Microbiota and host immune responses: a love-hate relationship

A complex relationship between the microbiota and the host emerges early at birth and continues throughout life. The microbiota includes the prokaryotes, viruses and eukaryotes living among us, all of which interact to different extents with various organs and tissues in the body, including the immune system. Although the microbiota is most dense in the lower intestine, its influence on host immunity extends beyond the gastrointestinal tract. These interactions with the immune system operate through the actions of various microbial structures and metabolites, with outcomes ranging from beneficial to deleterious for the host. These differential outcomes are dictated by host factors, environment, and the type of microbes or products present in a specific ecosystem. It is also becoming clear that the microbes are in turn affected and respond to the host immune system. Disruption of this complex dialogue between host and microbiota can lead to immune pathologies such as inflammatory bowel diseases, diabetes and obesity. This review will discuss recent advances regarding the ways in which the host immune system and microbiota interact and communicate with one another

The flavonoid luteolin prevents lipopolysaccharide-induced NF-kappaB signalling and gene expression by blocking IkappaB kinase activity in intestinal epithelial cells and bone-marrow derived dendritic cells

The nuclear factor (NF)-κB transcriptional system is a major effector pathway involved in inflammation and innate immune responses. The flavonoid luteolin is found in various herbal extracts and has shown anti-inflammatory properties. However, the mechanism of action and impact of luteolin on innate immunity is still unknown. We report that luteolin significantly blocks lipopolysaccharide (LPS)-induced IκB phosphorylation/degradation, NF-κB transcriptional activity and intercellular adhesion molecule-1 (ICAM-1) gene expression in rat IEC-18 cells. Using chromatin immunoprecipitation, we demonstrate that LPS-induced RelA recruitment to the ICAM-1 gene promoter is significantly reduced in luteolin-treated cells. Moreover, in vitro kinase assays show that luteolin directly inhibits LPS-induced IκB kinase (IKK) activity in IEC-18 cells. Using bone-marrow derived dendritic cells (BMDCs) isolated from interleukin (IL)-10−/− mice or from recently engineered transgenic mice expressing the enhanced green fluorescent protein (EGFP) under the transcriptional control of NF-κB cis-elements (cis-NF-κBEGFP), we found that luteolin blocks LPS-induced IκB phosphorylation and IKK activity, and decreases EGFP, IL-12 and tumour necrosis factor-α gene expression. Moreover, intraperitoneal administration of luteolin significantly inhibited LPS-induced EGFP expression in both peripheral blood mononuclear cells and splenocytes isolated from cis-NF-κBEGFP mice. These results indicate that luteolin blocks LPS-induced NF-κB signalling and proinflammatory gene expression in intestinal epithelial cells and dendritic cells. Modulation of innate immunity by natural plant products may represent an attractive strategy to prevent intestinal inflammation associated with dysregulated innate immune responses

Think Small: Zebrafish as a Model System of Human Pathology

Although human pathologies have mostly been modeled using higher mammal systems such as mice, the lower vertebrate zebrafish has gained tremendous attention as a model system. The advantages of zebrafish over classical vertebrate models are multifactorial and include high genetic and organ system homology to humans, high fecundity, external fertilization, ease of genetic manipulation, and transparency through early adulthood that enables powerful imaging modalities. This paper focuses on four areas of human pathology that were developed and/or advanced significantly in zebrafish in the last decade. These areas are (1) wound healing/restitution, (2) gastrointestinal diseases, (3) microbe-host interactions, and (4) genetic diseases and drug screens. Important biological processes and pathologies explored include wound-healing responses, pancreatic cancer, inflammatory bowel diseases, nonalcoholic fatty liver disease, and mycobacterium infection. The utility of zebrafish in screening for novel genes important in various pathologies such as polycystic kidney disease is also discussed

Les justes bornes de la richesse : fondements normatifs et mise en œuvre d’une richesse maximale

CotutelleDans cette thèse, je tente d’établir les fondements normatifs d’une richesse maximale qui comprend deux mesures complémentaires : un revenu maximal qui peut être mis en œuvre au moyen d’un impôt sur le revenu et un capital maximal, au moyen d’un impôt sur les successions, dont le taux marginal est de 100 % dans les deux cas. Je soutiens en effet qu’une telle mesure est juste, puisqu’elle respecte les principes développés au sein de trois théories principales : le libertarisme, le suffisantisme et le prioritarisme. Puis, je soutiens aussi qu’une telle mesure est efficace d’un point de vue économique, puisqu’elle permet de mieux diffuser les incitations financières, ce qui peut avoir des effets positifs sur la production et la répartition de la richesse. D’abord, je soutiens qu’une richesse maximale respecte le principe fondamental défendu par les libertariens, c’est-à-dire la propriété de soi. Pour ce faire, je m’appuie surtout sur deux arguments : le proviso et la théorie des marchés où le gagnant rafle la mise. D’abord, je montre que si l’on associe les ressources naturelles au capital, l’application d’un proviso au principe d’acquisition interdit l’appropriation illimitée des ressources naturelles, ce qui permet de justifier un capital maximal. Ensuite, je montre que si l’on associe les fruits du travail au revenu, les marchés où le gagnant rafle la mise permettent à certains individus de recevoir des revenus qui sont supérieurs aux fruits de leur travail, ce qui viole par excès le principe de la propriété de soi et permet de justifier un revenu maximal. Ensuite, je soutiens qu’une richesse maximale respecte les principes développés au sein de deux théories faisant partie de la tradition égalitariste : le suffisantisme et le prioritarisme. Pour ce faire, je montre que ces deux théories ne sont acceptables que si elles intègrent une autre théorie que l’on appelle le limitarisme. Selon cette théorie, toute richesse supérieure à celle dont un individu a besoin pour s’épanouir pleinement dans la vie peut être qualifiée d’immorale. Par conséquent, une telle théorie permet de justifier une richesse maximale, puisqu’elle ajoute un seuil de richesse au seuil de pauvreté que défendent déjà les suffisantistes et les prioritaristes. Enfin, je réponds à l’une des principales objections qui peuvent être soulevées contre une richesse maximale et qui porte sur l’efficacité économique du plafonnement des incitations financières. Je montre en effet qu’une richesse maximale, contrairement à ce que l’on pourrait croire, pourrait avoir des effets positifs sur la production et la distribution de la richesse. Pour ce faire, je m’appuie surtout sur trois arguments. D’abord, les incitations ont une importance surestimée en sciences économiques. Ensuite, il existe plusieurs formes d’incitations qui ne se réduisent nullement aux seules incitations financières. Enfin, il est préférable de diffuser largement les incitations financières plutôt que de les concentrer exagérément auprès d’une minorité d’individus.In this thesis, I try to establish the normative foundations for a maximum limit on wealth that includes two complementary measures: a maximum on income that can be implemented by means of an income tax, and a maximum on capital, which can be attained through a tax on inheritance; the marginal rate being 100% in both cases. Indeed, I argue that such a measure is fair, since it respects the principles developed in three main theories: libertarianism, sufficientarianism, and prioritarianism. Next, I argue that such a measure is economically efficient, since it allows to better spread financial incentives, which can have positive effects on the production and distribution of wealth. First, I maintain that a maximum limit on wealth respects the fundamental principle defended by libertarians, that is, self-ownership. To do this, I rely mainly on two arguments: the proviso and the theory of winner-takes-all markets. First, I show that if we associate natural resources with capital, the application of a proviso to the principle of acquisition prohibits the unlimited appropriation of natural resources, which justifies a maximum on capital. Then, I show that if the fruits of labor are associated with income, winner-takes-all markets allow certain individuals to receive incomes that are superior to the fruits of their labor, which violates the principle of self-ownership, and thus justifies a maximum on income. Secondly, I maintain that a maximum wealth respects the principles developed within two theories within the egalitarian tradition: those of sufficientarianism and prioritarianism. To do this, I show that these two theories are acceptable only if they integrate another theory named limitarianism. According to this theory, any wealth superior to that which an individual needs to live a flourishing life can be qualified as immoral. Consequently, such a theory makes it possible to justify a maximum wealth, since it adds a wealth threshold to the poverty threshold already defended by sufficientarians, and prioritarians. Finally, I respond to one of the main objections that can be raised against maximum wealth and which deals with the economic efficiency of the capping of financial incentives. In fact, I show that maximum wealth, contrary to what one might believe, could have positive effects on the production and distribution of wealth. To do this, I rely mainly on three arguments. First, incentives are overestimated in economics. Second, there are several forms of incentives that are not limited to financial incentives alone. Finally, it is preferable to disseminate financial incentives widely rather than to exaggeratedly concentrate them on a minority of individuals

Microbiota as a mediator of cancer progression and therapy

Complex and intricate circuitries regulate cellular proliferation, survival, and growth, and alterations of this network through genetic and epigenetic events result in aberrant cellular behaviors, often leading to carcinogenesis. Although specific germline mutations have been recognized as cancer inducers, the vast majority of neoplastic changes in humans occur through environmental exposure, lifestyle, and diet. An emerging concept in cancer biology implicates the microbiota as a powerful environmental factor modulating the carcinogenic process. For example, the intestinal microbiota influences cancer development or therapeutic responses through specific activities (immune responses, metabolites, microbial structures, and toxins). The numerous effects of microbiota on carcinogenesis, ranging from promoting, preventing, or even influencing therapeutic outcomes, highlight the complex relationship between the biota and the host. In this review, we discuss the latest findings on this complex microbial interaction with the host and highlight potential mechanisms by which the microbiota mediates such a wide impact on carcinogenesis

From promotion to management: The wide impact of bacteria on cancer and its treatment: Prospects & Overviews

In humans, the intestine is the major reservoir of microbes. Although the intestinal microbial community exists in a state of homeostasis called eubiosis, environmental and genetics factors can lead to microbial perturbation or dysbiosis, a state associated with various pathologies including inflammatory bowel diseases (IBD) and colorectal cancer (CRC). Dysbiotic microbiota is thought to contribute to the initiation and progression of CRC. At the opposite end of the spectrum, two recently published studies in Science reveal that the microbiota is essential for chemotherapeutic drug efficacy, suggesting a beneficial microbial function in cancer management. The dichotomy between the beneficial and detrimental roles of the microbiota during cancer initiation, progression and treatment emphasize the interwoven relationship between bacteria and cancer. Moreover, these findings suggest that the microbiota could be considered as a therapeutic target, not only at the level of cancer prevention, but also during management, i.e. by enhancing the efficacy of chemotherapeutics

The struggle within: Microbial influences on colorectal cancer:

Recently, an unprecedented effort has been directed at understanding the interplay between chronic inflammation and development of cancer, with the case of inflammatory bowel disease (IBD)-associated colorectal cancer at the forefront of this research endeavor. The last decade has been particularly fertile, with the discovery of numerous innovative paradigms linking various inflammatory, proliferative, and innate and adaptive immune signaling pathways to the development of colorectal cancer. Because of the preponderant role of the intestinal microbiota in the initiation and progression of IBD, recent efforts have been directed at understanding the relationship between bacteria and colorectal cancer. The microbiota and its collective genome, the microbiome, form a diverse and complex ecological community that profoundly impacts intestinal homeostasis and disease states. This review will discuss the differential influence of the microbiota on the development of IBD-associated colorectal cancer and highlight the role of innate immune sensor-dependent as well as -independent mechanisms in this pathology

Campylobacter jejuni Induces Colitis Through Activation of Mammalian Target of Rapamycin Signaling

Campylobacter jejuni is the worldwide leading cause of bacterial-induced enteritis. The molecular and cellular events that lead to campylobacteriosis are poorly understood. We identify mammalian target of rapamycin (mTOR) as a signaling pathway that leads to C jejuni-induced intestinal inflammation

Could a Swimming Creature Inform Us on Intestinal Diseases? Lessons from Zebrafish:

Understanding a complex pathology such as inflammatory bowel disease, where host genetics (innate and adaptive immunity, barrier function) and environmental factors (microbes, diet, and stress) interact together to influence disease onset and severity, requires multipronged approaches to model these numerous variables. Researchers have typically relied on preclinical models of mouse and rat origin to push the boundary of knowledge further. However, incorporation of novel vertebrate models may contribute to new knowledge on specific aspects of intestinal homeostasis. An emerging literature has seen the use of zebrafish as a novel animal system to study key aspects of host–microbe interactions in the intestine. In this review, we briefly introduce components of host–microbiota interplay in the developing zebrafish intestine and summarize key lessons learned from this animal system; review important chemically induced and genetically engineered zebrafish models of intestinal immune disorders; and discuss perspectives and limitations of the zebrafish model system

The Microbiota Protects against Ischemia/Reperfusion-Induced Intestinal Injury through Nucleotide-Binding Oligomerization Domain-Containing Protein 2 (NOD2) Signaling

Nucleotide-binding oligomerization domain-containing protein 2 (NOD2), an intracellular pattern recognition receptor, induces autophagy on detection of muramyl dipeptide (MDP), a component of microbial cell walls. The role of bacteria and NOD2 signaling toward ischemia/reperfusion (I/R)–induced intestinal injury response is unknown. Herein, we report that I/R-induced intestinal injury in germ-free (GF) C57BL/6 wild-type (WT) mice is worse than in conventionally derived mice. More important, microbiota-mediated protection against I/R-induced intestinal injury is abrogated in conventionally derived Nod2−/− mice and GF Nod2−/− mice. Also, WT mice raised in specific pathogen-free (SPF) conditions fared better against I/R-induced injury than SPF Nod2−/− mice. Moreover, SPF WT mice i.p. administered 10 mg/kg MDP were protected against injury compared with mice administered the inactive enantiomer, l-MDP, an effect lost in Nod2−/− mice. However, MDP administration failed to protect GF mice from I/R-induced intestinal injury compared with control, a phenomenon correlating with undetectable Nod2 mRNA level in the epithelium of GF mice. More important, the autophagy-inducer rapamycin protected Nod2−/− mice against I/R-induced injury and increased the levels of LC3+ puncta in injured tissue of Nod2−/− mice. These findings demonstrate that NOD2 protects against I/R and promotes wound healing, likely through the induction of the autophagy response