Impaired Aryl Hydrocarbon Receptor Ligand Production by the Gut Microbiota Is a Key Factor in Metabolic Syndrome

Natividad, Jane M.; Agus, Allison; Planchais, Julien; Lamas, Bruno; Jarry, Anne; Martin, Rebeca; Michel, Marie‐Laure; Chong-Nguyen, Caroline; Roussel, Ronan; Straube, Marjolène; Jégou, Sarah; McQuitty, Claire; Gall, Maude Le; Costa, Grégory Da; Lecornet, Emmanuelle; Michaudel, Chloé; Modoux, Morgane; Glodt, Jérémy; Bridonneau, Chantal; Sovran, Bruno; Dupraz, Louise; Bado, André; Richard, Mathias L.; Langella, Philippe; Hansel, Boris; Launay, Jean‐Marie; Xavier, Ramnik J.; Duboc, Henri; Sokol, Harry

doi:10.1016/j.cmet.2018.07.001

Cited by 401 publications

(406 citation statements)

References 45 publications

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“…Indeed, our enzymatic assays show strong adaptation of ALDH towards indolepyruvate, resulting preferentially in the formation of ILA, the most abundant of the aromatic lactic acids and microbial tryptophan catabolites detected in our two cohorts. This is potentially of fundamental importance, since AhR signalling is essential for gut barrier function 44, 45 and immune development 15, 46–48 . Microbiota-produced tryptophan-derived AhR ligands (e.g.…”

Section: Discussionmentioning

confidence: 99%

“…Microbiota-produced tryptophan-derived AhR ligands (e.g. indolealdehyde) have been shown to confer colonization resistance against gastrointestinal pathogens 16 , improve intestinal barrier function 44 , attenuate induced colitis 49 and improve features of metabolic syndrome 44 . Further, although AhR is conserved across invertebrates and vertebrates, microbiota-derived tryptophan agonists have shown human-AhR selectivity 50 .…”

Section: Discussionmentioning

confidence: 99%

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Breastmilk-promoted bifidobacteria produce aromatic amino acids in the infant gut

Laursen

Sakanaka

Burg

et al. 2020

Preprint

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26Breastfeeding profoundly shapes the infant gut microbiota, which is critical for early life immune 27 development. However, few breastmilk-dependent microbial metabolites mediating host-microbiota 28 interactions are currently known. We here demonstrate that breastmilk-promoted Bifidobacterium 29 species convert aromatic amino acids (tryptophan, phenylalanine and tyrosine) into their respective 30 aromatic lactic acids (indolelactate, phenyllactate and 4-hydroxyphenyllactate) via a previously 31 unrecognised aromatic lactate dehydrogenase. By longitudinal profiling of the gut microbiota 32 composition and metabolome of stool samples of infants obtained from birth until 6 months of age, 33 we show that stool concentrations of aromatic lactic acids is determined by the abundance of human 34 milk oligosaccharide degrading Bifidobacterium species containing the aromatic lactate 35 dehydrogenase. Finally, we demonstrate that stool concentrations of Bifidobacterium-derived 36 indolelactate are associated with the capacity of infant stool samples to activate the aryl 37 hydrocarbon receptor, a receptor important for maintenance of intestinal homeostasis and immune 38 system development. These findings open up new directions towards understanding the role of 39 breastmilk-promoted Bifidobacterium in mediating host-microbiota interactions in early life. 40 INTRODUCTION 41Human breastmilk is a perfectly adapted nutritional supply for the infant 1 . Breastfeeding provides 42 children with important short-term protection against infections, and may also provide long-term 43 metabolic benefits 1,2 . These benefits may partly be mediated through the gut microbiota, since 44 breastfeeding is the strongest determinant of gut microbiota composition and function during 45 infancy 3-5 . Human breastmilk contains human milk oligosaccharides (HMOs), which are complex, 46 highly abundant sugars serving as substrates for specific microbes including certain species of 47 Bifidobacterium 6 . This co-evolution between bifidobacteria and the host, mediated by HMOs, to a 48 large extent directs the colonization of the gut in early life, which has critical impact on the immune 49 system 7 . Depletion of specific microbes, including Bifidobacterium, in early life has been associated 50 with increased risk of allergy and asthma development in childhood 8,9 , and is suggested to 51 compromise immune function and lead to increased susceptibility to infectious disease 10,11 . Despite 52 Bifidobacterium dominating the gut of breastfed infants and being widely acknowledged as 53 beneficial, mechanistic insights on the contribution of these bacteria and their metabolites to 54 immune development during infancy remain limited. Recent studies show that microbial aromatic 55 amino acid metabolites including tryptophan-derived indoles 12 , via activation of the aryl 56 hydrocarbon receptor (AhR), can fortify the intestinal barrier 13,14 , protect against pathogenic 57 infections 15,16 and influence host metabolism 13,17,18 , which makes this...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Breastmilk-promoted bifidobacteria produce aromatic amino acids in the infant gut

Laursen

Sakanaka

Burg

et al. 2020

Preprint

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“…) and metabolic syndrome (Natividad et al . ). Intriguingly, serum concentrations of one tryptophan catabolite, indolepropionic acid, have been associated not only with reduced prevalence of type 2 diabetes but also with increased dietary fibre intake (de Mello et al .…”

Section: Diet‐derived Microbial Metabolites In Health and Diseasementioning

confidence: 97%

“…Yet, not all proteolytic degradation products are necessarily deleterious, as recent studies have suggested that microbial tryptophan catabolites contribute to maintenance of intestinal and systemic homeostasis by activation of the aryl hydrocarbon receptor (AHR), as recently reviewed (Roager & Licht 2018). Reduced concentrations of tryptophan catabolites have been observed in individuals with inflammatory bowel disease (Lamas et al 2016), neurological diseases (Rosas et al 2015;Rothhammer et al 2016) and metabolic syndrome (Natividad et al 2018). Intriguingly, serum concentrations of one tryptophan catabolite, indolepropionic acid, have been associated not only with reduced prevalence of type 2 diabetes but also with increased dietary fibre intake (de Mello et al 2017a(de Mello et al , 2017bTuomainen et al 2018).…”

Section: Microbial Proteolytic Degradation Productsmentioning

confidence: 99%

Diet‐derived microbial metabolites in health and disease

Roager

Dragsted

2019

Nutrition Bulletin

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The gut microbiota helps us digest food and has been associated with both good health and risk of disease. Although compositions of the gut microbiota are highly divergent, the gut microbiota exhibits a high level of functional redundancy making it difficult to reliably link gut microbiome patterns to health and diet across individuals. Thus, there is a need to move beyond profiling of the gut microbial composition to the assessment of gut microbial metabolic activity in order to expand knowledge on the impact of the gut microbiota on health. Metabolomics has already proven its utility in identifying gut‐derived microbial metabolites, which may be mediators of diet‐induced host–microbial crosstalk important for health. These diet‐derived metabolites include, among many others, the short‐chain fatty acids originating from bacterial degradation of dietary fibres and proteins, secondary bile acids derived from primary bile acids, microbial tryptophan catabolites resulting from proteolysis, imidazole propionate produced from histidine and trimethylamine N‐oxide, a host–microbial co‐metabolite of nutrients such as phosphatidylcholine, choline and L‐carnitine, present in high‐fat foods. These co‐metabolites have been associated with beneficial and detrimental effects in the host. However, the vast majority of metabolites measured by untargeted metabolomics in human blood and excreta remain unknown and may include additional microbial molecules of importance for health. Thus, there is great potential, yet to be explored, for identifying additional diet‐derived microbial products that affect the host. Herein, we review key advances, challenges and limitations in our understanding of diet–microbiome interactions and diet‐derived microbial metabolites in relation to human health and discuss how metabolomics may shed light on inter‐individual differences in dietary responses.

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“…Collectively, these results clearly show that the male rats had a worse stroke outcome as confirmed by their lower survival and greater sensory motor deficit as compared to age-matched female rats. is an estimate of health and an elevated F:B ratio is seen in aging and disease states such as metabolic syndrome (Natividad et al, 2018) and stroke (Park et al, 2019a, Spychala et al, 2018.…”

Section: Art As Response Variablementioning

confidence: 99%

Sex Differences in Stroke Outcome Are Associated With Constitutive Gut Dysbiosis and Stroke-induced Gut Permeability

El-Hakim

Mani

Eldouh

et al. 2020

Preprint

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Background: Sex differences in experimental stroke are well documented, such that adult males show worse outcomes compared to adult females, including greater infarct volume, increased stroke-induced mortality and more severe sensory-motor impairment. Based on recent evidence that gut dysbiosis may be an early response to stroke, the present study tested the hypothesis that in the acute phase, stroke will result in greater permeability of the gut blood barrier and gut dysbiosis in males as compared to females. Method: Male and female Sprague Dawley rats (5-7 months of age) were subject to endothelin (ET)-1-induced middle cerebral artery occlusion (MCAo). Fecal samples, blood draws and sensory motor tests were conducted pre and 2d after MCAo. Fecal samples were analyzed for 16s sequencing and short chain fatty acids (SCFAs). Gut permeability was assessed in serum samples using biomarkers of gut permeability as well as functional assays using size-graded dextrans. Results: We confirmed stroke-induced sex differences, including greater mortality and sensory motor deficit in males as compared to age-matched female rats. Remarkably, fecal 16s sequencing showed greater bacterial diversity in females at baseline (prior to stroke) while 2 days after stroke, these measures were similar between the sexes. In contrast, fecal levels of short chain fatty acids (SCFAs) which are usually beneficial, were higher in males. MCAo-induced gut permeability was much worse in males as compared to females, as indicated by histological analysis, biochemical markers in serum, and serum measurement of fluorescent-labeled dextrans following oral gavage. Additionally, males had higher serum levels of proinflammatory cytokines IL-17A, MCP-1, IL-5 and EGF compared to females after stroke. Predictive modeling indicated that markers of gut permeability were associated with stroke-induced sensory-motor impairment. Conclusions: Poor stroke outcomes in adult males is mirrored by increased gut permeability in this group. Additionally, these data suggest that constitutive sex differences in the diversity and richness of gut microbial communities may predispose better functional outcomes after stroke in females, and support the idea that preventative modification of the gut microbiome may reduce the risk for stroke in vulnerable populations such as the elderly or those with co-morbid conditions.

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Impaired Aryl Hydrocarbon Receptor Ligand Production by the Gut Microbiota Is a Key Factor in Metabolic Syndrome

Cited by 401 publications

References 45 publications

Breastmilk-promoted bifidobacteria produce aromatic amino acids in the infant gut

Breastmilk-promoted bifidobacteria produce aromatic amino acids in the infant gut

Diet‐derived microbial metabolites in health and disease

Sex Differences in Stroke Outcome Are Associated With Constitutive Gut Dysbiosis and Stroke-induced Gut Permeability

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