SummaryGlycosylation processes are under high natural selection pressure, presumably because these can modulate resistance to infection. Here, we asked whether inactivation of the UDP-galactose:β-galactoside-α1-3-galactosyltransferase (α1,3GT) gene, which ablated the expression of the Galα1-3Galβ1-4GlcNAc-R (α-gal) glycan and allowed for the production of anti-α-gal antibodies (Abs) in humans, confers protection against Plasmodium spp. infection, the causative agent of malaria and a major driving force in human evolution. We demonstrate that both Plasmodium spp. and the human gut pathobiont E. coli O86:B7 express α-gal and that anti-α-gal Abs are associated with protection against malaria transmission in humans as well as in α1,3GT-deficient mice, which produce protective anti-α-gal Abs when colonized by E. coli O86:B7. Anti-α-gal Abs target Plasmodium sporozoites for complement-mediated cytotoxicity in the skin, immediately after inoculation by Anopheles mosquitoes. Vaccination against α-gal confers sterile protection against malaria in mice, suggesting that a similar approach may reduce malaria transmission in humans.PaperFlick

Inflammatory bowel diseases (IBD) can be broadly divided into Crohn's disease (CD) and ulcerative colitis (UC) from their clinical phenotypes. Over 150 host susceptibility genes have been described, although most overlap between CD, UC and their subtypes, and they do not adequately account for the overall incidence or the highly variable severity of disease. Replicating key findings between two long-term IBD cohorts we have defined distinct networks of taxa associations within intestinal biopsies of CD and UC patients. Disturbances in an association network containing taxa of the Lachnospiraceae and Ruminococcaceae families, typically producing short chain fatty acids, characterize frequently relapsing disease and poor responses to treatment with anti-TNF-α therapeutic antibodies. Alterations of taxa within this network also characterize risk of later disease recurrence of patients in remission after the active inflamed segment of CD has been surgically removed.

IgA is the dominant immunoglobulin isotype produced in mammals, largely secreted across the intestinal mucosal surface. Although induction of IgA has been a hallmark feature of microbiota colonization following colonization in germ-free animals, until recently appreciation of the function of IgA in host-microbial mutualism has depended mainly on indirect evidence of alterations in microbiota composition or penetration of microbes in the absence of somatic mutations in IgA (or compensatory IgM). Highly parallel sequencing techniques that enable high-resolution analysis of either microbial consortia or IgA sequence diversity are now giving us new perspectives on selective targeting of microbial taxa and the trajectory of IgA diversification according to induction mechanisms, between different individuals and over time. The prospects are to link the range of diversified IgA clonotypes to specific antigenic functions in modulating the microbiota composition, position and metabolism to ensure host mutualism.

Iron (Fe) is a highly ample metal on planet earth (~35% of the Earth’s mass) and is particularly essential for most life forms, including from bacteria to mammals. Nonetheless, iron deficiency is highly prevalent in developing countries, and oral administration of this metal is so far the most effective treatment for human beings. Notably, the excessive amount of unabsorbed iron leave unappreciated side effects at the highly interactive host–microbe interface of the human gastrointestinal tract. Recent advances in elucidating the molecular basis of interactions between iron and gut microbiota shed new light(s) on the health and pathogenesis of intestinal inflammatory diseases. We here aim to present the dynamic modulation of intestinal microbiota by iron availability, and conversely, the influence on dietary iron absorption in the gut. The central part of this review is intended to summarize our current understanding about the effects of luminal iron on host–microbe interactions in the context of human health and disease.

The gut microbiota regulate susceptibility to multiple human diseases. The Nlrp6-ASC inflammasome is widely regarded as a hallmark host innate immune axis that shapes the gut microbiota composition. This notion stems from studies reporting dysbiosis in mice lacking these inflammasome components when compared with non-littermate wild-type animals. Here, we describe microbial analyses in inflammasome-deficient mice while minimizing non-genetic confounders using littermate-controlled Nlrp6-deficient mice and ex-germ-free littermate-controlled ASC-deficient mice that were all allowed to shape their gut microbiota naturally after birth. Careful microbial phylogenetic analyses of these cohorts failed to reveal regulation of the gut microbiota composition by the Nlrp6- and ASC-dependent inflammasomes. Our results obtained in two geographically separated animal facilities dismiss a generalizable impact of Nlrp6- and ASC-dependent inflammasomes on the composition of the commensal gut microbiota and highlight the necessity for littermate-controlled experimental design in assessing the influence of host immunity on gut microbial ecology.

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Microbiota colonization causes profound B cell stimulation and immunoglobulin induction, yet mammals colonized with many taxa have highly complex individualized immunoglobulin repertoires 1,2 . To deconstruct how the microbiota shapes the B cell pool and its functional responsiveness we have used a simplified model of defined transient microbial exposures by different taxa in germ-free mice 3 . B cell immunoglobulin repertoire development was followed by deep sequencing and in single cells. Intestinal mucosal exposure generated oligoclonal responses which differed from germ-free controls or from the diverse repertoire generated after intravenous systemic exposure. The IgA repertoire, predominantly to cellsurface antigens, did not expand following dose escalation, whereas increased systemic exposure broadened the IgG repertoire to both microbial cytoplasmic and cell-surface antigens. These microbial exposures induced characteristic immunoglobulin heavy chain B cell repertoires mainly at memory and plasma cell stages. Whereas sequential systemic exposure to different taxa diversified the IgG repertoire and facilitated alternate specific responses, sequential mucosal exposure produced limited overlapping repertoires and attrition of initial IgA binding specificities. This shows a contrast between a flexible response to systemic exposure with the need to avoid fatal sepsis, and a restricted response to mucosal exposure reflecting the generic nature of mucosal microbial mutualism. TEXTMammalian immunoglobulins (Ig) are composed of heavy (H) and light (L) chains, each assembled from one of many V H/L , (D H ) and J H/L gene segments during B cell development. The resulting genetic and structural immunoglobulin repertoire diversity and antigen recognition possibilities are further increased by additional nucleotide insertion during recombination, later somatic mutation, or class switch recombination from IgM and/or IgD to IgG, IgE or IgA. Selection and clonal expansion of particular B cells with an appropriate immunoglobulin specificity endows the system to respond to a huge variety of antigens.Comparisons of colonized and germ-free animals show that B cell numbers and immunoglobulin levels (especially IgG and IgA) are considerably amplified by colonization with a microbiota, some of which penetrate mucous membranes to prime systemic secondary lymphoid structures even in healthy hosts. 4,5 B cell repertoires have so far been shown to be largely unique to each individual animal 1,2 , although whether this is caused by differences in microbiota composition or the sequence of colonization in each animal is unknown.Using localized time-limited exposures of defined doses of single benign microbial taxa in germ-free animals 3 , we have addressed how the B cell repertoire is shaped by microbiota exposure at mucous membranes or in systemic lymphoid tissues, and how interactions between different exposure sites or subsequent exposures to different taxa affects the outcome. Distinct B cell Ig repertoires to intestinal microbes de...

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