年终盘点：2020年脑-肠-微生物轴十大研究突破
1.Nature—脑-肠轴和脑膜免疫学再突破！！科学家发现脑膜静脉窦周围存在肠道来源的IgA 浆细胞，其可抵抗血源性病菌侵袭入脑
Abstract
The central nervous system hashistorically been viewed as an immune-privileged site, but recent data haveshown that the meninges-the membranes that surround the brain and spinalcord-contain a diverse population of immune cells1. So far, studies havefocused on macrophages and T cells, but have not included a detailed analysisof meningeal humoral immunity. Here we show that, during homeostasis, the mouseand human meninges contain IgA-secreting plasma cells. These cells arepositioned adjacent to dural venous sinuses: regions of slow blood flow withfenestrations that can potentially permit blood-borne pathogens to access thebrain2. Peri-sinus IgA plasma cells increased with age and following a breachof the intestinal barrier. Conversely, they were scarce in germ-free mice, buttheir presence was restored by gut re-colonization. B cell receptor sequencingconfirmed that meningeal IgA cells originated in the intestine. Specificdepletion of meningeal plasma cells or IgA deficiency resulted in reducedfungal entrapment in the peri-sinus region and increased spread into the brainfollowing intravenous challenge, showing that meningeal IgA is essential fordefending the central nervous system at this vulnerable venous barrier surface.
参考文献：Gut-educated IgA plasma cells defendthe meningeal venous sinuses. Nature. 2020 Nov;587(7834):472-476.
2.Nature—孕鼠肠道微生物调控小鼠胎儿神经发育，尤其是丘脑-皮层轴突发生
Abstract
'Dysbiosis' of the maternal gutmicrobiome, in response to challenges such as infection1, altered diet2 andstress3 during pregnancy, has been increasingly associated with abnormalitiesin brain function and behaviour of the offspring4. However, it is unclearwhether the maternal gut microbiome influences neurodevelopment during criticalprenatal periods and in the absence of environmental challenges. Here weinvestigate how depletion and selective reconstitution of the maternal gutmicrobiome influences fetal neurodevelopment in mice. Embryos fromantibiotic-treated and germ-free dams exhibited reduced brain expression ofgenes related to axonogenesis, deficient thalamocortical axons and impairedoutgrowth of thalamic axons in response to cell-extrinsic factors. Gnotobioticcolonization of microbiome-depleted dams with a limited consortium of bacteriaprevented abnormalities in fetal brain gene expression and thalamocorticalaxonogenesis. Metabolomic profiling revealed that the maternal microbiomeregulates numerous small molecules in the maternal serum and the brains offetal offspring. Select microbiota-dependent metabolites promoted axonoutgrowth from fetal thalamic explants. Moreover, maternal supplementation withthese metabolites abrogated deficiencies in fetal thalamocortical axons.Manipulation of the maternal microbiome and microbial metabolites duringpregnancy yielded adult offspring with altered tactile sensitivity in twoaversive somatosensory behavioural tasks, but no overt differences in manyother sensorimotor behaviours. Together, our findings show that the maternalgut microbiome promotes fetal thalamocortical axonogenesis, probably throughsignalling by microbially modulated metabolites to neurons in the developingbrain.
参考文献：The maternal microbiome modulatesfetal neurodevelopment in mice. Nature. 2020 Oct;586(7828):281-286.
3.Nature—脑-肠轴再获突破！！肠道微生物通过肠-脑神经环路调控交感神经元活性
Abstract
Connections between the gut and brainmonitor the intestinal tissue and its microbial and dietary content1,regulating both physiological intestinal functions such as nutrient absorptionand motility2,3, and brain-wired feeding behaviour2. It is therefore plausiblethat circuits exist to detect gut microorganisms and relay this information toareas of the central nervous system that, in turn, regulate gut physiology4.Here we characterize the influence of the microbiota on enteric-associatedneurons by combining gnotobiotic mouse models with transcriptomics,circuit-tracing methods and functional manipulations. We find that the gutmicrobiome modulates gut-extrinsic sympathetic neurons: microbiota depletionleads to increased expression of the neuronal transcription factor cFos, andcolonization of germ-free mice with bacteria that produce short-chain fattyacids suppresses cFos expression in the gut sympathetic ganglia. Chemogeneticmanipulations, translational profiling and anterograde tracing identify asubset of distal intestine-projecting vagal neurons that are positioned to havean afferent role in microbiota-mediated modulation of gut sympathetic neurons.Retrograde polysynaptic neuronal tracing from the intestinal wall identifiesbrainstem sensory nuclei that are activated during microbial depletion, as wellas efferent sympathetic premotor glutamatergic neurons that regulategastrointestinal transit. These results reveal microbiota-dependent control ofgut-extrinsic sympathetic activation through a gut-brain circuit.
参考文献：Microbiota modulate sympatheticneurons via a gut-brain circuit. Nature. 2020 Jul;583(7816):441-446.
4.Nature—肠道细菌竟产生神经递质！！肠道细菌产生的神经递质调控宿主嗅觉反射行为
Abstract
Animals coexist in commensal,pathogenic or mutualistic relationships with complex communities of diverseorganisms, including microorganisms1. Some bacteria produce bioactiveneurotransmitters that have previously been proposed to modulate nervous systemactivity and behaviours of their hosts2,3. However, the mechanistic basis ofthis microbiota-brain signalling and its physiological relevance are largelyunknown. Here we show that in Caenorhabditis elegans, the neuromodulatortyramine produced by commensal Providencia bacteria, which colonize the gut,bypasses the requirement for host tyramine biosynthesis and manipulates a hostsensory decision. Bacterially produced tyramine is probably converted tooctopamine by the host tyramine β-hydroxylase enzyme. Octopamine, in turn,targets the OCTR-1 octopamine receptor on ASH nociceptive neurons to modulatean aversive olfactory response. We identify the genes that are required fortyramine biosynthesis in Providencia, and show that these genes are necessaryfor the modulation of host behaviour. We further find that C. elegans colonizedby Providencia preferentially select these bacteria in food choice assays, andthat this selection bias requires bacterially produced tyramine and hostoctopamine signalling. Our results demonstrate that a neurotransmitter producedby gut bacteria mimics the functions of the cognate host molecule to overridehost control of a sensory decision, and thereby promotes fitness of both thehost and the microorganism.
参考文献：A neurotransmitter produced by gutbacteria modulates host sensory behaviour. Nature. 2020 Jul;583(7816):415-420.
5.Nature—“脑-肠轴”再获突破！！迷走神经左侧肝支在调控肠道调节性T细胞稳态中发挥关键作用
Abstract
Recent clinical and experimentalevidence has evoked the concept of the gut-brain axis to explain mutualinteractions between the central nervous system and gut microbiota that areclosely associated with the bidirectional effects of inflammatory bowel diseaseand central nervous system disorders1-4. Despite recent advances in ourunderstanding of neuroimmune interactions, it remains unclear how the gut andbrain communicate to maintain gut immune homeostasis, including in theinduction and maintenance of peripheral regulatory T cells (pTreg cells), andwhat environmental cues prompt the host to protect itself from development ofinflammatory bowel diseases. Here we report a liver-brain-gut neural arc thatensures the proper differentiation and maintenance of pTreg cells in the gut.The hepatic vagal sensory afferent nerves are responsible for indirectlysensing the gut microenvironment and relaying the sensory inputs to the nucleustractus solitarius of the brainstem, and ultimately to the vagalparasympathetic nerves and enteric neurons. Surgical and chemical perturbationof the vagal sensory afferents at the hepatic afferent level reduced theabundance of colonic pTreg cells; this was attributed to decreased aldehydedehydrogenase (ALDH) expression and retinoic acid synthesis by intestinalantigen-presenting cells. Activation of muscarinic acetylcholine receptorsdirectly induced ALDH gene expression in both human and mouse colonicantigen-presenting cells, whereas genetic ablation of these receptors abolishedthe stimulation of antigen-presenting cells in vitro. Disruption of left vagalsensory afferents from the liver to the brainstem in mouse models of colitisreduced the colonic pTreg cell pool, resulting in increased susceptibility tocolitis. These results demonstrate that the novel vago-vagal liver-brain-gutreflex arc controls the number of pTreg cells and maintains gut homeostasis.Intervention in this autonomic feedback feedforward system could help in thedevelopment of therapeutic strategies to treat or prevent immunologicaldisorders of the gut.
参考文献：The liver-brain-gut neural arcmaintains the T reg cell niche in the gut. Nature. 2020 Sep;585(7826):591-596.
6.Nature—你猜小鼠对糖的偏好是决定于舌头，还是胃？研究发现小鼠肠-脑轴介导了糖偏好
Abstract
The taste of sugar is one of the mostbasic sensory percepts for humans and other animals. Animals can develop astrong preference for sugar even if they lack sweet taste receptors, indicatinga mechanism independent of taste1-3. Here we examined the neural basis forsugar preference and demonstrate that a population of neurons in the vagalganglia and brainstem are activated via the gut-brain axis to create preferencefor sugar. These neurons are stimulated in response to sugar but not artificialsweeteners, and are activated by direct delivery of sugar to the gut. Usingfunctional imaging we monitored activity of the gut-brain axis, and identifiedthe vagal neurons activated by intestinal delivery of glucose. Next, weengineered mice in which synaptic activity in this gut-to-brain circuit wasgenetically silenced, and prevented the development of behavioural preferencefor sugar. Moreover, we show that co-opting this circuit by chemogeneticactivation can create preferences to otherwise less-preferred stimuli.Together, these findings reveal a gut-to-brain post-ingestive sugar-sensingpathway critical for the development of sugar preference. In addition, theyexplain the neural basis for differences in the behavioural effects ofsweeteners versus sugar, and uncover an essential circuit underlying the highlyappetitive effects of sugar.
参考文献：The gut-brain axis mediates sugarpreference. Nature. 2020 Apr;580(7804):511-516.
7.Nature—ALS/FTD中肠道微生物是“坏”的？C9orf72抑制肠道微生物诱导的外周和中枢炎症
Abstract
A hexanucleotide-repeat expansion inC9ORF72 is the most common genetic variant that contributes to amyotrophiclateral sclerosis and frontotemporal dementia1,2. The C9ORF72 mutation actsthrough gain- and loss-of-function mechanisms to induce pathways that areimplicated in neural degeneration3-9. The expansion is transcribed into a longrepetitive RNA, which negatively sequesters RNA-binding proteins5 before itsnon-canonical translation into neural-toxic dipeptide proteins3,4. The failureof RNA polymerase to read through the mutation also reduces the abundance ofthe endogenous C9ORF72 gene product, which functions in endolysosomal pathwaysand suppresses systemic and neural inflammation6-9. Notably, the effects of therepeat expansion act with incomplete penetrance in families with a highprevalence of amyotrophic lateral sclerosis or frontotemporal dementia,indicating that either genetic or environmental factors modify the risk ofdisease for each individual. Identifying disease modifiers is of considerabletranslational interest, as it could suggest strategies to diminish the risk ofdeveloping amyotrophic lateral sclerosis or frontotemporal dementia, or to slowprogression. Here we report that an environment with reduced abundance ofimmune-stimulating bacteria10,11 protects C9orf72-mutant mice from prematuremortality and significantly ameliorates their underlying systemic inflammationand autoimmunity. Consistent with C9orf72 functioning to prevent microbiotafrom inducing a pathological inflammatory response, we found that reducing themicrobial burden in mutant mice with broad spectrum antibiotics-as well astransplanting gut microflora from a protective environment-attenuated inflammatoryphenotypes, even after their onset. Our studies provide further evidence thatthe microbial composition of our gut has an important role in brain health andcan interact in surprising ways with well-known genetic risk factors fordisorders of the nervous system.
参考文献：C9orf72 suppresses systemic andneural inflammation induced by gut bacteria. Nature. 2020 Jun;582(7810):89-94.
8.Nature—科学家发现小鼠胃肠道机械性感觉反馈调控摄食行为的相关神经环路
Abstract
Mechanosensory feedback from thedigestive tract to the brain is critical for limiting excessive food and waterintake, but the underlying gut-brain communication pathways and mechanismsremain poorly understood1-12. Here we show that, in mice, neurons in theparabrachial nucleus that express the prodynorphin gene (hereafter, PBPdynneurons) monitor the intake of both fluids and solids, using mechanosensorysignals that arise from the upper digestive tract. Most individual PBPdynneurons are activated by ingestion as well as the stimulation of the mouth andstomach, which indicates the representation of integrated sensory signalsacross distinct parts of the digestive tract. PBPdyn neurons are anatomicallyconnected to the digestive periphery via cranial and spinal pathways; we showthat, among these pathways, the vagus nerve conveys stomach-distension signalsto PBPdyn neurons. Upon receipt of these signals, these neurons produceaversive and sustained appetite-suppressing signals, which discourages theinitiation of feeding and drinking (fully recapitulating the symptoms ofgastric distension) in part via signalling to the paraventricular hypothalamus.By contrast, inhibiting the same population of PBPdyn neurons inducesoverconsumption only if a drive for ingestion exists, which confirms that theseneurons mediate negative feedback signalling. Our findings reveal a neuralmechanism that underlies the mechanosensory monitoring of ingestion andnegative feedback control of intake behaviours upon distension of the digestivetract.
参考文献：A neural circuit mechanism formechanosensory feedback control of ingestion. Nature. 2020 Apr;580(7803):376-380.
9.Nature—脑-肠-微生物轴再获突破！！肠道微生物加剧多发性硬化EAE模型的脊髓炎症反应和脱髓鞘病理学改变
Abstract
Accumulating evidence indicates thatgut microorganisms have a pathogenic role in autoimmune diseases, including inmultiple sclerosis1. Studies of experimental autoimmune encephalomyelitis (ananimal model of multiple sclerosis)2,3, as well as human studies4-6, haveimplicated gut microorganisms in the development or severity of multiplesclerosis. However, it remains unclear how gut microorganisms act on theinflammation of extra-intestinal tissues such as the spinal cord. Here we showthat two distinct signals from gut microorganisms coordinately activateautoreactive T cells in the small intestine that respond specifically to myelinoligodendrocyte glycoprotein (MOG). After induction of experimental autoimmuneencephalomyelitis in mice, MOG-specific CD4 T cells are observed in the smallintestine. Experiments using germ-free mice that were monocolonized withmicroorganisms from the small intestine demonstrated that a newly isolatedstrain in the family Erysipelotrichaceae acts similarly to an adjuvant toenhance the responses of T helper 17 cells. Shotgun sequencing of the contentsof the small intestine revealed a strain of Lactobacillus reuteri thatpossesses peptides that potentially mimic MOG. Mice that were co-colonized withthese two strains showed experimental autoimmune encephalomyelitis symptomsthat were more severe than those of germ-free or monocolonized mice. These datasuggest that the synergistic effects that result from the presence of these microorganismsshould be considered in the pathogenicity of multiple sclerosis, and thatfurther study of these microorganisms may lead to preventive strategies forthis disease.
参考文献：Gut microorganisms act together toexacerbate inflammation in spinal cords. Nature. 2020 Sep;585(7823):102-106.
10.Cell—重磅！！！丙酸通过纠正免疫紊乱以改善多发性硬化患者的病程
Abstract
Short-chain fatty acids are processedfrom indigestible dietary fibers by gut bacteria and have immunomodulatoryproperties. Here, we investigate propionic acid (PA) in multiple sclerosis(MS), an autoimmune and neurodegenerative disease. Serum and feces of subjectswith MS exhibited significantly reduced PA amounts compared with controls,particularly after the first relapse. In a proof-of-concept study, we supplementedPA to therapy-naive MS patients and as an add-on to MS immunotherapy. After 2weeks of PA intake, we observed a significant and sustained increase offunctionally competent regulatory T (Treg) cells, whereas Th1 and Th17 cellsdecreased significantly. Post-hoc analyses revealed a reduced annual relapserate, disability stabilization, and reduced brain atrophy after 3 years of PAintake. Functional microbiome analysis revealed increased expression ofTreg-cell-inducing genes in the intestine after PA intake. Furthermore, PAnormalized Treg cell mitochondrial function and morphology in MS. Our findingssuggest that PA can serve as a potent immunomodulatory supplement to MS drugs.
参考文献：Propionic Acid Shapes the MultipleSclerosis Disease Course by an Immunomodulatory Mechanism. Cell. 2020 Mar19;180(6):1067-1080.e16.
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2020年十大研究进展名录
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6. 年终盘点：2019年抑郁症领域十大基础研究进展（一半来自中国）
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15.年终盘点：2019年神经发育及成年神经再生十大研究突破
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