Lise Voland

Tiphaine Le Roy

Jean Debédat

Prof Karine Clément
email: karine.clement@inserm.fr

Gut microbiota and vitamin status in persons with obesity: a key interplay

Keywords: biotin, gut microbiota, micronutrients, obesity, vitamins

There are numerous factors involved in obesity progression and maintenance including systemic low-grade inflammation, adipose tissue dysfunction or gut microbiota dysbiosis.

Recently, a growing interest has arisen for vitamins' role in obesity and related disorders, both at the host and gut bacterial level. Indeed, vitamins are provided mostly by food but some, from the B and K groups in particular, can be synthesized by the gut bacterial ecosystem and absorbed in the colon. Knowing that vitamin deficiency can alter many important cellular functions and lead to serious health issues, it is important to carefully monitor the vitamin status of patients with obesity and potentially already existing comorbidities as well as dysbiotic gut microbiota and thus potentially altered bacterial metabolism of vitamins. In this review, we examined both murine and human studies, to assess the prevalence of sub-optimal levels of several vitamins in obesity and metabolic alterations. This review also examines the relationship between vitamins and the gut microbiota in terms of vitamin production and the modulation of the gut bacterial ecosystem in conditions of vitamin shortage or supplementation. Furthermore, some strategies to improve vitamin status of patients with severe obesity are proposed within this review.

Introduction

Obesity represents a global health issue with an ever-increasing prevalence over the last 50 years [START_REF] Clément | Trends in adult body-mass index in 200 countries from 1975 to 2014: a pooled analysis of 1698 population-based measurement studies with 19•2 million participants[END_REF][START_REF]NCD-RisC). Worldwide trends in body-mass index, underweight, overweight, and obesity from 1975 to 2016: a pooled analysis of 2416 population-based measurement studies in 128•9 million children, adolescents, and adults[END_REF] . It is expected that over 40% of the world's population will suffer from obesity by 2030 [START_REF] Kelly | Global burden of obesity in 2005 and projections to 2030[END_REF] . Obesity is associated with several complications such as type 2 diabetes, cardiovascular diseases and cancers [START_REF] Segula | Complications of obesity in adults: A short review of the literature[END_REF] . Triggered by multiple environmental factors, the development and progression of obesity are characterized by organ structural and biological alterations and systemic low-grade inflammation. Recently, the gut microbiota (GM) has emerged as a contributive "organ" in the development and maintenance of obesity.

The GM is a complex and abundant ecosystem composed of trillions of microorganisms including bacteria, viruses, archaea, fungi, and phages. The microorganisms present within the gut harbor a myriad of functions, and in particular, the GM is implicated in the fermentation of non-digestible food substrates. This microbial metabolism leads to the production of an important variety of metabolites, which in return are known to have a broad range of bioactivities, including immune modulation and intestinal barrier homeostasis. During obesity, an imbalance in the GM composition, functionality, as well as a decreased bacterial richness and diversity, collectively referred to as GM dysbiosis, have been reported by many studies [START_REF] Crovesy | Profile of the gut microbiota of adults with obesity: a systematic review[END_REF] .

Among the numerous GM-derived metabolites (as short chain fatty acids, secondary bile acid molecules, tryptophan derivates to cite only a few), vitamins have been relatively neglected in this context. Yet, gut bacteria are known to produce vitamins from the B and K groups [START_REF] Valdes | Role of the gut microbiota in nutrition and health[END_REF] . Vitamins are essential micronutrients, obtained from food and, to some extent, from gut bacterial synthesis. Vitamins serve as coenzymes or cofactors for numerous processes involved in host energy metabolism [START_REF] Huskisson | The Role of Vitamins and Minerals in Energy Metabolism and Well-Being[END_REF] (Table 1). For example, B vitamins play a key role in maintaining mitochondrial energy metabolism, which is altered by inadequate levels of any of those vitamins [START_REF] Depeint | Mitochondrial function and toxicity: role of B vitamins on the one-carbon transfer pathways[END_REF] (Table 1). Vitamin deficiency, due to an imbalanced diet, increased host physiological requirements or altered drug-micronutrient interactions, affects host health in varying ways and can lead to severe clinical consequences, ranging from fatigue to dermatological, digestive, cardiovascular or neurological and depressive disorders [START_REF] Porter | Causes, Consequences and Public Health Implications of Low B-Vitamin Status in Ageing[END_REF] (Table 1).

Dietary vitamin absorption occurs mainly in the small intestine for the dietary vitamins but it is now acknowledged that the distal gut may also contribute to vitamin absorption and especially bacterially-produced vitamins [START_REF] Said | Intestinal absorption of water-soluble vitamins in health and disease[END_REF] . Thus, the alteration of the intestinal environment and absorptive capacities potentially alters vitamins host vitamin status.

Despite increasing evidence of deep alterations of gut physiology as well as microbiota composition and functionality observed during obesity and metabolic disorders, the consequences on vitamins biosynthesis and availability have scarcely been studied. Herein, we review vitamin status alterations observed in obesity and metabolic disorders and focus on the production potential of vitamins by the GM as well as its modulation by both vitamin supplementation and deficiency, mostly focusing on B and D vitamins. We also discuss some future strategies for vitamin status management in severe obesity.

Evidence of vitamin deficiency in obesity and related metabolic disorders in humans

The optimal vitamin reference levels for the general population are reported by national or international expert committees such as the European Food Safety Authority (EFSA) [START_REF]Tolerable Upper Intake Levels for Vitamins and Minerals[END_REF] or the US Centers for Disease and Prevention through the National Health and Nutrition Examination Survey (NHANES). Lately, an increasing interest for vitamin status in subjects with obesity has arisen as many studies have revealed that obesity and related metabolic complications are associated with deficiencies or at least sub-optimal blood concentrations of many vitamins, which has been well-reviewed recently [START_REF] Astrup | Overfed but undernourished: recognizing nutritional inadequacies/deficiencies in patients with overweight or obesity[END_REF][START_REF] Thomas-Valdés | Association between vitamin deficiency and metabolic disorders related to obesity[END_REF] . Briefly, a series of studies exploring different populations with metabolic alterations revealed suboptimal blood level of B vitamins, including vitamin B1 (thiamine), B9 (folate), B6 (pyridoxine), B12 (cobalamin). A decrease of vitamin B9 has been observed in pregnant women with overweight in comparison to women with a BMI ranging between 18 and 25 kg/m² [START_REF] Santacruz | Gut microbiota composition is associated with body weight, weight gain and biochemical parameters in pregnant women[END_REF] . Similarly, another study on patients with severe obesity reported an important decrease of vitamin B6 serum concentrations as compared to patients without obesity [START_REF] Aasheim | Vitamin status in morbidly obese patients: a cross-sectional study[END_REF] .

Moreover, up to 75% patients with type 2 diabetes presented low blood concentration of vitamin B1 [START_REF] Thornalley | High prevalence of low plasma thiamine concentration in diabetes linked to a marker of vascular disease[END_REF] . Vitamin B12 levels have also been linked with obesity with a significant negative correlation reported between body mass index (BMI) and vitamin B12 blood levels in a cohort of almost 1000 patients with obesity [START_REF] Baltaci | Association of vitamin B12 with obesity, overweight, insulin resistance and metabolic syndrome, and body fat composition; primary care-based study[END_REF] . Moreover, the authors of this study also found a trend toward decreased vitamin B12 blood concentrations in subjects with insulin resistance or metabolic syndrome in comparison to participants without metabolic alterations [START_REF] Baltaci | Association of vitamin B12 with obesity, overweight, insulin resistance and metabolic syndrome, and body fat composition; primary care-based study[END_REF] . In another cohort of participants with overweight or obesity, 13% of participants were found to be deficient in vitamin B12 [START_REF] Geiker | Effect of low energy diet for eight weeks to adults with overweight or obesity on folate, retinol, vitamin B12, D and E status and the degree of inflammation: a post hoc analysis of a randomized intervention trial[END_REF] while in the general US population, the prevalence of vitamin B12 was found to be around 5% and increases with age [START_REF] Allen | How common is vitamin B-12 deficiency?[END_REF] . Interestingly, the serum levels of vitamin B12 are increased after a weight loss induced by a Low Energy Diet (LED) [START_REF] Geiker | Effect of low energy diet for eight weeks to adults with overweight or obesity on folate, retinol, vitamin B12, D and E status and the degree of inflammation: a post hoc analysis of a randomized intervention trial[END_REF] . Another B vitamin, vitamin B7 (biotin) has been shown to be decreased in subjects with moderate obesity [START_REF] Järvinen | Biotin-dependent functions in adiposity: a study of monozygotic twin pairs[END_REF] and type 2 diabetes [START_REF] Maebashi | Therapeutic Evaluation of the Effect of Biotin on Hyperglycemia in Patients with Non-Insulin Dependent Diabetes Mellitus[END_REF] . Yet, this vitamin has been neglected in the context of obesity and metabolic disorders; as well as other B vitamins such as vitamins B2 (riboflavin), B3 (niacin).

Vitamin deficiency in metabolic disorders extends to vitamin D as well. In Geiker et al., insufficient levels of vitamin D were observed in 72% of the participants before the LEDinduced weight loss, and again, the serum concentration of vitamin D was increased after the nutritional intervention [START_REF] Geiker | Effect of low energy diet for eight weeks to adults with overweight or obesity on folate, retinol, vitamin B12, D and E status and the degree of inflammation: a post hoc analysis of a randomized intervention trial[END_REF] . Unlike B vitamins, the links between vitamin D status and obesity and its complications have been investigated in a larger number of studies and were reported as early as 1985 [START_REF] Liel | Low circulating vitamin D in obesity[END_REF] . It has been commonly accepted that vitamin D deficiency can be estimated via the serum concentration of the vitamin D metabolite, 25-hydroxycholecalciferol [25(OH)D], the active form of vitamin D, which integrates both the dietary intake and the endogenous production. For example, analyses in a large population of older individuals revealed a significant inverse association between BMI and more specifically adiposity (especially in the 3 rd and 4 th quartile when fat percentage was divided in quartiles) and serum 25(OH)D concentrations [START_REF] Araghi | BMI and body fat mass is inversely associated with vitamin D levels in older individuals[END_REF] . Moreover, several groups also showed inverse correlations between 25(OH)D serum concentrations and markers of metabolic alterations such as triglycerides [START_REF] Botella-Carretero | Vitamin D deficiency is associated with the metabolic syndrome in morbid obesity[END_REF] or fasting glucose and the HOMA-IR index, a surrogate marker of insulin resistance [START_REF] Devaraj | Low Vitamin D Levels in Northern American Adults with the Metabolic Syndrome[END_REF] . An observational transversal study including 73 patients with morbid obesity confirmed the higher prevalence of vitamin D deficiency in comparison to the population without obesity [START_REF] Botella-Carretero | Vitamin D deficiency is associated with the metabolic syndrome in morbid obesity[END_REF] . Here, they found that 50.7% of the participants had vitamin D deficiency.

They also reported an increased prevalence of vitamin D deficiency associated with the occurrence of metabolic syndrome in this population. This correlation was confirmed in a large study of over 2 500 Chinese men and women, in which, lower 25(OH)D serum concentration was associated with increased insulin resistance among the participants with overweight or obesity [START_REF] Lu | Plasma 25-Hydroxyvitamin D Concentration and Metabolic Syndrome Among Middle-Aged and Elderly Chinese Individuals[END_REF] . Finally, a recent meta-analysis of 43 studies confirmed this inverse association between serum concentration of vitamin D and risk of metabolic syndrome in the general adult population [START_REF] Hajhashemy | Serum vitamin D levels in relation to metabolic syndrome: A systematic review and dose-response meta-analysis of epidemiologic studies[END_REF] . In animals, vitamin D deficiency associates with worsened obesity condition, glucose intolerance and insulin resistance induced by a high-fat diet whereas no such effect for animals experimenting vitamin D deficiency under standard diet were observed [START_REF] Su | Vitamin D Signaling through Induction of Paneth Cell Defensins Maintains Gut Microbiota and Improves Metabolic Disorders and Hepatic Steatosis in Animal Models[END_REF] . Thus, it seems that inadequate levels of vitamin D in the context of obesity could worsen the individual metabolic health. Low levels of vitamin D are not only linked with different health conditions such as loss of bone density but also diabetes, high blood pressure, or multiple sclerosis. It also appears that vitamin D deficiency can impede bariatric surgeryinduced metabolic improvements. Interestingly, in a mouse model of vertical sleeve gastrectomy, deficient levels of vitamin D were linked with decreased weight loss and glucose homeostasis improvements, as well as intestinal inflammation and permeability [START_REF] Zhang | Effects of vitamin D deficiency on the improvement of metabolic disorders in obese mice after vertical sleeve gastrectomy[END_REF] . In addition to those metabolic observations regarding vitamin D, many studies also reported strong links of this vitamin with adipose tissue in terms of vitamin D storage but also modulation of adipocyte differentiation or even energy metabolism and inflammation by this vitamin. These aspects have been largely and well-reviewed recently [START_REF] Park | The Role of Vitamin D in Adipose Tissue Biology: Adipocyte Differentiation, Energy Metabolism, and Inflammation[END_REF] .

Alteration of vitamin status in the context of bariatric surgery

Vitamin deficiency in obesity has also been investigated in subjects with severe obesity undergoing bariatric surgery. For example, studies showed that the prevalence of vitamin B1 deficiency in patients with severe obesity before bariatric surgery is between 15.5% 31 and 29% [START_REF] Flancbaum | Preoperative nutritional status of patients undergoing Roux-en-Y gastric bypass for morbid obesity[END_REF] . In the general population, vitamin B1 deficiency is associated with inadequate intake and is more prevalent in underdeveloped countries whereas in industrialized countries, vitamin B1 deficiency is rare and mostly related to alcoholism [START_REF] Fattal-Valevski | Thiamine (Vitamin B1)[END_REF] . Vitamin B9 has also been found to be decreased in patients with severe obesity before the surgery at a rate of 63.2% [START_REF] Krzizek | Prevalence of Micronutrient Deficiency in Patients with Morbid Obesity Before Bariatric Surgery[END_REF] , a much higher percentage in comparison to the general population prevalence of 2% reported by a recent study in the US [START_REF] Diaz | Prevalence of Folic Acid Deficiency and Cost Effectiveness of Folic Acid Testing: A Single Center Experience[END_REF] . Importantly, these studies focused on bariatric surgery candidates who follow weight-loss efforts for several months before the procedures, as recommended by international guidelines [START_REF] Mechanick | Clinical practice guidelines for the perioperative nutrition, metabolic, and nonsurgical support of patients undergoing bariatric procedures -2019 update: cosponsored by American Association of Clinical Endocrinologists/American College of Endocrinology, The Obesity Society, American Society for Metabolic & Bariatric Surgery, Obesity Medicine Association, and American Society of Anesthesiologists[END_REF] . As such, these patients may have reduced vitamin intake due to changes in their diet. Flancbaum and colleagues also revealed a high proportion (68%) of patients presenting with a vitamin D deficiency before the surgery, which was confirmed in two other cohorts with deficiency rates of 74.35% 37 and 76% [START_REF] Al-Mutawa | Nutritional Status of Bariatric Surgery Candidates[END_REF] . In comparison, a study of vitamin D blood concentrations in elderly people across 11 European countries reported a prevalence of vitamin D deficiency in 36% of men and 42 % of women in the general population [START_REF] Van Der Wielen | Serum vitamin D concentrations among elderly people in Europe[END_REF] . This percentage was even lower in the US population with a prevalence of vitamin D deficiency of 4.0% and 17.4% for inadequacy [START_REF] Orces | The Prevalence and Determinants of Vitamin D Inadequacy among U.S. Older Adults: National Health and Nutrition Examination Survey 2007-2014[END_REF] . To note, vitamin D blood concentration is dependent on the season as well as geographical location, which could explain such discrepancies between prevalence in different populations and studies. The two latter studies investigating vitamin D blood concentrations also reported vitamin B12 deficiency in those patients, reaching 12.3% 37 and 16% 38 respectively. Moreover, most vitamins are absorbed in the small intestine, a segment bypassed after malabsorptive procedures (e.g., Roux-en-Y Gastric Bypass or biliopancreatic derivation). This purposefully-induced malabsorption further deteriorates vitamin status after the surgical procedure, which may not normalize despite systematic vitamin supplementation. During surgical follow-up, monitoring patients' vitamin status should be reinforced, which is highlighted by studies of micronutrient deficiencies after Roux-en-Y gastric bypass as well as sleeve gastrectomy [START_REF] Verger | Micronutrient and Protein Deficiencies After Gastric Bypass and Sleeve Gastrectomy: a 1-year Follow-up[END_REF][START_REF] Ha | Micronutrient status in bariatric surgery patients receiving postoperative supplementation per guidelines: Insights from a systematic review and metaanalysis of longitudinal studies[END_REF] . In fact, despite medical recommendation of micronutrients and especially multivitamins supplementation after the surgery, evidence of decreased compliance has been reported after 10 years of follow-up increasing the risk of vitamin deficiency [START_REF] Mehaffey | Nutrient Deficiency 10 Years Following Roux-en-Y Gastric Bypass: Who's Responsible?[END_REF] . It is also possible that the optimization of the pre-operative vitamin status could also contribute to better outcomes of the surgery. It has been suggested that vitamin D could, for example, contribute to improved weight loss following bariatric surgery [START_REF] Slusher | A therapeutic role for vitamin D on obesity-associated inflammation and weight-loss intervention[END_REF] . A recent review addressed this concern in terms of vitamin status and the physiological, metabolic and also bacterial changes associated with bariatric surgery [START_REF] Clément | A place for vitamin supplementation and functional food in bariatric surgery?[END_REF] . More attention should be given to vitamin status of patients before and after the bariatric surgery as suggested by recent guidelines published by the British Obesity and Metabolic Surgery Society [START_REF] O'kane | British Obesity and Metabolic Surgery Society Guidelines on perioperative and postoperative biochemical monitoring and micronutrient replacement for patients undergoing bariatric surgery-2020 update[END_REF] . The aforementioned studies suggest that acting on the pre-intervention vitamin deficiency might help potentialize metabolic improvement, although more clinical interventions ought to be performed to confirm this hypothesis.

Gut microbiota; a source of vitamin production

The composition of the GM has now been meticulously studied over the last decade thanks to major advances in sequencing technologies. Nevertheless, a recent shift towards understanding the functionality of the ecosystem allows for more complete comprehension of how GM modulations are involved in health and diseases. Gut bacteria produce a very large number of metabolites having an impact on the host metabolism [START_REF] Agus | Gut microbiota-derived metabolites as central regulators in metabolic disorders[END_REF] . The gut bacteria can produce vitamin K and B vitamins [START_REF] Hill | Intestinal flora and endogenous vitamin synthesis[END_REF] ; however the interest for the study of the relationship between GM and vitamin metabolism is only recent and increasing.

The number of available bacterial genomes increased significantly with the advances in sequencing technologies and metagenomic processing methods, which have allowed for better characterization of GM species and their metabolic capabilities. In 2015, Magnúsdóttir et al., used the PubSEED platform, which provides genome annotations across thousands of genomes, to analyze the ability of human GM organisms to synthesize B vitamins [START_REF] Magnúsdóttir | Systematic genome assessment of Bvitamin biosynthesis suggests co-operation among gut microbes[END_REF] . Thus, they were able to determine that the biosynthesis of B vitamins was common among the species found in the human GM. They also predicted B vitamin synthesis abilities that matched published experimental data. It appears that the synthesis of vitamin B2 and vitamin B3 were most commonly found among all the genomes assessed. Altogether, this study reinforces the idea that the GM, as an ecosystem, is able to produce vitamins and possibly participates to vitamin homeostasis of the host. Yet, this paper revealed that the production of vitamins by the GM is not sufficient to cover host daily requirements. Moreover, the vitamins synthesized in the gut mostly benefit the neighboring non-producing bacteria through cross-feeding between organisms. To this end, bacterial genome analyses have illustrated that bacterial species can be vitamin prototrophs (capable of de novo synthesis) or auxotrophs (dependent on the uptake and salvage of vitamins) highlighting the importance of cross-feeding between GM species [START_REF] Rodionov | Micronutrient Requirements and Sharing Capabilities of the Human Gut Microbiome[END_REF] .

Further evidence of GM mutualism for vitamins comes from co-culture in vitro experiments showing that Anaerobutyricum halii is able to synthesize and provide Akkermansia muciniphila with B12 vitamin, which is used for propionate production [START_REF] Belzer | Microbial Metabolic Networks at the Mucus Layer Lead to Diet-Independent Butyrate and Vitamin B12 Production by Intestinal Symbionts[END_REF] . Such cross-feeding mechanisms have also been observed in vivo, where non-producing bacteria survive during limitation of vitamin intake suggesting the existence of vitamin sharing between producing and non-producing bacteria [START_REF] Sharma | B-Vitamin Sharing Promotes Stability of Gut Microbial Communities[END_REF] . Bacterial mutualism thus contributes to maintaining a relative GM stability thanks to the sharing of micronutrient resources in case of shortage or level modulation due to vitamin intake variability [START_REF] Sharma | B-Vitamin Sharing Promotes Stability of Gut Microbial Communities[END_REF] . Noteworthy Anaerobutyricum halii and Akkermansia muciniphila are both commensal bacteria associated with improved metabolism [START_REF] Cani | Next-Generation Beneficial Microbes: The Case of Akkermansia muciniphila[END_REF][START_REF] Udayappan | Oral treatment with Eubacterium hallii improves insulin sensitivity in db/db mice[END_REF] .

Together with experimental work, the access to genomic annotation allowed for the identification of specific vitamin producing bacterial strains. It is now known for example, that species from the genera Lactobacillus and Bifidobacterium can produce vitamin B9. Indeed, both in vitro and in vivo experiments demonstrated that Bifidobacterial strains are able to increase the vitamin B9 concentration either in the medium or of the host [START_REF] Pompei | Folate Production by Bifidobacteria as a Potential Probiotic Property[END_REF][START_REF] Pompei | Administration of Folate-Producing Bifidobacteria Enhances Folate Status in Wistar Rats[END_REF] . This ability of vitamin B9 production by Lactobacillus and Bifidobacterium was assessed via the analysis of genome sequences. The presence of genes and enzymes involved in different steps of the vitamin B9 production pathway allowed to infer theoretical capacity of the studied strains to produce this vitamin at least from a precursor molecule [START_REF] Rossi | Folate production by probiotic bacteria[END_REF] . Nevertheless, it is important to note that the presence of genes involved in the production of a vitamin does not account for its effective production by the bacteria. Thus, experimental validation (in vitro and in vivo) remains crucial to identify potential vitamin-producing strains that could then be developed as probiotics.

To explore the contribution of GM's vitamin synthesis, in various diseases including metabolic diseases, in vivo experiments are needed. Germ-Free (GF) rodents are an initial model used to determine the general contribution of the GM to metabolic pathways or host physiology. In the absence of GM in GF mice, a systemic deficiency in different vitamins was reported [START_REF] Gustafsson | Effects of Vitamin K-Active Compounds and Intestinal Microorganisms in Vitamin K-Deficient Germfree Rats[END_REF][START_REF] Fridericia | Refection, a Transmissible Change in the Intestinal Content, enabling Rats to grow and thrive without Vitamin B in the Food[END_REF] , suggesting again that those vitamins can be produced by the GM and that microbial vitamin production contributes, at least partially, to vitamin homeostasis of the host. Among those vitamins, earlier studies showed that GF rats developed spontaneously a vitamin K deficiency leading to increased mortality of the animals [START_REF] Gustafsson | Effects of Vitamin K-Active Compounds and Intestinal Microorganisms in Vitamin K-Deficient Germfree Rats[END_REF] . The side effects of vitamin K deficiency were corrected by vitamin K1 supplementation and most interestingly with the gut colonization of single strains of bacteria (Escherichia coli or Sarcina-like micrococcus).

Similar results have been found for B vitamins as rats fed a diet deprived of B vitamins stopped growing after 1 to 3 weeks and died prematurely [START_REF] Fridericia | Refection, a Transmissible Change in the Intestinal Content, enabling Rats to grow and thrive without Vitamin B in the Food[END_REF] . Yet, in this early study, one rat behaved differently and recovered from the deficiency. When its feces were added to the diet of another group of rats fed the same diet, the symptoms of vitamin B deficiency disappeared in those animals, suggesting that B vitamin-producing bacteria could be present in the feces these rats were given.

Other evidence of B vitamin production by intestinal microorganisms have been reported. The total output of vitamin B7 measured in feces and urine has been shown to be six times greater than the intake in humans, suggesting a production by the GM [START_REF] Bender | Nutritional Biochemistry of the Vitamins[END_REF][START_REF] Oppel | Studies of Biotin Metabolism in Man. Part I. The Excretion of Biotin in, Human Urine[END_REF] while this needs further exploration. Interestingly, vitamin B7 deficiency induced alopecia only in GF animals and not in conventionally raised animals suggesting that the GM contributes to this vitamin metabolism [START_REF] Hayashi | Intestinal Dysbiosis and Biotin Deprivation Induce Alopecia through Overgrowth of Lactobacillus murinus in Mice[END_REF] . A similar phenotype was observed in vitamin B7-deficient mice treated with an antibiotic, vancomycin, again suggesting a contribution of GM to vitamin B7 production. Moreover, those animals presented further reduction in bacterial diversity as well as major increase of Lactobacillus genus and in particular Lactobacillus murinus in comparison to antibiotic treated animals receiving sufficient levels of vitamin B7. Regarding other B vitamins, GM depletion via antibiotic treatment resulted in a decrease of vitamin B6 levels in colonic content in mice [START_REF] Miki | The Bactericidal Lectin RegIIIβ Prolongs Gut Colonization and Enteropathy in the Streptomycin Mouse Model for Salmonella Diarrhea[END_REF] .

These observations all identify the GM as a major contributor to the host's vitamin status. Nevertheless, the contribution of the GM's vitamin production to host vitamin circulating levels remains to be experimentally established, in healthy and disease conditions. Indeed, in the context of obesity, alteration in GM richness, diversity and functional anomalies have repeatedly been reported [START_REF] Agus | Gut microbiota-derived metabolites as central regulators in metabolic disorders[END_REF][START_REF] Chatelier | Richness of human gut microbiome correlates with metabolic markers[END_REF][START_REF] Cotillard | Dietary intervention impact on gut microbial gene richness[END_REF][START_REF] Prifti | Major microbiota dysbiosis in severe obesity: fate after bariatric surgery[END_REF] . Whether these alterations are linked to deficient bacterial vitamin metabolism and production need to be investigated in depth.

Consequence of vitamin deficiencies on GM composition

As raised above, the production of vitamin K by the GM has been known for several decades; but the effect of its deficiency on the GM composition has been studied very recently. Thus, mice fed a vitamin K deficient diet displayed reduced abundance of Lactobacillus and enrichment in Ruminococcus, Anaerostipes genera as well as Muribaculaceae family in comparison to animals supplemented with vitamin K [START_REF] Ellis | Dietary vitamin K is remodeled by gut microbiota and influences community composition[END_REF] .

A murine study investigating the effect of different micronutrient-deficient (vitamin A, vitamin B9, iron, zinc, or multiple deficiencies) diet on the GM revealed that the vitamin A deficiency had the higher impact [START_REF] Hibberd | The effects of micronutrient deficiencies on bacterial species from the human gut microbiota[END_REF] , although vitamin A is not produced by the GM. The analysis of the GM of mice fed a vitamin A deficient diet revealed an increase of Bacteroides vulgatus and an increase of Bacteroides dorei. Once the deficiency was corrected via a micronutrient sufficient supplementation of the diet, the initial levels of those bacteria were also restored.

In a human study investigating the GM children with vitamin A deficiency, changes in the bacterial community composition were also reported [START_REF] Feng | Faecal microbiota from children with vitamin A deficiency impairs colonic barrier function in germ-free mice: the possible role of alterative bile acid metabolites[END_REF] . Increased abundances of Blautia and Faecalibacterium genera and decreased abundances of Bifidobacterium, Bacteroides and Shigella were observed in these children. The modulations of Bifidobacterium and Bacteroides levels were even transmitted via fecal microbiota transfer of the children's feces into germfree animals. At the phylum level, a decrease of Bacteroidetes was observed in mice fed a vitamin A-deficient diet [START_REF] Tian | Vitamin A deficiency in mice alters host and gut microbial metabolism leading to altered energy homeostasis[END_REF] . This decrease is associated with an increase of the Firmicutes/Bacteroidetes ratio in those animals, which has been reported associated with obesity and metabolic alterations [START_REF] Ley | Microbial ecology: human gut microbes associated with obesity[END_REF] , despite discrepancies in recent studies [START_REF] Jumpertz | Energy-balance studies reveal associations between gut microbes, caloric load, and nutrient absorption in humans123[END_REF][START_REF] Duncan | Human colonic microbiota associated with diet, obesity and weight loss[END_REF] . To be noted, in this study, vitamin A-deficient animals presented characteristics of pre-diabetes with hyperglycemia and delayed response to insulin injection, emphasizing the potential links with metabolic alterations.

In the last decade, there has been an increasing number of studies investigating the links between vitamin D and the GM. One of them investigated the factors explaining the most the variance in alpha-diversity of the human GM, and found that the serum concentration of 1,25(OH)2D was the most contributing variable, explaining 5% of the variance of the alphadiversity [START_REF] Thomas | Vitamin D metabolites and the gut microbiome in older men[END_REF] . In terms of specific compositional changes associated with vitamin D deficiency, it seems that vitamin D deficiency (in models of knock-out mice for the vitamin D receptor (VDR), not able to produce 1,25(OH)2D) appeared to be associated with a decrease of the abundance of the phylum Firmicutes [START_REF] Ooi | Vitamin D Regulates the Gut Microbiome and Protects Mice from Dextran Sodium Sulfate-Induced Colitis123[END_REF] and the associated families Ruminococcaceae, Lachnospiraceae, Lactobacillaceae and Streptococcaceae. Interestingly, in another study on VDR KO mice, a significant decrease of the abundance of the genus Lactobacillus was observed in comparison to wild-type animals [START_REF] Jin | Lack of Vitamin D Receptor Causes Dysbiosis and Changes the Functions of the Murine Intestinal Microbiome[END_REF] . In a human trial on older men, a positive association was also found between serum 1,25(OH)2D levels and the abundance of the genus Ruminococcus 74 . On the contrary, vitamin D deficiency seems to be associated with an increase in Bacteroidetes and Proteobacteria phyla, and more precisely Bacteroidaceae and Desulfovibrionaceae families [START_REF] Ooi | Vitamin D Regulates the Gut Microbiome and Protects Mice from Dextran Sodium Sulfate-Induced Colitis123[END_REF] . This increase was again confirmed in the study from Jin and colleagues, in which an increase in the genus Bacteroides was noticed in VDR KO animals [START_REF] Jin | Lack of Vitamin D Receptor Causes Dysbiosis and Changes the Functions of the Murine Intestinal Microbiome[END_REF] . In the murine study by Zhang et al., investigating the effect of vitamin D deficiency on the metabolic improvements after vertical sleeve gastrectomy, they also analyzed the effects on the GM composition. The authors revealed that, despite known beneficial effects induced by the surgery itself, deficient levels of vitamin D were associated with limited improvements of the gut dysbiosis induced by the high-fat diet feeding. Indeed, the effects of the surgery, a decrease of Firmicutes and an increase of Bacteroidetes phyla abundance, were weaker in the group of vitamin-D-deficient animals post-surgery in comparison to the group with normal levels of vitamin D [START_REF] Zhang | Effects of vitamin D deficiency on the improvement of metabolic disorders in obese mice after vertical sleeve gastrectomy[END_REF] .

The effect of B vitamins deficiency on the GM has also been recently studied in the context of metabolic diseases. In a recent study, the effects of low B6 vitamin levels on host phenotype and GM of weaning rats was explored [START_REF] Mayengbam | Dietary Vitamin B6 Deficiency Impairs Gut Microbiota and Host and Microbial Metabolites in Rats[END_REF] . The animals receiving a standard chow diet with low levels of vitamin B6 displayed a decreased body weight and circulating triglycerides levels compared to control animals as well as changes in the GM composition.

Indeed, an increase in Lachnospiraceae and a decrease of Bacteroides were observed in both male and female rats.

In patients with obesity, an association was found between low niacin (vitamin B3) intake and reduced alpha-diversity as well as levels of Bacteroidetes. These findings were particularly significant in subjects with obesity and insulin-resistance but not with overt type 2 diabetes [START_REF] Fangmann | Targeted Microbiome Intervention by Microencapsulated Delayed-Release Niacin Beneficially Affects Insulin Sensitivity in Humans[END_REF] . The authors suggested that in patients with type 2 diabetes, medications such as metformin known to modulate the GM [START_REF] Forslund | Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota[END_REF][START_REF] Sun | Gut microbiota and intestinal FXR mediate the clinical benefits of metformin[END_REF] should be taken into account to explain those differences.

These collective findings illustrate the need to investigate the interplay between GM, vitamin and host metabolism. Yet, few studies investigated the effects of vitamin deprivation on the GM composition in the context of obesity and metabolic disorders. Considering the links between obesity, GM dysbiosis and alteration of vitamin status as presented above, it is important to study these factors to decipher the mechanisms involved.

Effect of vitamin supplementation on GM

Recent interest regarding the effect of vitamin supplementation on the composition of the GM has led to an increase of publications on this topic. A recent review extensively summarized the effects of vitamins and other dietary micronutrients such as polyphenols and minerals on the composition of the GM [START_REF] Yang | Role of Dietary Nutrients in the Modulation of Gut Microbiota: A Narrative Review[END_REF] . Although no clear patterns of GM modulation can be identified from this review due to a relatively low number of studies for some vitamins and a great variability in experimental designs, it seems that vitamin supplementation can induce significant changes in GM composition.

In the context of obesity, the establishment of multiple large cohorts in the last decade has allowed the collection of important data sets of microbiome analysis, clinical and lifestyle information. Data from the American Gut Project were used to assess the impact of vitamin B and/or D supplementation on the GM in groups of people with normal weight (NW) or overweight (OW) [START_REF] Jiang | Vitamin B and vitamin D as modulators of gut microbiota in overweight individuals[END_REF] . Despite no significant impact on alpha-diversity indexes in all groups, the vitamin supplementation alone had almost no effect in NW group but had beneficial impact in OW. Noteworthy, vitamin B supplementation induced a significant decrease in Tenericutes at the phylum level and several groups at the family level (Mogibacteriaceae, Porphyromonadaceae, Coriobacteriaceae and Comamonadaceae). All these bacterial families have been associated with infections, inflammation and even obesity in the literature, suggesting that vitamin B supplementation in the context of obesity could help decrease the abundance of pathogens in the GM [START_REF] Almuzara | First report of Comamonas kerstersii causing urinary tract infection[END_REF][START_REF] Giannelli | Microbiota and the gut-liver axis: Bacterial translocation, inflammation and infection in cirrhosis[END_REF][START_REF] Clavel | Enterorhabdus caecimuris sp. nov., a member of the family Coriobacteriaceae isolated from a mouse model of spontaneous colitis, and emended description of the genus Enterorhabdus Clavel et al[END_REF][START_REF] Wu | Characterization of the salivary microbiome in people with obesity[END_REF] . Regarding vitamin D supplementation, effects on the GM composition were observed both in the NW and OW groups. In NW group, it induced a decrease of several families Erysipelotrichaceae, Turicibacteraceae and Bifidobacteriaceae.

The same effect on this last beneficial family was observed among OW participants, as well as a decrease of pathogens (Actinomycetaceae) for this group. The effects of a combined vitamin B and D supplementation was also investigated and showed a decrease of Lachnospiraceae and Enterobacteriaceae, which have been shown to be associated with obesity and production of endotoxins respectively [START_REF] Kameyama | Intestinal colonization by a Lachnospiraceae bacterium contributes to the development of diabetes in obese mice[END_REF][START_REF] Xie | Clinical features and antimicrobial resistance profiles of important Enterobacteriaceae pathogens in Guangzhou representative of Southern China, 2001-2015[END_REF] .

Vitamin supplements, and in particular vitamin D, also had an important impact on the functionality of the GM [START_REF] Jiang | Vitamin B and vitamin D as modulators of gut microbiota in overweight individuals[END_REF] . In NW groups, there was a decrease in genes implicated in aminoacids biosynthesis and an increase of vitamin biosynthesis (related to vitamin B1 and B5) in the GM of people supplemented with vitamin D. Those pathways were not impacted by vitamin D in the OW group. Here again, the association of the two vitamins had specific effect regarding the functional machinery of bacteria. The authors observed a decrease in the potential of amino acid consumption by GM and of the degradation of polysaccharides in the OW group. This paper supports the beneficial effects of vitamin D (alone or combined with vitamin B) on microbial communities in a context of overweight or obesity, although effects vary according to the severity of obesity.

Another recent trial of vitamin D supplementation over 16 weeks in overweight and patients with obesity showed modulation of the GM composition [START_REF] Naderpoor | Effect of Vitamin D Supplementation on Faecal Microbiota: A Randomised Clinical Trial[END_REF] . Despite no effect on alpha-diversity, vitamin D supplementation was associated with an increase of Lachnospira genus and a decrease of the abundance of Blautia genus in comparison to the group receiving placebo. Moreover, the authors observed a significant correlation between serum levels of 25(OH)D and the abundance of Coprococcus genus. Yet, these studies remain quite small in size as only 17 people received vitamin D supplementation and 15 received the placebo in the Naderpoor study [START_REF] Naderpoor | Effect of Vitamin D Supplementation on Faecal Microbiota: A Randomised Clinical Trial[END_REF] . In the study from Jiang and colleagues, the groups of people with overweight supplemented with only vitamin D, or only vitamin B, or both vitamins comprised respectively 88, 16 and 214 individuals, and supplementation was based on dietary supplement intakes self-reported by patients [START_REF] Jiang | Vitamin B and vitamin D as modulators of gut microbiota in overweight individuals[END_REF] .

In a murine study of weaning male C57BL/6J, the effect of vitamin A supplementation in condition of standard chow diet (CD) or high fat high sugar diet (HFSD) was studied [START_REF] Biyong | Dietary vitamin A supplementation prevents early obesogenic diet-induced microbiota, neuronal and cognitive alterations[END_REF] .

Vitamin A was administered in the form of retinol, directly incorporated to the diet. After 9 weeks of follow-up, the supplementation with vitamin A (+VitA) limited HFSD-induced fat mass gain but was not able to reverse metabolic alterations induced by the diet. At the GM level, this study revealed that retinol supplementation prevented most of the compositional changes induced by HFSD. First, vitamin A supplementation protected against the decrease of alpha-diversity induced by HFSD, as HFSD+VitA animals had alpha-diversity values to the level of the CD group. In CD groups, a decrease of alpha-diversity was observed in the vitamin A supplemented group, to the surprise of the authors. Second, HFSD-feeding led to a decrease of Porphyromonadaceae and Mycoplasmataceae and an increase of Family XIII in comparison to CD group. All these changes were prevented by administration of vitamin A, which in addition increased the abundance of Lachnospiraceae.

These studies reinforce the links between vitamins and GM as oral vitamin supplementation is reported to induce modifications of the GM composition.

Future strategies of vitamin status management in obesity

Knowing the alteration of vitamin status in some patients with obesity, the obesityassociated dysbiosis and relationships observed between GM and vitamin metabolism, several strategies can be considered to optimize vitamin levels subjects with obesity.

Whereas obesity is often considered as a disease characterized by over-nutrition, it is also well recognized that there are issues of malnutrition, explaining at least partially inadequate vitamin intakes observed during obesity. Thus, a well-balanced and micronutrientsufficient diet could help prevent deficiencies in some cases. In case of deficiency or suboptimal levels, the oral vitamin supplementation also seems rational to rescue the host's vitamin status. However, most vitamins are absorbed in the small intestine and only small amounts of dietary intake reach the colonic bacterial ecosystem. Yet, as summarized in this review, many studies showed that vitamins can modulate the distal GM composition and have even been included in the definition of prebiotics by the International Scientific Association for Probiotics and Prebiotics (ISAPP) in 2016. Thus, delivery tools allowing for oral vitamin supplementation specifically targeting the colon might be useful. A recent control trial investigated such systems to administer several vitamins (vitamin C, B2, E, D and A) in 96 healthy volunteers and revealed modifications of the microbial composition and metabolic activity such as an increased of bacterial diversity and fecal short-chain fatty acids [START_REF] Pham | Effects of colon-targeted vitamins on the composition and metabolic activity of the human gut microbiome-a pilot study[END_REF] . At the species level, the authors observed an increase in Bifidobacterium longum and Anaerobutyricum hallii, both studied for their beneficial effects in several health conditions [START_REF] Pham | Effects of colon-targeted vitamins on the composition and metabolic activity of the human gut microbiome-a pilot study[END_REF] .

Similar studies in patients with severe obesity would be helpful to further investigate the effects of vitamin supplementation in this context, also taking into account the potential risk of over-dosing vitamin supplementation.

Probiotic supplementation of strains known to produce vitamins can also be a strategy to rescue vitamin bacterial metabolism, altered in obesity. As reviewed by LeBlanc and colleagues, it has been demonstrated that specific bacterial strains are able to produce vitamins. For example, Lactobacillus rhamnosus GG can produce three B vitamins in culture medium which are vitamin B1, B2 and B9 [START_REF] Leblanc | Beneficial effects on host energy metabolism of short-chain fatty acids and vitamins produced by commensal and probiotic bacteria[END_REF] . Bifidobacterium adolescentis DSM 1835O [START_REF] Strozzi | Quantification of Folic Acid in Human Feces After Administration of Bifidobacterium Probiotic Strains[END_REF] has been shown to increase vitamin B9 fecal levels in humans. For such a strategy, it is important to identify strains capable of complete de novo synthesis. As proposed by Engevik and colleagues, an alternative could be to rely on cross-feeding, mentioned above, and construct probiotic combinations of strains depending on one another for the production of intermediates involved in the vitamin synthesis [START_REF] Engevik | Microbial Metabolic Capacity for Intestinal Folate Production and Modulation of Host Folate Receptors[END_REF] . It would be thus of interest to investigate how the host can benefit from these bacterial cross-talks. Yet, the long-term engraftment of probiotics remains a challenge for long-term therapeutic perspectives.

Prebiotics can influence the growth and metabolism of specific gut bacteria, thus, their use to promote bacterial vitamin production could also be envisaged. A recent in silico study reported that inulin and short-chain fructo-oligosaccharides supplementation could increase the production of an intermediate of the vitamin D biosynthesis pathway [START_REF] Gokhale | Provitamin D 3 modulation through prebiotics supplementation: simulation based assessment[END_REF] . This effect seems to be mediated by the secretion of short-chain fatty acids induced by the prebiotic supplementation. The authors thus suggest that prebiotic supplementation could help decrease vitamin D deficiency linked to insufficiency of this intermediate in this study.

Appropriate in vivo and clinical studies should be designed to confirm the potential use of these strategies in vitamin status management in severe obesity.

Conclusion

Increasing evidence of sub-optimal or even deficient blood concentrations of a number of vitamins in obesity and metabolic alterations have been consistently reported. There is therefore a clinical need to increase the awareness of medical care givers and patients regarding vitamin status, especially for long-term follow-up and in the context of nutritional or surgical interventions. The reported evidence of modulations of both bacterial vitamin production and GM composition and functionality in condition of vitamin depletion and supplementation reinforce the links between vitamins and GM. In this direction, the GM dysbiosis observed in metabolic alterations and obesity could participate to the altered vitamin host status observed in several cohorts. The restoration of a functional ecosystem via a balanced diet, colon-targeted vitamin, probiotic or prebiotic supplementation of either vitamin-producing single strains or combination of strains relying on cross-feeding (Figure 1) can thus contribute to an improved vitamin metabolism and status. The potential effects on metabolic health of such strategies should also be studied as well as the mechanisms involved in these interactions between vitamins, gut microbiota and metabolic health.

Figure 1 -

 1 Figure 1 -Intended strategies for host vitamin status improvement in obesity and metabolic alterations. Improvement of vitamin metabolism can be envisioned via nutritional intervention with micronutrient sufficient and balanced diet, but also oral vitamin supplementation, for example via colon targeted system to deliver the vitamin directly to the gut microbial ecosystem and finally via probiotic administration of either single

Table 1 -

 1 Functions, recommended levels and deficiency consequences of B and D vitamins -Adapted from Vitamin and mineral requirements in human nutrition[START_REF]World Health Organization, Food and Agriculture Organization of the United Nations[END_REF]

	Vitamin	Name	Function	Daily recommended amounts	Optimal circulating levels	Deficiency biochemical diagnosis	Deficiency consequences
	Vitamin B1	Thiamin	Coenzyme functions in metabolism of carbohydrates and branched-chain amino acids	Men: 1.2 mg/Woment: 1.1mg	75-195 nmol/L (Whitfield et al., 2018)	Thiamine Pyrophosphate effect (TPPE) > 25% (WHO,1999)	Beriberi, polyneuritis and neurological symptoms
	Vitamin B2	Riboflavin	Coenzyme functions in numerous oxidation and reduction reactions	Men: 1.3 mg/Women: 1.0 mg	100-650 nmol/L	Erythrocyte glutathione reductase activation coefficient (EGRAC) >1.80 (Lanyau-Dominguez et al., 2020)	Growth, cheilosis, angular stomatitis, and dermatitis
	Vitamin B3	Niacin	Cosubstrate/coenzyme for hydrogen transfer with numerous dehydrogenases	Men: 16 mgNEs/Women: 14 mgNEs (Niacin equivalents)	4100-69000 nmol/L	Urinary excretion of N1-methylnicotinamide (NMN) < 5.8 µmol (Redzic and Gupta, 2021)	Pellagra with diarrhoea, dermatitis, and dementia
	Vitamin B5	Pantothenic acid	Constituent of coenzyme A and phophopantetheine involved in fatty acid metabilsm	Men: 5.0 mg/Women: 5.0 mg	1600-2700 nmol/L (NIH)	Serum : <1000 nmol/L (NIH)	Fatigue, sleep disturbances, impared coordination and nausea
	Vitamin B6	Pyridoxine	Coenzyme functions in metabolism of amino acids, glycogen, and sphingoid bases	Men: 1.3 mg/Women: 1.3 mg	20-200 nmol/L (NIH)	Serum: <20 nmol/L (NIH)	Nasolateral seborrhoea, glossitis and peripheral neuropathy
	Vitamin B7	Biotin	Coenzyme functions in bicarbonate-dependent carboxylations	Men: 30 µg /Women: 30 µg	0.8-1.7 nmol/L	Serum: <0.8 nmol/L	Fatigue, depression, nausea, dermatits, and muscular pains
	Vitamin B9	Folate	Function in producing genetic material (RNA, DNA) and amino acids	Men: 400 µg/ Women: 400 µg	> 6.8 nmol/L	< 6.8 nmol/L	Anemia, digestive and neurological disorders
	Vitamin B12	Cobalamin	Functions in the development, myelination and function of the central nervous system	Men: 2.4 µg/Women: 2.4 µg 0,185-0,600 pmol/L	Serum: < 0,18 nmol/L	Anemia, fatigue, weakness
	Vitamin D	Calciferol	Maintenance of normal blood level of calcium and phosphate	Men: 10 µg/Women: 10 µg	100-200 nmol/L	Serum: <75 nmol/L	Fatigue, bone pain, muscle weakness, depression

Acknowledgement

The authors thank Leducq Foundation, the European commission (Join Program Initiative (JPI)), the European Union's 7 th Framework Program for research, technological development and demonstration (HEALTH-F4-2012-305312 -METACARDIS), and the Fondation pour la Recherche Médicale (FDT202106012793) for supporting the research topic addressed in this review. We thank Timothy Swartz for his thorough re-reading of this article.

The authors thank Leducq Foundation, the European commission (Join Program Initiative (JPI)), the European Union's 7 th Framework Program for research, technological development and demonstration (HEALTH-F4-2012-305312 -METACARDIS), and the Fondation pour la Recherche Médicale (FDT202106012793) for supporting the research topic addressed in this review. We thank Timothy Swartz for his thorough re-reading of this article.

Conflict of interest

The authors have no conflict of interest.