IgA response to symbiotic bacteria as a mediator of gut homeostasis

Colonization of germ-free mice with a normal gut microbiota elicits bacteria-specific IgA antibody responses. The effects of these responses on microbial and host biology remain poorly defined. Therefore, we developed a gnotobiotic mouse model where the microbiota is reduced to one bacterial species, and the antibody repertoire to a single, monoclonal IgA against the bacterium's capsular polysaccharide. Bacteroides thetaiotaomicron was introduced into germ-free wild-type, immunodeficient Rag1(-/-), or Rag1(-/-) mice harboring IgA-producing hybridoma cells. Without IgA, B. thetaiotaomicron elicits a more robust innate immune response and reacts to this response by inducing genes that metabolize host oxidative products. IgA reduces intestinal proinflammatory signaling and bacterial epitope expression, thereby balancing suppression of the oxidative burst with the antibody's negative impact on bacterial fitness. These results underscore the adaptive immune system's critical role in establishing a sustainable host-microbial relationship. Immunoselection of bacterial epitope expression may contribute to the remarkable strain-level diversity in this ecosystem.     

The tumor suppressor Apc controls planar cell polarities central to gut homeostasis

The stem cells (SCs) at the bottom of intestinal crypts tightly contact niche-supporting cells and fuel the extraordinary tissue renewal of intestinal epithelia. Their fate is regulated stochastically by populational asymmetry, yet whether asymmetrical fate as a mode of SC division is relevant and whether the SC niche contains committed progenitors of the specialized cell types are under debate. We demonstrate spindle alignments and planar cell polarities, which form a novel functional unit that, in SCs, can yield daughter cell anisotropic movement away from niche-supporting cells. We propose that this contributes to SC homeostasis. Importantly, we demonstrate that some SC divisions are asymmetric with respect to cell fate and provide data suggesting that, in some SCs, mNumb displays asymmetric segregation. Some of these processes were altered in apparently normal crypts and microadenomas of mice carrying germline Apc mutations, shedding new light on the first stages of progression toward colorectal cancer.     

From slow waves to sleep homeostasis: new perspectives

EEG slow waves are the epitome of deep nonREM sleep. The level of slow-wave activity (SWA; defined as spectral power in the 0.5-4.5 Hz band) in the initial part of sleep is determined by prior sleep and waking, and thereby represents a marker of a homeostatic sleep regulating process (Process S). Models based on SWA were successful in simulating sleep architecture in a variety of experimental protocols. SWA is an exceptional sleep variable in that it is little influenced by circadian phase and variations of the photoperiod. There is recent evidence that it is not waking per se but the absence of sleep, which engenders a rise in sleep propensity. Thus animals emerging from the hypometabolic states of hibernation or daily torpor exhibit an increase in SWA akin to sleep deprivation. Recent human studies showed SWA to be a marker of a local, use-dependent facet of sleep. Selective activation of specific cortical areas during waking enhanced SWA over the activated region during sleep. A frontal predominance of power in the 2-Hz band was documented in the initial part of a normal sleep episode. Sleep homeostasis may be a valuable concept for exploring the evolutionary origin of sleep. Thus 'rest homeostasis' has been demonstrated in invertebrate species, and the search for homologies of rest and sleep on a molecular genetic level has begun. Conceptualizing and characterizing sleep as a regulated process may eventually shed light on its function.     

From complex gut communities to minimal microbiomes via cultivation

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Enteric VIP-producing neurons maintain gut microbiota homeostasis through regulating epithelium fucosylation

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Vitamin A deficiency in mice alters host and gut microbial metabolism leading to altered energy homeostasis

Vitamin A deficiency (A−) is a worldwide public health problem. To better understand how vitamin A status influences gut microbiota and host metabolism, we systematically analyzed urine, cecum, serum and liver samples from vitamin A sufficient (A+) and deficient (A−) mice using ¹H NMR-based metabolomics, quantitative (q)PCR and 16S rRNA gene sequencing coupled with multivariate data analysis. The microbiota in the cecum of A− mice showed compositional as well as functional shifts compared to the microbiota from A+ mice. Targeted ¹H NMR analyses revealed significant changes in microbial metabolite concentrations including higher butyrate and hippurate and decreased acetate and 4-hydroxyphenylacetate in A+ relative to A− mice. Bacterial butyrate-producing genes including butyryl-CoA:acetate CoA-transferase and butyrate kinase were significantly higher in bacteria from A+ versus bacteria from A− mice. A− mice had disturbances in multiple metabolic pathways including alterations in energy (hyperglycemia, glycogenesis, TCA cycle and lipoprotein biosynthesis), amino acid and nucleic acid metabolism. A− mice had hyperglycemia, liver dysfunction, changes in bacterial metabolism and altered gut microbial communities. Moreover, integrative analyses indicated a strong correlation between gut microbiota and host energy metabolism pathways in the liver. Vitamin A regulates host and bacterial metabolism, and the result includes alterations in energy homeostasis.     

From soil to gut: Bacillus cereus and its food poisoning toxins

Bacillus cereus is widespread in nature and frequently isolated from soil and growing plants, but it is also well adapted for growth in the intestinal tract of insects and mammals. From these habitats it is easily spread to foods, where it may cause an emetic or a diarrhoeal type of food-associated illness that is becoming increasingly important in the industrialized world. The emetic disease is a food intoxication caused by cereulide, a small ring-formed dodecadepsipeptide. Similar to the virulence determinants that distinguish Bacillus thuringiensis and Bacillus anthracis from B. cereus, the genetic determinants of cereulide are plasmid-borne. The diarrhoeal syndrome of B. cereus is an infection caused by vegetative cells, ingested as viable cells or spores, thought to produce protein enterotoxins in the small intestine. Three pore-forming cytotoxins have been associated with diarrhoeal disease: haemolysin BL (Hbl), nonhaemolytic enterotoxin (Nhe) and cytotoxin K. Hbl and Nhe are homologous three-component toxins, which appear to be related to the monooligomeric toxin cytolysin A found in Escherichia coli. This review will focus on the toxins associated with foodborne diseases frequently caused by B. cereus. The disease characteristics are described, and recent findings regarding the associated toxins are discussed, as well as the present knowledge on virulence regulation.     

From circadian rhythms to cancer chronotherapeutics

Mammalian circadian rhythms result from a complex organization involving molecular clocks within nearly all “normal” cells and a dedicated neuroanatomical system, which coordinates the so-called “peripheral oscillators.” The core of the central clock system is constituted by the suprachiasmatic nuclei that are located on the floor of the hypothalamus. Our understanding of the mechanisms of circadian rhythm generation and coordination processes has grown rapidly over the past few years. In parallel, we have learnt how to use the predictable changes in cellular metabolism or proliferation along the 24h time scale in order to improve treatment outcome for a variety of diseases, including cancer. The chronotherapeutics of malignant diseases has emerged as a result of a consistent development ranging from experimental, clinical, and technological prerequisites to multicenter clinical trials of chronomodulated delivery schedules. Indeed large dosing-time dependencies characterize the tolerability of anticancer agents in mice or rats, a better efficacy usually results from treatment administration near the least toxic circadian time in rodent tumor models. Programmable in time multichannel pumps have allowed to test the chronotherapy concepts in cancer patients and to implement chronomodulated delivery schedules in current practice. Clinical phase I and II trials have established the feasibility, the safety, and the activity of the chronotherapy schedules, so that this treatment method has undergone further evaluation in international multicenter phase III trials. Overall, more than 2000 patients with metastatic disease have been registered in chronotherapy trials. Improved tolerability and/or better antitumor activity have been demonstrated in randomized multicenter studies involving large patient cohorts. The relation between circadian rhythmicity and quality of life and even survival has also been a puzzling finding over the recent years. An essential step toward further developments of circadian-timed therapy has been the recent constitution of a Chronotherapy cooperative group within the European Organization for Research and Treatment of Cancer. This group now involves over 40 institutions in 12 countries. It is conducting currently six trials and preparing four new studies. The 19 contributions in this special issue reflect the current status and perspectives of the several components of cancer chronotherapeutics.     

From imino sugars to cancer glycoproteins

This review summarizes fifty years of carbohydrate chemistry, from studies of reaction mechanisms and development of synthetic methods to the design of specific compounds for investigations of cancer glycoproteins. Through these years of intensive research, many carbohydrate derivatives were shown to be biologically relevant, for example the fragments of bacterial polysaccharides and imino sugars that were potent inhibitors of glycosidases. Oligosaccharides and O- glycopeptides with GalNAc-Ser/Thr linkages were essential for studies of cancer immunology and the specificities and inhibition of cancer glycosyltransferases. Thus carbohydrate chemistry has provided the basis for our knowledge of the biochemistry and immunology of cancer cell glycoproteins.     

Epithelial-cell recognition of commensal bacteria and maintenance of immune homeostasis in the gut

Mucosal surfaces such as the intestinal tract are continuously exposed to both potential pathogens and beneficial commensal microorganisms. This creates a requirement for a homeostatic balance between tolerance and immunity that represents a unique regulatory challenge to the mucosal immune system. Recent findings suggest that intestinal epithelial cells, although once considered a simple physical barrier, are a crucial cell lineage for maintaining intestinal immune homeostasis. This Review discusses recent findings that identify a cardinal role for epithelial cells in sampling the intestinal microenvironment, discriminating pathogenic and commensal microorganisms and influencing the function of antigen-presenting cells and lymphocytes.     

Microbiota transplantation reveals beneficial impact of berberine on hepatotoxicity by improving gut homeostasis

Berberine has been shown to reduce acute liver injury although the underlying mechanism is not fully understood. Because of the anatomic connection, the liver is constantly exposed to gut-derived bacterial products and metabolites. In this study, we showed that berberine has beneficial effects on both hepatotoxicity and intestinal damage in a rat model of chronic or acute liver injury. Microbiota transplantation from the rats with chronic hepatotoxicity could aggravate acute hepatotoxicity in mice treated with diethylnitrosamine (DEN). In rat models with gut homeostasis disruption induced by penicillin or dextran sulfate sodium (DSS), their fecal microbiota could also cause an enhanced hepatotoxicity of recipient mice. When treated with berberine, the DSS-induced enteric dysbacteriosis could be mitigated and their fecal bacteria were able to reduce acute hepatotoxicity in recipient mice. This study indicates that berberine could improve intestinal dysbacteriosis, which reduces the hepatotoxicity caused by pathological or pharmacological intervention. Fecal microbiota transplantation might be a useful method to directly explore homeostatic alteration in gut microbiota.     

A high methionine and low folate diet alters glucose homeostasis and gut microbiome

Hyperhomocysteinemia (HHcy) is considered as a risk factor for several complications, including cardiovascular and neurological disorders. A high methionine low folate (HMLF) diet chronically causes HHcy by accumulating homocysteine in the systemic circulation. Elevated Hcy level is also associated with the incidence of diabetes mellitus. However, very few studies focus on the impact of HMLF diet on glucose homeostasis, and that on gut microbiome profile. HHcy was induced by feeding C57BL/6 mice a HMLF diet for 8 weeks. The HMLF diet feeding resulted in a progressive body weight loss, and development of slight glucose intolerance and insulin resistance in HHcy mice. Notably, the HMLF diet alters the gut microbiome profile and increases the relative abundance of porphyromonadaceae family of bacteria in HHcy mice. These findings provide new insights into the roles of dysregulated glucose homeostasis and gut flora in the pathogenesis of HHcy-related complications.