The potential for probiotic manipulation of the gastrointestinal microbiome

Multiple internal and external sites of the healthy human body are colonized by a diversity of symbiotic microbes. The microbial assemblages found in the intestine represent some of the most dense and diverse of these human-associated ecosystems. Unsurprisingly, the enteric microbiome, that is the totality of microbes, their combined genomes, and their interactions with the human body, has a profound impact on physiological aspects of mammalian function, not least, host immune response. Lack of early-life exposure to certain microbes, or shifts in the composition of the gastrointestinal microbiome have been linked to the development and progression of several intestinal and extra-intestinal diseases, including childhood asthma development and inflammatory bowel disease. Modulating microbial exposure through probiotic supplementation represents a long-held strategy towards ameliorating disease via intestinal microbial community restructuring. This field has experienced somewhat of a resurgence over the past few years, primarily due to the exponential increase in human microbiome studies and a growing appreciation of our dependence on resident microbiota to modulate human health. This review aims to review recent regulatory aspects related to probiotics in food. It also summarizes what is known to date with respect to human gastrointestinal microbiota - the niche which has been most extensively studied in the human system - and the evidence for probiotic supplementation as a viable therapeutic strategy for modulating this consortium.     

Role of the enteric microbiota in intestinal homeostasis and inflammation

The mammalian intestine encounters many more microorganisms than any other tissue in the body thus making it the largest and most complex component of the immune system. Indeed, there are greater than 100 trillion (10¹⁴) microbes within the healthy human intestine, and the total number of genes derived from this diverse microbiome exceeds that of the entire human genome by at least 100-fold. Our coexistence with the gut microbiota represents a dynamic and mutually beneficial relationship that is thought to be a major determinant of health and disease. Because of the potential for intestinal microorganisms to induce local and/or systemic inflammation, the intestinal immune system has developed a number of immune mechanisms to protect the host from pathogenic infections while limiting the inflammatory tissue injury that accompanies these immune responses. Failure to properly regulate intestinal mucosal immunity is thought to be responsible for the inflammatory tissue injury observed in the inflammatory bowel diseases (IBD; Crohn disease, ulcerative colitis). An accumulating body of experimental and clinical evidence strongly suggests that IBD results from a dysregulated immune response to components of the normal gut flora in genetically susceptible individuals. The objective of this review is to present our current understanding of the role that enteric microbiota play in intestinal homeostasis and pathogenesis of chronic intestinal inflammation.     

Prolonged antibiotic treatment induces a diabetogenic intestinal microbiome that accelerates diabetes in NOD mice

Accumulating evidence supports that the intestinal microbiome is involved in Type 1 diabetes (T1D) pathogenesis through the gut-pancreas nexus. Our aim was to determine whether the intestinal microbiota in the non-obese diabetic (NOD) mouse model played a role in T1D through the gut. To examine the effect of the intestinal microbiota on T1D onset, we manipulated gut microbes by: (1) the fecal transplantation between non-obese diabetic (NOD) and resistant (NOR) mice and (2) the oral antibiotic and probiotic treatment of NOD mice. We monitored diabetes onset, quantified CD4+T cells in the Peyer''s patches, profiled the microbiome and measured fecal short-chain fatty acids (SCFA). The gut microbiota from NOD mice harbored more pathobionts and fewer beneficial microbes in comparison with NOR mice. Fecal transplantation of NOD microbes induced insulitis in NOR hosts suggesting that the NOD microbiome is diabetogenic. Moreover, antibiotic exposure accelerated diabetes onset in NOD mice accompanied by increased T-helper type 1 (Th1) and reduced Th17 cells in the intestinal lymphoid tissues. The diabetogenic microbiome was characterized by a metagenome altered in several metabolic gene clusters. Furthermore, diabetes susceptibility correlated with reduced fecal SCFAs. In an attempt to correct the diabetogenic microbiome, we administered VLS#3 probiotics to NOD mice but found that VSL#3 colonized the intestine poorly and did not delay diabetes. We conclude that NOD mice harbor gut microbes that induce diabetes and that their diabetogenic microbiome can be amplified early in life through antibiotic exposure. Protective microbes like VSL#3 are insufficient to overcome the effects of a diabetogenic microbiome.     

昆虫肠道防御及微生物稳态维持机制

在长期的进化过程中,昆虫形成了独特的肠道防御系统,主要由物理屏障和免疫系统共同作用来抵御外来微生物的入侵。如大部分后生动物一样,昆虫肠道上皮细胞无时无刻不与微生物接触,其种类从有益的共生菌、随食物进入的微生物到影响宿主生命的病原菌。在这样一种复杂的环境中,为了实现防御肠道病原微生物的同时又能维持共生微生物稳定的目的,宿主肠道上皮细胞必须在免疫应激和免疫耐受之间保持一种稳态平衡。Duox-ROS免疫系统和免疫缺陷(immune deficiency,Imd)信号通路作为肠道免疫反应的基本途径,必然参与调节此过程。本文从昆虫肠道防御组成、肠道免疫信号通路作用分子机制以及肠道免疫系统在肠道微生物群落稳态维持中的作用的最新研究进展进行综述。     

Gut microbes in cardiovascular diseases and their potential therapeutic applications

Microbial ecosystem comprises a complex community in which bacteria interact with each other.The potential roles of the intestinal microbiome play in human health have gained considerable attention.The imbalance of gut microbial community has been looked to multiple chronic diseases.Cardiovascular diseases(CVDs)are leading causes of morbidity worldwide and are influ-enced by genetic and environmental factors.Recent advances have provided scientific evidence that CVD may also be attributed to gut microbiome.in this review,we highlight the complex interplay between microbes,their metabolites,and the potential influence on the generation and development of CVDs.The therapeutic potentiai of using intestinal microbiomes to treat CVD is also discussed.it is quite possible that gut microbes may be used for clinical treatments of CVD in the near future.     

Beneficial microbes going underground of root immunity

Plant roots interact with an enormous diversity of commensal, mutualistic, and pathogenic microbes, which poses a big challenge to roots to distinguish beneficial microbes from harmful ones. Plants can effectively ward off pathogens following immune recognition of conserved microbe‐associated molecular patterns (MAMPs). However, such immune elicitors are essentially not different from those of neutral and beneficial microbes that are abundantly present in the root microbiome. Recent studies indicate that the plant immune system plays an active role in influencing rhizosphere microbiome composition. Moreover, it has become increasingly clear that root‐invading beneficial microbes, including rhizobia and arbuscular mycorrhiza, evade or suppress host immunity to establish a mutualistic relationship with their host. Evidence is accumulating that many free‐living rhizosphere microbiota members can suppress root immune responses, highlighting root immune suppression as an important function of the root microbiome. Thus, the gate keeping functions of the plant immune system are not restricted to warding off root‐invading pathogens but also extend to rhizosphere microbiota, likely to promote colonization by beneficial microbes and prevent growth‐defense tradeoffs triggered by the MAMP‐rich rhizosphere environment.     

Dysfunction of the intestinal microbiome in inflammatory bowel disease and treatment

Background

The inflammatory bowel diseases (IBD) Crohn's disease and ulcerative colitis result from alterations in intestinal microbes and the immune system. However, the precise dysfunctions of microbial metabolism in the gastrointestinal microbiome during IBD remain unclear. We analyzed the microbiota of intestinal biopsies and stool samples from 231 IBD and healthy subjects by 16S gene pyrosequencing and followed up a subset using shotgun metagenomics. Gene and pathway composition were assessed, based on 16S data from phylogenetically-related reference genomes, and associated using sparse multivariate linear modeling with medications, environmental factors, and IBD status.

Results

Firmicutes and Enterobacteriaceae abundances were associated with disease status as expected, but also with treatment and subject characteristics. Microbial function, though, was more consistently perturbed than composition, with 12% of analyzed pathways changed compared with 2% of genera. We identified major shifts in oxidative stress pathways, as well as decreased carbohydrate metabolism and amino acid biosynthesis in favor of nutrient transport and uptake. The microbiome of ileal Crohn's disease was notable for increases in virulence and secretion pathways.

Conclusions

This inferred functional metagenomic information provides the first insights into community-wide microbial processes and pathways that underpin IBD pathogenesis.     

Computational methods and challenges in analyzing intratumoral microbiome data

The human microbiome is intimately related to cancer biology and plays a vital role in the efficacy of cancer treatments, including immunotherapy. Extraordinary evidence has revealed that several microbes influence tumor development through interaction with the host immune system, that is, immuno–oncology–microbiome (IOM). This review focuses on the intratumoral microbiome in IOM and describes the available data and computational methods for discovering biological insights of microbial profiling from host bulk, single-cell, and spatial sequencing data. Critical challenges in data analysis and integration are discussed. Specifically, the microorganisms associated with cancer and cancer treatment in the context of IOM are collected and integrated from the literature. Lastly, we provide our perspectives for future directions in IOM research.     

Autoimmunity and the microbiome: T‐cell receptor mimicry of “self” and microbial antigens mediates self tolerance in holobionts

I propose a T‐cell receptor (TcR)‐based mechanism by which immunity mediates both “genetic self” and “microbial self” thereby, connecting microbiome disease with autoimmunity. The hypothesis is based on simple principles. First, TcR are selected to avoid strong cross‐reactivity with “self,” resulting in selection for a TcR repertoire mimicking “genetic self.” Second, evolution has selected for a “microbial self” that mimics “genetic self” so as to share tolerance. In consequence, our TcR repertoire also mimics microbiome antigenicity, providing a novel mechanism for modulating tolerance to it. Also, the microbiome mimics the TcR repertoire, acting as a secondary immune system. I call this TcR‐microbiome mimicry “holoimmunity” to denote immune tolerance to the “holobiont self.” Logically, microbiome‐host mimicry means that autoimmunity directed at host antigens will also attack components of the microbiome, and conversely, an immunological attack on the microbiome may cross‐react with host antigens producing “holoautoimmunity.”