Intestinal Fucose as a Mediator of Host–Microbe Symbiosis

Pickard, Joseph M.; Chervonsky, Alexander V.

doi:10.4049/jimmunol.1500395

Cited by 149 publications

(158 citation statements)

References 72 publications

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“…Fucosylglycans decorate proteins and lipids throughout the mammalian gastrointestinal tract and play an important role in host-microbe symbiosis 42 . Recent findings revealed that commensal bacteria mediate the expression of IL-22 by innate lymphoid cells which in turn stimulate α(1,2) fucosyltransferase (Fut2) 43 , and individuals lacking a functional copy of FUT2 display significant differences in their gut microbiome community structure 44 .…”

Section: Discussionmentioning

confidence: 99%

Fucosylation Deficiency in Mice Leads to Colitis and Adenocarcinoma

et al. 2017

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Background & Aims De novo synthesis of GDP-fucose, a substrate for fucosylglycans, requires sequential reactions mediated by GDP-mannose 4,6-dehydratase (GMDS) and GDP-4-keto-6-deoxymannose 3,5-epimerase-4-reductase (FX or TSTA3). GMDS deletions and mutations are found in 6%–13% of colorectal cancers; these mostly affect ascending and transverse colon. We investigated whether lack of fucosylation consequent to loss of GDP-fucose synthesis contributes to colon carcinogenesis. Methods FX deficiency and GMDS deletion produce the same biochemical phenotype of GDP-fucose deficiency. We studied a mouse model of fucosylation deficiency (Fx–/– mice) and mice with the full-length Fx gene (controls). Mice were placed on standard chow or fucose-containing diet (equivalent to a control fucosylglycan phenotype). Colon tissues were collected and analyzed histologically or by ELISAs to measure cytokine levels; T cells were also collected and analyzed. Fecal samples were analyzed by 16s rRNA sequencing. Mucosal barrier function was measured by uptake of fluorescent dextran. We transplanted bone marrow cells from Fx–/– or control mice (Ly5.2) into irradiated 8-week old Fx–/– or control mice (Ly5.1). We performed immunohistochemical analyses for expression of Notch and the hes family bHLH transcription factor (HES1) in colon tissues from mice and a panel of 60 human colorectal cancer specimens (27 left-sided, 33 right-sided). Results Fx–/– mice developed colitis and serrated-like lesions. The intestinal pathology of Fx–/– mice was reversed by addition of fucose to the diet, which restored fucosylation via a salvage pathway. In the absence of fucosylation, dysplasia appeared and progressed to adenocarcinoma in up to 40% of mice, affecting mainly the right colon and cecum. Notch was not activated in Fx–/– mice fed standard chow, leading to decreased expression of its target Hes1. Fucosylation deficiency altered the composition of the fecal microbiota, reduced mucosal barrier function and altered epithelial proliferation marked by Ki67. Fx–/– mice receiving control bone marrow cells had intestinal inflammation and dysplasia, and reduced expression of cytokines produced by cytotoxic T cells. Human sessile serrated adenomas and right-sided colorectal tumors with epigenetic loss of MLH1 had lost or had lower levels of HES1 than other colorectal tumor types or nontumor tissues. Conclusions In mice, fucosylation deficiency leads to colitis and adenocarcinoma, loss of Notch activation, and downregulation of Hes1. HES1 loss correlates with development of human right-sided colorectal tumors with epigenetic loss of MLH1. These findings indicate that carcinogenesis in a subset of colon cancer is consequent to a molecular mechanism driven by fucosylation deficiency and/or HES1-loss.

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Section: Discussionmentioning

confidence: 99%

Fucosylation Deficiency in Mice Leads to Colitis and Adenocarcinoma

et al. 2017

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“…However, those data were obtained by adding the compounds intracranially or incorporated in the culture medium. To our knowledge there was no published data about the role of dietary Fuc or fucosylated compounds, on the regulation or maintenance of CNS synapses, although some studies pointed out Fuc as an important mediator of host-microbe symbiosis under normal [38] or pathological scenarios [39]. This may imply Fuc as a potential compound for GBA activation.…”

Section: Discussionmentioning

confidence: 99%

Dietary 2’-Fucosyllactose Enhances Operant Conditioning and Long-Term Potentiation via Gut-Brain Communication through the Vagus Nerve in Rodents

et al. 2016

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2´-fucosyllactose (2´-FL) is an abundant human milk oligosaccharide (HMO) in human milk with diverse biological effects. We recently reported ingested 2´-FL stimulates central nervous system (CNS) function, such as hippocampal long term potentiation (LTP) and learning and memory in rats. Conceivably the effect of 2´-FL on CNS function may be via the gut-brain axis (GBA), specifically the vagus nerve, and L-fucose (Fuc) may play a role. This study had two aims: (1) determine if the effect of ingested 2´-FL on the modulation of CNS function is dependent on the integrity of the molecule; and (2) confirm if oral 2´-FL modified hippocampal LTP and associative learning related skills in rats submitted to bilateral subdiaphragmatic vagotomy. Results showed that 2´-FL but not Fuc enhanced LTP, and vagotomy inhibited the effects of oral 2´-FL on LTP and associative learning related paradigms. Taken together, the data show that dietary 2´-FL but not its Fuc moiety affects cognitive domains and improves learning and memory in rats. This effect is dependent on vagus nerve integrity, suggesting GBA plays a role in 2´-FL-mediated cognitive benefits.

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“…The high level of glycosylation shields the protein backbone of the extracellular domain from proteolytic attack by bacteria and host proteases, and contributes to barrier formation. On the other hand, mucosal sugars such as fucose are released by certain microbiota and serve as a food source to maintain a healthy microbial community [5]. A wide range of oligosaccharide structures can be attached to mucins and the glycan composition of these structures can vary both within and between cell types due to the differential expression of glycosyltransferases.…”

Section: General Features Of Transmembrane Mucinsmentioning

confidence: 99%

Transmembrane Mucins: Signaling Receptors at the Intersection of Inflammation and Cancer

Putten¹,

Strijbis²

2017

J Innate Immun

214

213

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Mucosal surfaces line our body cavities and provide the interaction surface between commensal and pathogenic microbiota and the host. The barrier function of the mucosal layer is largely maintained by gel-forming mucin proteins that are secreted by goblet cells. In addition, mucosal epithelial cells express cell-bound mucins that have both barrier and signaling functions. The family of transmembrane mucins consists of diverse members that share a few characteristics. The highly glycosylated extracellular mucin domains inhibit invasion by pathogenic bacteria and can form a tight mesh structure that protects cells in harmful conditions. The intracellular tails of transmembrane mucins can be phosphorylated and connect to signaling pathways that regulate inflammation, cell-cell interactions, differentiation, and apoptosis. Transmembrane mucins play important roles in preventing infection at mucosal surfaces, but are also renowned for their contributions to the development, progression, and metastasis of adenocarcinomas. In general, transmembrane mucins seem to have evolved to monitor and repair damaged epithelia, but these functions can be highjacked by cancer cells to yield a survival advantage. This review presents an overview of the current knowledge of the functions of transmembrane mucins in inflammatory processes and carcinogenesis in order to better understand the diverse functions of these multifunctional proteins.

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Intestinal Fucose as a Mediator of Host–Microbe Symbiosis

Cited by 149 publications

References 72 publications

Fucosylation Deficiency in Mice Leads to Colitis and Adenocarcinoma

Fucosylation Deficiency in Mice Leads to Colitis and Adenocarcinoma

Dietary 2’-Fucosyllactose Enhances Operant Conditioning and Long-Term Potentiation via Gut-Brain Communication through the Vagus Nerve in Rodents

Transmembrane Mucins: Signaling Receptors at the Intersection of Inflammation and Cancer

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