health of the gut epithelium, resulting in a better absorption of the micronutrient by the host. This review aims to summarise the current knowledge on the bilateral relationship that exists between the intestinal microbiota and micronutrients and discuss emerging themes. A recurrent theme will be the bi-directional character of the relationship, with micronutrient status of the host modifying the microbial composition of the gastrointestinal tract [START_REF] Tian | Vitamin A deficiency in mice alters host and gut microbial metabolism leading to altered energy homeostasis[END_REF][START_REF] Zimmermann | The effects of iron fortification on the gut microbiota in African children: a randomized controlled trial in Cote d'Ivoire[END_REF]), but with also the intestinal microbiota modulating the bioavailability of micronutrients and thereby the micronutrient status of the host [START_REF] Rossi | Folate Production by Probiotic Bacteria[END_REF]. We have restricted the scope of this review to four micronutrients important for global public health: iron, zinc, vitamin A and vitamin B9.

Micronutrients and host health

Micronutrients play a central role in metabolism and the maintenance of tissue functions that govern human health [START_REF] Basu | Intestinal absorption in health and disease: micronutrients[END_REF]. However, despite efforts to diversify diets to better meet micronutrients needs [START_REF] Mallard | Micronutrient Adequacy and Dietary Diversity Exert Positive and Distinct Effects on Linear Growth in Urban Zambian Infants[END_REF], the prevalence of micronutrient deficiencies remains very high in all parts of the world, including in industrialised countries [START_REF] Biesalski | Hidden Hunger[END_REF]. Children and women are the most affected, due to higher requirements to sustain growth and higher loses (e.g. menses). The clinical signs of single micronutrient deficiencies are varied and often micronutrient-specific [START_REF] Allen | Guidelines on food fortification with micronutrients[END_REF].

Iron deficiency is considered the most common form of micronutrient malnutrition, with more than 2 billion people estimated to be iron-deficient [START_REF] Zimmermann | Nutritional iron deficiency[END_REF]. Iron deficiency anemia is a common disease associated to insufficient iron intake and iron stores [START_REF] Miller | Iron deficiency anemia: a common and curable disease[END_REF]. Factors contributing to iron deficiency include (i) a low intake of haem iron, which has a higher bioavailability than non-haem iron, (ii) diets with a high content of phytates or phenolic compounds responsible for a lower bioavailability [START_REF] Petry | Polyphenols and phytic acid contribute to the low iron bioavailability from common beans in young women[END_REF] and (iii) chronic inflammation, leading to higher levels of hepcidin, downregulating iron absorption [START_REF] Rivella | Disorders of Iron Metabolism: Iron Deficiency and Iron Overload and Anemia of Chronic Diseases[END_REF]. Zinc deficiency is not only associated with growth retardation in children, leading to stunting, but also diminished immunocompetence, thereby increase the susceptibility of children to diarrhoeal disease, pneumonia and perhaps malaria [START_REF] Hambidge | Human zinc deficiency[END_REF]. Moreover, it seems that zinc deficiency can predispose to other micronutrient deficiencies [START_REF] Biesalski | Nutrition meets the microbiome: micronutrients and the microbiota[END_REF]). Zinc deficiency is estimated to affect more than1 billion people worldwide [START_REF] Wessells | Estimating the global prevalence of zinc deficiency: results based on zinc availability in national food supplies and the prevalence of stunting[END_REF].

Similarly, vitamin A deficiency leads to decreased immunocompetence, as well as reduced integrity of intestinal epithelial mucosa [START_REF] Hall | Essential Role for Retinoic Acid in the Promotion of CD4+ T Cell Effector Responses via Retinoic Acid Receptor Alpha[END_REF]. Half-yearly high dose vitamin A supplements are given to children less than 5 years of age in many low-and middle income countries in a drive to decrease child mortality [START_REF] Imdad | Impact of vitamin A supplementation on infant and childhood mortality[END_REF], but impact on vitamin A status is questionable. Insufficient folate intake during pregnancy is associated with neural tube defects during the first weeks of embryonic life [START_REF] Bailey | Folic Acid Supplements and Fortification Affect the Risk for Neural Tube Defects, Vascular Disease and Cancer: Evolving Science[END_REF]. In the general population, folate deficiency also leads to megaloblastic anaemia, and neurological symptoms that partly overlap with those found in vitamin B12 deficiency [START_REF] Allen | Guidelines on food fortification with micronutrients[END_REF]. It is estimated that more than 20% of women of reproductive age in low-and middle income countries are folate deficient [START_REF] Lm | Global folate status in women of reproductive age: a systematic review with emphasis on methodological issues[END_REF].

3. The complexity of host-bacteria interaction: the case of iron.

For a complete overview on iron, bacteria and host interplay we would like to refer to a recent review [START_REF] Seyoum | Iron homeostasis in host and gut bacteriaa complex interrelationship[END_REF]. Here we have summarized the elements which describe the complexity of this relationship [START_REF] Seyoum | Iron homeostasis in host and gut bacteriaa complex interrelationship[END_REF].

As human are not able to actively excrete iron, its absorption is tightly regulated in the duodenum (Figure 1) [START_REF] Zimmermann | Nutritional iron deficiency[END_REF]. Heme iron and non-heme iron are absorbed through two distinct pathways [START_REF] Fuqua | Intestinal iron absorption[END_REF], with heme iron absorbed by a heme carrier protein 1 (HCP1) at the border of the duodenal brush membrane. Non-heme iron, usually in its ferric form, is not bioavailable and must be reduced to the ferrous form by duodenal cytochrome b (DCYTB), before being transported over the duodenal brush membrane by the divalent metal transporter (DMT1) [START_REF] Canonne-Hergaux | Cellular and subcellular localization of the Nramp2 iron transporter in the intestinal brush border and regulation by dietary iron[END_REF]. Iron is also absorbed in the ileum and colon since the presence of DMT1 has been described [START_REF] Bouglé | Influence of Short-Chain Fatty Acids on Iron Absorption by Proximal Colon[END_REF]. But the role of these absorption sites on the host iron status remains to be estimated [START_REF] Yeung | Prebiotics and Iron Bioavailability-Is There a Connection?[END_REF]. Iron homeostasis is regulated by hepcidin, a hormone that circulates in the plasma and inhibits the release of iron into the plasma through different mechanisms [START_REF] Nemeth | Regulation of iron metabolism by hepcidin[END_REF]. Hepcidin is upregulated during systemic inflammation, thereby reducing iron bioavailability.

But pathogenic bacteria could induce systemic inflammation, thereby reducing the intestinal bioavailability of iron [START_REF] Nicolas | Hepcidin, A New Iron Regulatory Peptide[END_REF].

Iron is also essential for many bacteria, requiring it for their growth [START_REF] Zaharik | The Salmonella enterica Serovar Typhimurium Divalent Cation Transport Systems MntH and SitABCD Are Essential for Virulence in an Nramp1G169 Murine Typhoid Model[END_REF]. Bacteria can acquire iron through different mechanisms such as using ferric-specific chelators called siderophores, absorbing ferrous iron after reducing ferric iron or using host iron compounds such as heme or transferrin.

Despite its bacteriostatic function, lactoferrin, which is found in milk, can also be used by bacteria with specific receptors [START_REF] Vega-Bautista | The Impact of Lactoferrin on the Growth of Intestinal Inhabitant Bacteria[END_REF].

Siderophores are a wide family comprising hundreds of forms produced and secreted by manymicroorganisms [START_REF] Chu | Siderophore uptake in bacteria and the battle for iron with the host; a bird's eye view[END_REF]. The resulting ferric-siderophores complex are internalised via specific outer membrane proteins. Bacteria can also use siderophores produced by other bacteria, through the production of outer membrane receptors with different ligand-binding sites. Siderophores are expressed in case of bacterial iron deficiency, thus not in iron-sufficient environments [START_REF] Troxell | Transcriptional regulation by Ferric Uptake Regulator (Fur) in pathogenic bacteria[END_REF].

In anaerobic conditions and at low pH, iron is mainly in the form of ferrous iron, which can be transported directly by bacteria, mainly through the dedicated transport system feo [START_REF] Lau | Bacterial ferrous iron transport: the Feo system[END_REF].

Transportation of heme-iron, transferrin, lactoferrin is through specific receptors or direct absorption [START_REF] Seyoum | Iron homeostasis in host and gut bacteriaa complex interrelationship[END_REF]. Regulation of iron uptake is highly important in bacteria since iron is toxic at high doses. The Fur regulation system represses transcription of genes involved in iron uptake when iron concentration is too high [START_REF] Banci | Metallomics and the Cell: Some Definitions and General Comments[END_REF]. It is important to note that most of our knowledge of bacterial iron absorption comes from research done on pathogenic bacteria. It has been considered for a long time that a few beneficial bacteria, such as members of Lactobacillus genus, do not require iron for their growth [START_REF] Archibald | Lactobacillus plantarum, an organism not requiring Iron[END_REF]. Nevertheless, specific systems have been identified in L. plantarum and L. sakei [START_REF] Duhutrel | Iron sources used by the nonpathogenic lactic acid bacterium Lactobacillus sakei as revealed by electron energy loss spectroscopy and secondary-ion mass spectrometry[END_REF][START_REF] Verplaetse | Heme Uptake in Lactobacillus sakei Evidenced by a New Energy Coupling Factor (ECF)-Like Transport System[END_REF]. Most probably, other systems may exist, and studying these bacteria may reveal new iron absorption pathways. At the main site of iron absorption, in the duodenum, there are roughly 10 3 bacteria/g, which is less than in the jejunum (10 4 bacteria/g) and far less that in the colon where up to 10 12 bacteria/g of content can found [START_REF] O'hara | The gut flora as a forgotten organ[END_REF]. Also, members of Lactobacillus genus are numerous in the small intestine where iron absorption is maximum, thus the role of these bacteria on iron absorption by the host should receive more attention, to determine whether they play or not a role in bioavailability of iron for the host.

It has been calculated that iron concentration in the colon should be high, which is by far more than the minimum requirement for bacterial grow [START_REF] Mccance | The absorption and excretion of iron following oral and intravenous administration[END_REF]. But the bioavailability of iron for bacteria depends also on a range of factors (form of iron, iron speciation, pH, oxygen levels). For bacteria and human, non-heme iron is the most affected by the composition of the food matrix and the physico-chemical composition of the lumen. Indeed, non-heme iron is linked in many food matrixes to inhibitors, such as polyphenols, fibres or phytates, which can be degraded by dedicated bacterial enzymes, thus resulting in a better iron absorption [START_REF] Reddy | Food Phytates[END_REF]. This property is usually utilised in fermentation, where bacteria to reduce the concentration of inhibitors in the food, resulting in higher iron bioavailability.

But the presence of phytases has been demonstrated also for a number of bacteria found in the gut (including the ones in the small intestine). It was suggested that whatever the phytates content of the food, all iron in the food matrix should be liberated since bacteria from the gut exhibit phytase activity [START_REF] Stentz | A Bacterial Homolog of a Eukaryotic Inositol Phosphate Signaling Enzyme Mediates Cross-kingdom Dialog in the Mammalian Gut[END_REF]. However, this appears to be in conflict with real-life observations, where phytate-high diets are linked to iron deficiency. Also, some promoters of iron bioavailability, such as lactic acid, are produced by a number of bacteria, present all along the digestive tract. The acidified intestinal environment could also degrade complexes chelating micronutrients and facilitate absorption of iron [START_REF] Biesalski | Nutrition meets the microbiome: micronutrients and the microbiota[END_REF]. Bacteria can also produce short chain fatty acids (SCFA) by fermentation of non-digestible carbohydrates from the diet, which will lower the luminal pH, and thus reduce ferric to ferrous iron, thereby improving its absorption by bacteria and host [START_REF] Alexander | Perspective: Physiologic Importance of Short-Chain Fatty Acids from Nondigestible Carbohydrate Fermentation[END_REF].

It is obvious from above that gut bacteria play an important role in modulating the bioavailability of iron for the host. However, host factors can modulate iron uptake by bacteria, for example, in the case of inflammation, through the synthesis of lipocalin, which will bind to the siderophores and thus counter the trapping of iron by the intestinal bacteria [START_REF] Flo | Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron[END_REF]. Recently, is has been suggested that rather than a battle for minerals, commensal bacteria use different mechanisms not only to liberate and capture iron, but also to share iron among themselves and with their host [START_REF] Kramer | Bacterial siderophores in community and host interactions[END_REF][START_REF] Lechardeur | Discovery of Intracellular Heme-binding Protein HrtR, Which Controls Heme Efflux by the Conserved HrtB-HrtA Transporter in Lactococcus lactis*[END_REF].

Overall, it appears that depending on the model used (in vitro, animals or humans) results are dramatically different, making any generalization difficult. One of the few consistent results is the decrease in the proportion of bacteria of the phylum Actinobacteria in case of iron-deficiency anemia [START_REF] Muleviciene | Iron deficiency anemiarelated gut microbiota dysbiosis in infants and young children: A pilot study[END_REF]. In the case of iron supplementation or fortification, the chemical form of iron used (ferrous sulfate, ferrous furamate, NaFeEDTA, ferric sodium ethylenediaminetetraacetate) seems to affect bacterial composition differently [START_REF] Baldi | Balancing Safety and Potential for Impact in Universal Iron Interventions. Global Landscape of Nutrition Challenges in Infants and Children[END_REF][START_REF] Go | Chapter 39 -Wheat Flour Fortification to Prevent Iron-Deficiency Anemia[END_REF][START_REF] Powell | A nanodisperse ferritin-core mimetic that efficiently corrects anemia without luminal iron redox activity[END_REF]. Surprisingly, no general trends could be identified, even in the same model and using the same method with iron supplementation [START_REF] Seyoum | Iron homeostasis in host and gut bacteriaa complex interrelationship[END_REF]. For example, in human models, iron supplementation was associated with an increase (68), a decrease (69) and had no effect (70) on the population of bacteria of the phylum Firmicutes. The only consistent results were for Lactobacillaceae family and the phylum Actinobacteria. Indeed, Lactobacillaceae always decreased during iron supplementation, whatever the model used [START_REF] Jaeggi | Iron fortification adversely affects the gut microbiome, increases pathogen abundance and induces intestinal inflammation in Kenyan infants[END_REF][START_REF] Kortman | Low dietary iron intake restrains the intestinal inflammatory response and pathology of enteric infection by food-borne bacterial pathogens[END_REF][START_REF] Kortman | Microbial Metabolism Shifts Towards an Adverse Profile with Supplementary Iron in the TIM-2 In vitro Model of the Human Colon[END_REF]. Also, against all expectations, the effect of iron supplementation was not directly opposite to that of iron deficiency (39).

Role of bacteria in zinc bioavailability

Zinc is involved in vital processes such as DNA synthesis, transcription, and translation [START_REF] Falchuk | The molecular basis for the role of zinc in developmental biology[END_REF]. Zinc absorption occurs in the duodenum and involve the transmembrane zinc transporter protein Zip4 (figure 2). Zinc is then shuttled to the metalloprotein synthesis sites by the zinc-regulated proteins ZnT2-10 or exported to the circulation by Zinc transporters ZnT1 [START_REF] Zhu | Transition metals and host-microbe interactions in the inflamed intestine[END_REF]. Contrarily to iron, zinc can also be actively excreted in case of excess. It will go from the circulation to the enterocytes by the protein Zip5 at the basolateral side of these cells and an efflux from the enterocyte to the lumen via ZnT5 [START_REF] Maares | A Guide to Human Zinc Absorption: General Overview and Recent Advances of In Vitro Intestinal Models[END_REF].

In food, zinc can be complexed with antinutrient factors such as phytates or polyphenols, thus reducing its absorption [START_REF] Kortman | Nutritional iron turned inside out: intestinal stress from a gut microbial perspective[END_REF]. Zinc that is not absorbed in the small intestine will reach the colon and its possible absorption by colonocytes where the zinc transporters are also expressed [START_REF] Gopalsamy | The Relevance of the Colon to Zinc Nutrition[END_REF]. As for iron, the phytase activity found in many members of the commensal bacteria as well as their ability to metabolise polyphenols could increase the bioavailability of zinc for the host.

In bacteria, zinc is rapidly bound to small molecules such as metallothionein or is transported to metalloprotein synthesis sites by zinc chaperones [START_REF] Capdevila | Bacterial Strategies to Maintain Zinc Metallostasis at the Host-Pathogen Interface*[END_REF]. Zinc uptake by bacteria is regulated by the zinc uptake repressor Zur and the zinc efflux repressor CzrA [START_REF] Capdevila | Bacterial Strategies to Maintain Zinc Metallostasis at the Host-Pathogen Interface*[END_REF]. As in the case for iron, most studies were done on pathogens, rather than on commensal bacteria. Some pathogenic bacteria can overcome zinc limited conditions (nutritional immunity produced by host through sequestration of essential micronutrients such as zinc by secreting calprotectin) by expressing a high affinity transporter (ZnuABC) [START_REF] Liu | Zinc Sequestration by the Neutrophil Protein Calprotectin Enhances Salmonella Growth in the Inflamed Gut[END_REF]. Zinc can also be actively exported in case of excess [START_REF] King | Zinc Homeostasis in Humans[END_REF].

Zinc deficiency has been repetitively associated with chronic diarrhoea [START_REF] Biesalski | Nutrition meets the microbiome: micronutrients and the microbiota[END_REF]. The effect of zinc supplementation on the intestinal microbiota has been mainly studied in animal models. It has been used in poultry and pig industry at pharmaceutical dose to reduce gastrointestinal infections and diarrhoea [START_REF] Souffriau | Mechanistic insights into the protective impact of zinc on sepsis[END_REF]. Zinc has antimicrobial activity and different studies underlined the changes of bacterial composition of the different parts of the gut (from stomach to colon) induced by such high doses of zinc [START_REF] Hojberg | Influence of Dietary Zinc Oxide and Copper Sulfate on the Gastrointestinal Ecosystem in Newly Weaned Piglets[END_REF][START_REF] Pieper | Dose-dependent effects of dietary zinc oxide on bacterial communities and metabolic profiles in the ileum of weaned pigs[END_REF][START_REF] Starke | The impact of high dietary zinc oxide on the development of the intestinal microbiota in weaned piglets[END_REF][START_REF] Vahjen | Increased dietary zinc oxide changes the bacterial core and enterobacterial composition in the ileum of piglets[END_REF]. Depending on the studies, there was a reduction or an increase of Enterobacteriaceae and lactic acid bacteria [START_REF] Hojberg | Influence of Dietary Zinc Oxide and Copper Sulfate on the Gastrointestinal Ecosystem in Newly Weaned Piglets[END_REF][START_REF] Pieper | Dose-dependent effects of dietary zinc oxide on bacterial communities and metabolic profiles in the ileum of weaned pigs[END_REF][START_REF] Starke | The impact of high dietary zinc oxide on the development of the intestinal microbiota in weaned piglets[END_REF][START_REF] Vahjen | Increased dietary zinc oxide changes the bacterial core and enterobacterial composition in the ileum of piglets[END_REF]. One study showed that Ruminococcus genus was predicting host zinc adequacy [START_REF] Reed | Alterations in the Gut (Gallus gallus) Microbiota Following the Consumption of Zinc Biofortified Wheat (Triticum aestivum)-Based Diet[END_REF]. Bacterial compositional changes were accompanied by changes in the metabolism of the bacteria as shown the increase colonic concentration of short chain fatty acids (SCFA) [START_REF] Pieper | Dose-dependent effects of dietary zinc oxide on bacterial communities and metabolic profiles in the ileum of weaned pigs[END_REF]. As for iron, studies on zinc status and host microbiota mainly focused on pathogenic conditions, and little is known about the role of bacteria in a normal situation.

Acquisition of folates by host and bacteria

Several commensal bacteria have been shown to synthesize certain vitamins. The role of intestinal bacteria in the production of vitamin K has been known for several decades, but bacteria can also be a source of folates for the host, even if the extent of the overall contribution is still unknown [START_REF] Rowland | Gut microbiota functions: metabolism of nutrients and other food components[END_REF].

Folate or vitamin B9 is necessary for DNA methylation and replication, as well as for cell division, which is characteristic of better growth [START_REF] Duthie | Impact of Folate Deficiency on DNA Stability[END_REF]. Folates from the diet exist in mono and poly-glutamate forms, which are deconjugated to the monoglutamate form and then absorbed in the ileum via specific transporter FFLR1,2 (proton-coupled folate transporter (PCFT). In the epithelium, folate monoglutamate is converted into an active form, tetrahydrofolate (THF). Then, it is transported to the blood [START_REF] Hosomi | The Specific Roles of Vitamins in the Regulation of Immunosurveillance and Maintenance of Immunologic Homeostasis in the Gut[END_REF][START_REF] Said | Intestinal absorption of water-soluble vitamins in health and disease[END_REF]. In the colon, a version of the same receptors has been identified [START_REF] Maynard | A bacterial route for folic acid supplementation[END_REF].

Bacteria require folate for their growth, with some bacteria being prototrophic and can synthesize folate from precursors present in the environment (figure 3). The others, auxotrophic, must acquire folate from the environment. All of them have transporters for folates or folates precursors [START_REF] Jaehme | Diversity of membrane transport proteins for vitamins in bacteria and archaea[END_REF][START_REF] Putnam | B vitamin acquisition by gut commensal bacteria[END_REF].

The ability to synthesize folate is found in different taxonomy communities [START_REF] Magnúsdóttir | Systematic genome assessment of B-vitamin biosynthesis suggests co-operation among gut microbes[END_REF]. Some bacteria also have uncomplete synthesis pathways in their genome [START_REF] Jaehme | Diversity of membrane transport proteins for vitamins in bacteria and archaea[END_REF]. A body of data are in favour of a significant contribution of bacterial folates synthesis to host status. Early studies reported that human folate concentration in faecal samples where 300-500 µg/day, while dietary intakes were below 100 µg/day, suggesting a synthesis of folate by the gut bacteria [START_REF] Denko | The excretion of B-complex vitamins in the urine and feces of seven normal adults[END_REF][START_REF] Girdwood | The intestinal content in pernicious anemia of factors for the growth of Streptococcus faecalis and Lactobacillus leichmannii[END_REF]. Modification of gut microbiota composition due to fibers consumption may result in increased folate concentration in colonic content or in circulation [START_REF] Aufreiter | Dietary Oligosaccharides Increase Colonic Weight and the Amount but Not Concentration of Bacterially Synthesized Folate in the Colon of Piglets[END_REF][START_REF] Sepehr | Folate derived from cecal bacterial fermentation does not increase liver folate stores in 28-d folate-depleted male Sprague-Dawley rats[END_REF]. Also, despite that folate absorption rate in the large intestine is 100 time slower than in the small intestine, labelled folates specifically encapsulated to reach and disintegrate in the colon, were incorporated in host tissue (100,101). Direct ingestion of folate producing bacteria can also improve folate status of rodents on folic acid deficient diets (102-104). Another study showed that, in a model of Caenorabditis Elegans, bacteria can convert folic acid into tetrahydrofolates, which are better absorbed by the host (105). The metabolic capacity of the gut microbiota depends on its composition but also on the physiological characteristics of the host. For example, genes coding enzymes involved in the folate biosynthesis, are found more frequently in gut microbiota of babies young children as compared to adults (106).

Interestingly, the microbiome of children suffering from malnutrition showed a significant lower abundance of genes in multiple path-ways involved in B-vitamin metabolism [START_REF] Gehrig | Effects of microbiota-directed foods in gnotobiotic animals and undernourished children[END_REF]).

Contrarily to irons and zinc, it has been shown that the dietary folate deficiency doesn't affect the gut bacterial composition (108). Perhaps because of the presence of phototrophic bacteria, producing folates in periods of deficiency, fluctuations in folate intake have less impact on gut flora. (95,109).

Role of gut microbiota in vitamin A absorption and metabolism

Dietary vitamin A is found in the form of carotenoids and retinyl esters, respectively present in vegetables and animal products (110). The uptake of carotenoids and retinol occurs in the upper half of small intestine (110,111).

Vitamin A directly contributes to the maintenance of the gut barrier by regulating proliferation and differentiation of immune cells in the intestinal epithelium and plays a crucial role in the resistance to pathogens invasion in the gut [START_REF] Hall | Essential Role for Retinoic Acid in the Promotion of CD4+ T Cell Effector Responses via Retinoic Acid Receptor Alpha[END_REF]112,113). The epithelial and mucosal cells, in symbiosis with commensal bacteria, constitute a first physical barrier against external bacteria and contribute to the regulation of the gut microbiota composition (114,115). Disruption of the integrity of the intestinal barrier can lead to poor absorption of nutrients, and various diseases in the host, including inflammatory bowel disorders (116,117) Vitamin A and carotenoids are dietary fat-soluble components that require solubilization by micelles prior to absorption in enterocytes ( 118). An emulsification phase into droplets occurs in the stomach and duodenum, with vitamin A being incorporated into micelles formed with bile salts (119,120).

Carotenoids can be absorbed by passive diffusion, while retinoid are absorbed through carrierdependent proteins (111). Only free forms of retinoids can be absorbed so that retinyl-esters must be hydrolyzed to retinol either by pancreatic enzymes or by a retinyl esters hydrolase (REH) present in the mucus (121,122). After absorption retinol is reesterified with long-chain fatty acids by the enzyme lecithin-retinol acyltransferase (LRAT) or by retinol dehydrogenases (RDHs) into retinal (figure 4). The bioavailability of carotenoids can be affected by various food components among which the cell wall structure and composition of vegetables in the food matrix which form a physical barrier, thus limiting the action of digestives enzymes (130). Pectins and some polyphenols such as naringenin have been shown to decrease the carotenoid bioavailability in vitro by binding cholesterol and bile salts in the lumen, and thus inhibiting the micelles formation (131). In contrast, pectins can be degraded by numerous commensals bacteria (132) and this degradation in the gut may increase the bioavailability of carotenoids. Also, the gut microbiota synthesizes enzymes or complement proteins, such as bacterial lipocalins, which could contribute to the transport of retinoid in enterocyte (133,134). Similarly, the intestinal microbiota can digest dietary fibers and thus release β-carotene or others entangled micronutrients [START_REF] Biesalski | Nutrition meets the microbiome: micronutrients and the microbiota[END_REF].

Additionally, gut bacterial population can also regulate the host metabolism of retinol modulating the production of retinoic acid (RA) which drives the immune responses. Grizotte-Lake showed that bacteria of Clostridium class can regulates RA concentration in the gut epithelium by suppressing the gene Rdh7 expression, which pilot the transformation of retinol into retinoic acid (135). Moreover, this study showed that commensal bacteria communities lower RA production which is balanced by an increase in the liver storage form and favour the RE pathways; whereas potentially pathogenic bacteria promoted RA production.

The availability of retinoids in the gut environment can modulate the microbial composition. For example, the gut microbial composition of vitamin A-deficient mice had lower abundance of bacteria of genus Enterococcus, Lactobacillus and of the species Clostridium difficile from the phylum Firmicutes, as well as species from the genus Escherichia from the Proteobacteria phylum compared to non-deficient mice (136). The effect of vitamin A deficiency on a model of initially germ-free mice inoculated with a community of bacterial species found in human gut, resulted in a strong increase of Bacteroides vulgatus proportion [START_REF] Hibberd | The effects of micronutrient deficiencies on bacterial species from the human gut microbiota[END_REF]. In this last study, it was suggested that the modulation of gut microbiota composition can be can induced by the altered bile acid metabolism associated with acute vitamin A deficiency.

In mice, the proportion of Bacteroides members was lower in vitamin A deficient mice, and several class family and genus proportion were different between vitamin A deficient and vitamin A sufficient groups [START_REF] Tian | Vitamin A deficiency in mice alters host and gut microbial metabolism leading to altered energy homeostasis[END_REF]. In children with autism, vitamin A supplementation increased the proportion of bacteria from the order Bacteroidales and reduced the one of the genus Bifidobacterium (137). The modulation of gut microbiota composition by vitamin A can also serve as indirect pathway to modulate immune responses at the intestinal level. For example, according to experiments conducted in a mouse model, vitamin A can modulate the abundance of Segmented Filamenteous Bacteria (SFB), a group of bacteria able to induce the differentiation of Th17 Cells (136,138).

Conclusion

In summary, there is a lack of data on the effect of micronutrients (vitamin A, vitamin B9, iron and zinc) on gut microbial composition, but it seems likely that the interplay between micronutrients and the microbiome is an important factor in determining risk for vitamin and mineral deficiencies, and thus for global public health. Hence, policies designated to fight micronutrient deficiencies should start to take this compartment into consideration.

Given the huge differences among protocols, the outcomes measured and the interpretation of results, harmonization is urgently needed (106). Also, studies on micronutrient metabolism should be expanded to include the general gut microbial composition, not just pathogenic bacteria, as has long been done in the case of iron. Better cooperation between microbial scientists, food scientists, nutritional scientists, would create the opportunities to fight micronutrient deficiencies in an innovative way.

Figure 1 .

 1 Figure 1. Schematic representation of the gut microbiota role in the intestinal absorption of iron.

Figure 2 .

 2 Figure 2. Schematic representation of the gut microbiota role in the intestinal absorption of zinc.

Figure 3 .

 3 Figure 3. Schematic representation of the gut microbiota role in the intestinal absorption of vitamin

  In the enterocyte, carotenoids are directly converted into all-trans retinal by carotene-15,15'dioxygenase [BCO(D)M] (123). Retinaldehyde can be irreversibly converted with retinaldeshydrogenases (RALDH) into bioactive retinoic acid molecules or converted into retinol ester by LRAT, to be stored in the liver (124). The secretion of secondary or tertiary bile salts produced by bacteria belonging to Lactobacillus, Bifidobacterium, Bacteroides or Clostridium genus could favour the solubilisation of vitamin A and improve its absorption (125) since bile salts are essential for the micellarisation process (126).One role of bacteria is a direct synthesize of carotenoids or an indirect effect on their bioavailability. Indeed, the genome of bacteria from the gut has analogues of different enzymes, found in animal and plant products, which allow the synthesis of carotenoids and retinoids from Acetyl-CoA through the mevalonate pathway (MVA) (127,128). In addition, bacteria from the genus Bacteroides, Enterococcus and Streptococcus possess the genes brp/blh that are similar to the host BCM(D)O genes, and hence could convert β-carotene into all-trans retinal (129).

Figure 4 .

 4 Figure 4. Schematic representation of the the gut microbiota in the intestinal absorption of vitamin A.

The effects of iron on the intestinal microbiota has been the most studied, as iron deficiency is likely the most widespread nutritional deficiency [START_REF] Zimmermann | Nutritional iron deficiency[END_REF]. But more studies into the effects of other micronutrients (vitamin A, zinc, B-vitamins) are needed, alone or in combination, to elucidate the interaction between micronutrients, the microbiome and the host.


Stéphane Pouyllau

Jean-Luc Minel

Mélanie Bunel

Adrien Desseigne

Nicolas Sauret

Laurent Capelli

Pauline Busonera

Olivier Jouguet Baude

Hélène

ISIDORE celebrates its 10th anniversary

Keywords: isidore, moteur de recherche, outil de découverte, réseau social académique, réseaux de neurones, latent dirichlet analysis, topic modelling search engine, discovery tool, academic social network, isidore, topic modelling, neural networks, latent dirichlet analysis

Isidore celebrates its 10th anniversary

In 2011, the first version of ISIDORE1 was published. Its 10th anniversary is an opportunity to recall the history of the project and to present its future outlines, currently being defined within the framework of the "Huma-Num Open Science" program2 . This year ISIDORE passed the 10 million mark in terms of documents and data indexed, enriched and categorized from more than 9000 databases and data repositories worldwide. More than 2000 researchers already have an account, taking advantage of the many customizable scientific monitoring and discovery features.

So, what is ISIDORE?

Initially, ISIDORE is a search engine for discovering and finding publications, digital data and profiles of researchers in the social sciences and humanities (SSH) from around the world. It allows the full text of several million documents (articles, doctoral theses and dissertations, reports, datasets, web pages, database records, descriptions of archives, etc.) as well as event reports (seminars, conferences, etc.) to be searched. In addition, ISIDORE links these mil-lions of documents together by enriching them with scientific concepts provided by SSH research communities.

It is accessible on the Web on the "isidore.science" 3 web portal.

It also offers scientific social network functionalities. As such, it falls into the category of search engines and assistants and offers many features to organize scientific monitoring.

Founding principles

ISIDORE harvests data and publication repositories in order to retrieve metadata and full text, enrich and index them. The exploitation of document metadata as well as of full text enriches the documents, firstly, by linking them to concepts of scientific controlled vocabularies (thesauri, authority lists, etc.) published either by SSH scientific communities, or by large international research libraries, and secondly, by identifying authors with unique identifiers (ORCID, IDRef, IdHAL, VIAF, etc.). The decision to use the repositories coming from large infrastructures such as national libraries, and to align them with those developed by SSH research teams, puts ISIDORE at the heart of the sociotechnical devices of information retrieval. One of the strong points of ISIDORE is the different types of semantic processing performed:

• Annotation or semantic enrichment: the terms present in the document metadata, most often taken from the author keywords, title and abstract, are compared to the repository entries using an algorithm based on a morphological analysis of the terms. If an equivalence is found between a term from the document and an entry in one of the repositories, then the resource will be linked to that repository entry. The repositories are multilingual and aligned with each other. Thus, the semantic annotation is multilingual. Today, ISIDORE enriches in three languages: English, French and Spanish. -For researchers and the world of libraries, documentation and archives, a publication of enriched metadata in the Linked Open Data according to the principles of the Semantic Web (RDF) and through a SPARQL end point5 .

In addition, ISIDORE is used by other portals and sites that exploit certain of its "software components". In 2017, as part of a hackathon with Canadian colleagues from Erudit, the ISIDORE on-demand6 device was born. This modular device now irrigates other portals such as DARIAH7 (with for example the experience of the Parallel Semantic Search Engine), STYLO8 or library discovery tools.

Today, ISIDORE is an ecosystem offering research tools for researchers, doctoral students, librarians and archivists, developers and data-scientists.

A bit of history

The In 2015, ISIDORE was redesigned for the first time to offer enrichment in 3 languages: French, English and Spanish, using the power of the Semantic Web and the terminological alignment between these 3 languages on thousands of concepts. This has already been done for several decades by national libraries and scientists, in major international repositories such as Rameau (Bibliothèque nationale de France, France), LCSH (Library of Congress, USA), or BNE (Biblioteca National de España, Spain), but also in scientific repositories produced by the international SSH scientific communities. In 2018, a major interface update was carried out in order to internationalize ISIDORE through the implementation of a multilingual interface and to add many features for users. Designed with the direct help of SSH researchers (historians, sociologists, geographers, linguists, etc.) and designers from Atelier Universel company, this new interface, based on the principles of a social network between researchers and a scientific monitoring tool, led to the creation of a new website, isidore.science, which is now part of an international distribution such as, for example, the catalogs of the European Open Science Cloud11 and Re3Data12 .

Ten years of learning

In 2009, the conception and realization of ISIDORE were based on a few assumptions and convictions of the founders [START_REF] Poupeau | Bilan de 15 Ans de Réflexion Sur La Gestion Des Données Numériques[END_REF]. The first step was to offer a unified access portal to all scientific publications and data produced by the community of researchers in the social sciences and humanities, since in 2009, searching for a publication required access to about ten portals (HAL-SHS, Persée, Cairn, just for France, etc.), each offering a specific search interface. It was then a question of exploiting the possibilities offered by the use of disciplinary thesauri, to offer more powerful search functionalities than those offered at that time by existing search engines (Google Scholar in particular). This is what is called semantic enrichment in the "isidorian" language (see above). This exploitation was concretized by displaying the generic terms proposed by the various thesauri on the Web interface.

There was also a desire to exploit the possibilities offered by machine learning to categorize documents. This learning technique requires a training set composed of several hundred articles for each category in order to build the classifier (mainly using HAL-SHS and collaborations with INIST-CNRS from 2015 for English and Spanish). The final goal was to contribute to the interoperability between the different repositories of scientific publications by clarifying the data model (the ontology) and formalizing it in the languages of the Semantic Web (RDF, RDFS, SKOS, OWL). Over the ten years, these convictions and hypotheses have been confronted with the implacable criticism of users. It became apparent, through discussions with user panels, that the display of enrichments had limitations and could be a source of errors. Semantic enrichment and automatic categorization offer particularly powerful search tools, but their visualization needed to be redesigned, in particular by exploiting multilingualism. This is the first lesson that was implemented in the current version of ISIDORE.

Towards tomorrow…

The multiplication of search and discovery engines since the early 2000s has made the information search landscape (Pouyllau S. 2020) more complex for researchers [START_REF] Chaudiron | Quelles Analyses de L'usage Des Moteurs de Recherche[END_REF]. ISIDORE, through its inclusion in 2013 in the Huma-Num ecosystem, benefits however from an integration of digital services (centralized authentication, data repositories created with NAKALA13 and harvestable, etc.). But while the Web interfaces have flourished, the search functionalities, which rely on the quality of the indexed data, and on the capacity of the socio-technical device to analyze, group, sort and link them, have mostly remained in their initial state. The creation of processing chains in Machine Learning and especially their exploitation require fast and often complex life cycles in terms of choices and scientific validation of enrichment repositories. However, the development of new technologies, such as Deep Learning or Topic Modelling, opens new horizons.

ISIDORE in the Huma-Num eco-system: from continuous improvement to the HNSO program

Since its creation, ISIDORE has evolved regularly, especially in terms of its semantic enrichment workflows and information processing components. Since 2015, with the addition of annotation, categorization and enrichment in English and Spanish, the processing chains have been extensively updated and reworked. While the year 2018 was dedicated to the evolution of the interfaces and the addition of scientific social network functionalities, since 2019, Huma-Num teams have been working on several improvements that are in progress. We present two of them below, which are currently being finalized.

Managing data in ISIDORE and the arrival of real time in data indexing

Created with a limited number of sources to harvest and index, ISIDORE has grown rapidly in 10 years and the question of real-time updating was quickly raised. The limited resources at the beginning, the difficulties stabilizing the team and other choices such as multilingualism in annotation and categorization have significantly delayed the development of this functionality. For several months, the Huma-Num team, and in particular its ACCES division, which develops the code and components of ISIDORE with Antidot as an industrial partner, have been working on the implementation of a rapid harvesting system: ISIDORE will be updated on a daily basis rather than monthly. The specifications are complex because ISIDORE is not limited to indexing metadata and full text, and the entire processing chain had to be redesigned. In this evolution of ISIDORE, a new database, containing the sources -i.e. the databases to be collected and harvested (in OAI-PMH or with the help of the Sitemap/XML couple and expression in RDFa of metadata) -has been designed by the AC-CES division. It will allow data providers to edit their databases, add collection portals, etc.

Knowing the authors better in order to discover their work and establish collaborations

Another ongoing improvement is the detection of document authors. Author identification is a major feature since ISIDORE offers an academic social network layer. Following authors, discovering the journals in which they publish, the works they deposit in open archives, etc. requires the reliability of author detection and of ISIDORE's ability to, for example, disambiguate homonyms and associate the right identifiers (IdRef, Wikidata, BnF, ORCID, VIAF, ISNI, etc.) to the right people. Beyond that, the aim is to offer new functionalities such as suggesting contact between people working on similar subjects but belonging to different countries or schools of thought, or detecting emerging research themes or experts in a very specialized field [START_REF] Pouyllau | We": A Proposal for the Triple Platform[END_REF]. With the industrial partner Antidot, a new processing workflow has been developed, which allows the analysis of author forms, using machine learning techniques. This is a difficult and meticulous task, which will also require the inclusion of tests with panels of researchers to continuously improve this type of device over the long term.

ISIDORE at the heart of Huma-Num, the work carried out within the framework of the "HNSO" program

More broadly, Huma-Num is committed, with the "Huma-Num Science Ouverte" program financed by the national fund for open science, to developing a vast program of improvement of the two core components: ISIDORE and NAKALA.

In this context, a number of bridges have been built between ISIDORE and NAKALA, in particular in the use of repositories and thesauri provided by the international SSH communities. Using ISIDORE repositories to help researchers index their datasets more efficiently in NAKALA, and using the full text of datasets deposited in NAKALA to improve the classification of documents in ISIDORE, are at the heart of the work being carried out at present and until 2024 in the framework of this "Huma-Num Open Science" program. Beyond the interconnections, which are part of the IT aspects of the development, it is also the entire document workflow that must be rethought, in particular at the level of the life cycle (regular updates, etc.) of the scientific repositories and the ontology of ISIDORE types. This work is being undertaken within the framework of this program. With the joint development of HumanID14 , the "hub" for authentication and access to Web services proposed by Huma-Num, a "seamless" integration of services for researchers is being created at Huma-Num and prefigures what will undoubtedly be at the heart of the vast COMMONS project15 , developed in cooperation with the OpenEdition and Métopes infrastructures. Beyond the software components and methods, HNSO is interested in the future of ISIDORE, in the evolution of information retrieval practices of researchers. This is one of the missions of the HN Lab, whose activities, revolving around 4 research axes, feed the HNSO program and thus the development of ISIDORE.

Towards new methods for semantic content enrichment: neural networks or Topic Modelling

In the last 10 years, semantic classification and annotation techniques have made great progress. Two approaches offer a more efficient categorization and less time-consuming processing. First, the recent progress made in the last five years in the development of Deep Learning architectures based on neural networks (CNN, LSTM, Tranformers) and the construction of large coverage language resources (BERT and DocBERT (Adhikari A. 2019), FLAUBERT, CAMEMBERT, etc.) provide categorizations with an F1 score close to 91%. Nevertheless, these approaches still require training corpora that can be complex to produce. Another approach, Topic Modelling or Latent Dirichlet Analysis (LDA), which is based on the construction of a probabilistic model (Blei, 2001) does not require a training corpus. On the other hand, the categories assigned to the articles (the topics) cannot be predefined. The advantage of these methods -for a tool anchored in research communities that work on very different fields and objects -is that they are better suited to the topics produced by the schools of thought. Nowadays, the emergence of these topics, which can be seen as "short-lived potential concepts", is accelerated by the very rapid diffusion of articles and books in open access. These topics could be linked to the repositories produced by communities, to the repositories of national libraries already present since 2010 in ISIDORE, or even to scientific definitions coming from cooperative devices such as wikidata, full text article database, etc. For example, the work carried out by the HN Lab on the journals "Intermédialités et Études françaises" in partnership with the DSI Group may contribute to these reflections16 . As we can see, in terms of semantic annotation chains, several avenues for improvement are open for the next 10 years of ISIDORE.

  main steps Designed in 2009, the realization of ISIDORE was led by the team of the Very Large Equipment (Très grand équipement) Adonis operated by the CNRS(Maignien 2011) with the assistance of the Atos Consulting company. ISIDORE was developed between October 2009 and December 2010 by the teams of the Centre pour la communication scientifique directe (CCSD) with the involvement of Antidot SA, Sword and Mondéca. ISIDORE was launched in "beta" version(Pouyllau 2011) on December 8, 2010, during the Adonis meeting in Valpré (France) and in full version on April 4, 2011 9 . It is currently developed and operated by the Huma-Num infrastructure 10 teams who continuously improve the different parts and technological components.

  It also became clear that the rapid evolution of research topics requires very regular updates of the repositories from the SSH research communities and updates of the classifier training base. These tasks are extremely time-consuming and could not be performed regularly. A count via a SPARQL query indicates that on July 19, 2021, out of 3,381,711 article-type documents present in ISIDORE, only 2,215,744 are categorized with a confidence of more than 70%, i.e. almost 35% of articles are uncategorized. This second lesson invites us to reflect on the new technologies available to overcome this difficulty. Interoperability, via APIs and the Sparql endpoint, has not led to cross-use with other repositories, particularly on a European scale, whereas other institutions, such as BnF, or projects such as Biblissima, seem to have made better use of these functionalities. The FAIR principles have reinforced the initial choices (the F, A and I) but also questioned the separation between ISIDORE and NAKALA, the latter being in charge of preserving research data (the R). Today, the links between ISIDORE and NAKALA need to be rethought: this is the core of the Huma-Num Open Science program currently underway.

https://isidore.science

Program funded by the National Open Science Fund of the Ministry of Research, Higher Education and Innovation.

https//isidore.science/api

https://isidore.science/sqe

https://rd.isidore.science/ondemand

https://www.dariah.eu

STYLO is a Canadian text editor developped by the Chaire de recherche du Canada sur les écritures numériques (University of Montréal) and the company PiNinja , with the help of Erudit and Huma-Num. See https://stylo.huma-num.fr

https://www.aefinfo.fr/depeche/244085-sciences-humaines-et-sociales-isidore-nouveauportail-web-30-du-cnrs

10 https://www.huma-num.fr

https://marketplace.eosc-portal.eu/services/isidore

http://doi.org/10.17616/R35V2Q

NAKALA, by Huma-Num, is an interoperable and secure service for depositing all types of data (e.g. text files, audio, video, images or other types) in order to share them. See https://documentation.huma-num.fr/humanum-en/

https://humanid.huma-num.fr

See (in French) : https://humanum.hypotheses.org/6466

This work is part of the Revue2.0 research program conducted at the University of Montreal. See HN Lab log for more information.