74 do long-lived plasma cells maintain a healthy microbiota in the gut__h

1、TREIMM 1436 No. of Pages 13OpinionDo Long-Lived Plasma Cells Maintain a Healthy Microbiota in the Gut?Frode L. Jahnsen,1,* Espen S. Bkkevold,1 Johannes R. Hov,2,3 and Ole J. Landsverk1Disruptions to the gut microbiota have been associated with a variety of diseases. Understanding the underlying mech

2、anisms that regulate the main- tenance of a healthy microbiota may therefore have therapeutic implications. Secretory IgA play a unique role in immunemicrobiota crosstalk by directly binding to bacteria in the gutlumen. Microbe-specic IgA responses co- develop with the assembly of the gut microbiota

3、 during infancy, and resemble those of adults by 2 years postnatally in the healthy host. We propose here that microbiota-specic IgA-producing gut plasma cells generated during infancy live for many decades and contribute to a stable microbiota commu- nity. We furthermore suggest that members of the

4、 microbiota that induce long-lasting IgA responses in the gut are putative targets for therapeutic interventions.TheGutMicrobiotaandMucosalImmunityThe tens of trillions of microbes that inhabit the human intestinal tract form a complex ecological community which is essential for our physiology, meta

5、bolism, and immune functions (Box 1). Most gut microbes are either harmless or have benecial properties for the host, and protect agat invading pathogens. Disruption of the normal balance between the gut microbiota (see Glossary) and the host has been associated with obesity, malnutrition, autoimmun

6、e diseases, inammatory bowel disease (IBD), neurological disorders, and cancer 13. Given the profound effects of the microbiota for health and disease there is great interest in understanding the underlying regulatory mechanisms that govern the maintenance of healthy microbiota as a basis for therap

7、eutic interventions.The mammalian host has developed a multilayered system to control the microbiota, and this includes both the innate and the adaptive arms of the immune system as well as epithelial protective mechanisms such as the mucus barrier and antimicrobial peptides 35. These protective com

8、ponents have different effects on the microbiota depending on age of the host, the developmental stage of the microbial community, the type of microbe, and environmental factors 6. Nonetheless,togethertheseprotectivemechanismscreate asymbioticrelationship between the host and the microbiota that is

9、necessary to maintain intestinal homeostasis and prevent disease.1Department of Pathology and Centre for Immune Regulation, Oslo University Hospital Rikshospitalet and the University of Oslo, Oslo, Norway 2Norwegian PSC Research Center and Researchtitute of Internal Medicine, Division of Surgery, In

10、ammatory Diseases and Transplantation, Oslo University Hospital and University of Oslo, Oslo, Norway3Department of Gastroenterology, Division of Medicine, Oslo University Hospital, Oslo, NorwayApproximately 80% of antibody-secreting plasma cells (PCs) in the human body are located in the gastrointes

11、tinal tract. They produce secretory antibodies (mainly immunoglobulin A, IgA) that are actively transported over the surface epithelium to the gut lumen, and therefore have a unique capacity to interact directly with gut microbes. It is generally accepted that IgA play an*Correspondence: f.l.jahnsen

12、medisin.uio.no (F.L. Jahnsen).important protective role in defense agat pathogens and toxthrough a variety ofnoninammatory activities that increase their clearance and prevent their access to theTrends in Immunology, Month Year, Vol. xx, No. yy /10.1016/j.it.2017.10.006 1 2017 Elsevier

13、 Ltd. All rights reserved.TrendsIn infants, the gut microbiota co devel ops with microbiota specic IgA responses. The diversity of the micro biota and the IgA repertoire resemble those of adults by the age of 2 years.Experimental mice lacking secretory IgA in the gut lumen display disruption of the

14、gut microbiota, suggesting that IgA plays an important role in regulat ing the microbiota composition.A fraction of the gut microbiota is coated with microbiota specic IgA. The IgA coated bacteria may have both benecial and detrimental effects, suggesting that bacteria initiating immune responses ar

15、e important for gut homeostasis and our health.A large fraction of the IgA producing plasma cells reside in the human intes tine for decades. This shows that IgA responses in the gut can be persistent and suggests that long lived plasma cells are important for the diversity and stability of a health

16、y microbiota.TREIMM 1436No. of Pages 13intestinal epithelium (reviewed in 711). Moreover, IgA can reduce bacterial virulence and growth 7. More recently it has been shown that IgA also interact with the microbiota 711.A large fraction of resident commensal bacteria is coated by IgA (and IgM), and th

17、is affects their growth and microbial functions 1113. Moreover, by blocking the transepithelial transport of secretory antibodies it was shown that the absence of IgA (and IgM) in the intestinal lumen disturbs the stability of the microbiota and compromises gut homeostasis 14, strongly suggesting th

18、at secretory antibodies play an important role in host immunemicrobiota cross- talk. To control the composition of the microbiota there are data to suggest that the generation of microbe-specic IgA responses is persistent 15. However, whether long-lived PCs exist in the gut has been an open question

19、 for many years 10,16. Recently, we reported that a large fraction of antibody-secreting PCs lives for decades in the human small intestine 17. This nding represents an important shift in the concept of gut humoral immunity, and shows that IgA responses can be extremely persistent. In this review we

20、 will focus on recent progress in our understanding of how a normal microbiota co-develops with mucosal IgA responses, and we discuss howlong-lasting antibody responses in the gut may play an important role in reinforcing a stable, diverse, and healthy microbiota, and how mechanisms by which IgA sha

21、pe the composition of the microbiota may have therapeutic implications.The Development of a Healthy Gut MicrobiotaRecent reports have increased ouright into what denes normal/healthy postnatal devel-opment of the microbiota community. Although debated, the currently most-accepted theory is that the

22、fetus lives in a sterile environment 18, but is rapidly colonized during and after birth. Based on a series of studies following birth cohorts with healthy growth phenotypes from regions with different socioeconomic, geographic, and cultural settings 6,13,1921, the key concepts that dene the develop

23、ment of a normal gut microbiota are as follows: after birth the bacterial diversity increases progressively, and at 3 years of postnatal life the complexity of the gut microbiota community resembles that of an adult 21. Although there is large interindividual variation between children within each c

24、ohort, and large differences in the phylogenetic composition of the microbiota between different countries (especially between low-income versus high-income countries), it has been possible to identify a group of age-discriminatory bacterial taxa that change in their relative representation during t

25、he rst 23 years of postnatal life. These temporal changes in bacterial representation have thus made it possible to dene a program of normal microbiota development within a given geographic or cultural setting.2 Trends in Immunology, Month Year, Vol. xx, No. yyGlossaryAicda: the gene encoding activa

26、tion induced cytidine deaminase, answitch recombination of immunoglobulin genes.APRIL: a proliferation inducing ligand that is important for B cell development and long term survival of plasma cells.Class-switch recombination: the mechanism by which a B cell changes the production of antibodies from

27、 one isotype to another; this is mediated by genomic excision of DNA segments encoding the constant regions of different antibody heavy cha .Common variable immunodeciency: an immune disorder characterized by frequent infections due to low antibody levels, most notably of IgG, IgM, and IgA. Fecal mi

28、crobiota transplantation (FMT): a procedure in which fecal matter from a healthy donor is mixed with a saline solution and transferred to a recipient patient by colonoscopy, endoscopy, or enema. Germ-free mice: mice raised in germ free isolators, which have no microorganisms living on or within them

29、.Gnotobiotic mice: germ freeanimals colonized with only dened stra(usually one) of microorganisms.Ighm: the gene encoding theconstant region of the IgM isotype of antibodies.Microbiota: the community of commensal, symbiotic, and pathogenic microorganisms that is found on or within a multicellular ho

30、st organism.Phylum: a level of biological classication that ranks below kingdom but above class.Plasma cell (PC): B cell derived leukocytes in tissues that secrete large amounts of antibodies.Somatic hypermutation: a process to diversify B cell receptors by mutations in the variable regions of immun

31、oglobulin genes.Taxon: one or more populations of organisms grouped into a unit with shared phylogeny and characteristics that separate them from other units. In the context of microbiota, taxa include operational taxonomic unitsBox 1. Overview of the Gut Microbiota in Health and DiseaseThe gut micr

32、obiota is composed of about 1013 bacteria and unquantied numbers of fungi, viruses, and other microorganisms 86. It has extensive metabolic activity, representing an integrated part of host metabolism and immunity. Gut microbial composition is altered in a large number of chronic diseases. This may

33、be termed dysbiosis, often characterized by reduced diversity or altered abundance of benecial or harmful bacteria. Whether dysbiosis causes disease or is caused by the disease or by associated features such as an altered lifestyle is not known. However, it has now been shown that many diseases can

34、be transferred to healthy mice by inoculating gut microbiota from affected individuals, making a strong casefor a causative role of the microbiota. There are numerous examples of host microbe crosstalk suggesting that manipulation of the gut microbiota may have therapeutic potential. Nevertheless, h

35、ow an altered gut microbial content inuences host physiology is in many cases not known. One important aspect is that the overall functions of the gut microbes may be more important than the abundance of individual species. By characterizing the functional metagenome, in other words all the microbia

36、l genes present in gut, it is possible to identify metabolicpathways altered in different phenotypes. Importantly, these metagenomic alterations mayoften be reected in fecal or circulating levels of microbial metabolites, in other words by byproducts of bacterial metabolism of dietary compounds, for

37、 example. Some disease states have been associated with increased levels of specic microbial metabolites which may be directly involved in pathogenesis, providing one example of thefunctional metagenome as a putative player in health and disease.TREIMM 1436 No. of Pages 13The factors that are import

38、ant for the initial microbiota assembly and development during infancyremainpoorlyunderstood, but includehostgenetics, the prenatalenvironment,delivery mode, diet (including milk feeding), and environmental exposure (e.g., antibiotics) 6,22. Studies have shown that vaginally delivered neonates harbo

39、red their maternal vaginal bacteria, whereas in C-sectioned delivered infants their maternal skin bacteria were over-represented 23,24. These differences gradually decrease over time, but a bacterial signature associated with C-section delivery is still detectable until 1224 months of life 25,26. Th

40、e benecial properties of breastfeeding are in part related to factors secreted in breast milk, including IgA,lactoferrin, and defens27,28. Interestingly, recent study in mice showed that the maternalmicrobiota shapes the immune system of the offspring because maternal antibodies transfer microbial m

41、olecules during pregnancy and in milk 29. This indicates that the maternal microbiota prepares the newborn for microbial colonization. Other studies have also shown that secretory antibodies in milk are determinants of long-term microbiota composition in thegut 3032. Breast milk contahuman milk olig

42、osaccharides (HMOs) that act as an energysource for colonic bacteria and promote colonization by Bidobacterium strathat has beenassociated with improved gut barrier function and protection from enteropathogen infection 6,22. The cessation of breast feeding and introduction of solid foods also has an

43、 effect on gut microbial community conguration 26.The microbiota co-develops with the immune system during postnatal life, and the mucosalimmune system is considered to play an important rolehaping the gut microbiota commu-nity (reviewed recently in 2,3). Interestingly, gut IgA responses to bacteria

44、l members of the microbiota were recently shown to co-develop in parallel with the developing microbiota during the two rst postnatal years 13. Many of the targeted bacteria were age-discriminatory taxa,suggesting that IgA is directly involvedhaping postnatal microbiota assembly.Despite the recent r

45、eports discussed above, the mechanisms that control the development of a normal microbiota are still poorly understood. However, the use of gnotobiotic mice may turn out to be a promising strategy to test how various factors inuence microbiota development, and how changes of the microbiota are relat

46、ed to disease processes, by transferring bacterialstrafrom humans into germ-free mice 6,33.Stability and Resilience of the Adult Human Gut MicrobiotaA limited number of studies suggest that the individual gut microbiota is relatively stable over time, although with some day-to-day variability 34,35.

47、 Courses of antibiotics lead to rapid changes in the microbiota prole, with gradual normalization towards baseline which largely takes place within 26 weeks, but may take up to 12 months 3638. Diet is a well-known contributor to microbial composition, but the association between long-term diet and t

48、he microbiota prole is only moderate 39. By contrast, short-term major dietary changes may have a strong impact on the microbial prole, returning to normal when the diet is normalized 40. The gold standard for external reset of the gut microbiota, fecal microbiota trans- plantation (FMT), may also o

49、nly have short-term effects. While FMT usually leads to long- lasting resolution of C. difcile colitis, treatment in a condition such as ulcerative colitis, which is associated with a more complex (but dysbiotic) microbiota than C. difcile colitis, showed increased similarity with the donor for only

50、 4 to 12 weeks in most patients, although some patients maintain a donor-like microbiota for up to 1 year 41,42. The latter was associated with long-lasting remission. Overall, the available data suggest not only that external factors may lead to signicant alterations of microbiota composition but a

51、lso that in many cases these alterationsaretransient,graduallyreturning to the baseline state. However,depending on so far unknown factors (host or the nature of the perturbation or both) the microbiota may re-establishTrends in Immunology, Month Year, Vol. xx, No. yy 3clusters of organisms grouped

52、by DNA sequence similarities of taxonomic marker genes, for example bacterial 16S rRNA genes. RAG genes: recombination activating genes encode enzymes that are involved in diversication of lymphocyte antigen receptors by promoting the rearrangement and recombination of gene segments within the varia

53、ble regions of such receptors.TREIMM 1436 No. of Pages 13an altered new state of equilibrium 43. The fact that the gut microbiota is in part heritable, and is inuenced by host genetic variation 44,45, means that the microbiota composition at such equilibrium states may in part be determined by host

54、genes. The effect of host genetics on microbial composition in adults is only moderate, estimated to account for 10% of gut microbiota variation 46, suggesting that acquired or exogenous factors, in addition to interaction effects within the gut, are at least as important for gut microbiota stabilit

55、y.DevelopmentofIgAResponsesApproximately 80% of all PCsin the body arelocatedin theintestinal tract that produces grams of antibodies every day 10. Intestinal PCs produce mainly dimers and some larger polymers of IgA (79%and 90% in the smallandlargeintestine, respectively), whereas a minorfractionpr

56、oduces pentameric IgM (18% and 6%, respectively) 47. Both antibody classes interact with the trans- membrane poly Ig receptor (pIgR) located on the basolateral side of secretory epithelial cells that actively translocate IgA and IgM to the apical side (Figure 1). In thesecells the pIgR is proteolyti

57、cally cleaved to release secretory (S) Igs that perform their protective functions as free antibodies in the gut lumen. SIgA (and SIgM) is therefore uniquely positioned as the major antigen-specic mechanism by which the adaptive immune system can physically interact with the gut microbiota.Atbirthon

58、lysmallamountsofIgAareproducedlocallyinthegut,andthenewbornthereforerelies on IgA antibodies present in the breast milk. The development of local IgA production depends on microbial colonization, as demonstrated by the fact that germ-free mice possess only few plasma cells 48,49. Intestinal bacteria-specic IgA production is rapidly triggered in response to mono- colonization, even after transientexposure to live bacteria50. However, the ability to inducean IgAresponsedependsonthetypeofmicrobe.Bymono-colonizinggerm-freemicewith53single bacterial species it was sho