http://envismadrasuniv.org/Physiology/pdf/Gut%20flora%20in%20health%20and%20disease.pdf

Gut flora in health and disease

Ecological and evolutionary forces shaping microbial diversity in the human intestine.

https://www.cell.com/cell/pdf/S0092-8674(05)00451-4.pdf

An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system.

Antibodies targeting CTLA-4 have been successfully used as cancer immunotherapy. We find that the antitumor effects of CTLA-4 blockade depend on distinct Bacteroides species. In mice and patients, T cell responses specific for B. thetaiotaomicron or B. fragilis were associated with the efficacy of CTLA-4 blockade. Tumors in antibiotic-treated or germ-free mice did not respond to CTLA blockade. This defect was overcome by gavage with B. fragilis, by immunization with B. fragilis polysaccharides, or by adoptive transfer of B. fragilis–specific T cells. Fecal microbial transplantation from humans to mice confirmed that treatment of melanoma patients with antibodies against CTLA-4 favored the outgrowth of B. fragilis with anticancer properties. This study reveals a key role for Bacteroidales in the immunostimulatory effects of CTLA-4 blockade.

/pdf/anticancer-immunotherapy-by-ctla-4-blockade-relies-on-the-4ggl8xlkba.pdf

Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota

Humans are colonized by multitudes of commensal organisms representing members of five of the six kingdoms of life; however, our gastrointestinal tract provides residence to both beneficial and potentially pathogenic microorganisms. Imbalances in the composition of the bacterial microbiota, known as dysbiosis, are postulated to be a major factor in human disorders such as inflammatory bowel disease. We report here that the prominent human symbiont Bacteroides fragilis protects animals from experimental colitis induced by Helicobacter hepaticus, a commensal bacterium with pathogenic potential. This beneficial activity requires a single microbial molecule (polysaccharide A, PSA). In animals harbouring B. fragilis not expressing PSA, H. hepaticus colonization leads to disease and pro-inflammatory cytokine production in colonic tissues. Purified PSA administered to animals is required to suppress pro-inflammatory interleukin-17 production by intestinal immune cells and also inhibits in vitro reactions in cell cultures. Furthermore, PSA protects from inflammatory disease through a functional requirement for interleukin-10-producing CD4+ T cells. These results show that molecules of the bacterial microbiota can mediate the critical balance between health and disease. Harnessing the immunomodulatory capacity of symbiosis factors such as PSA might potentially provide therapeutics for human inflammatory disorders on the basis of entirely novel biological principles.

A microbial symbiosis factor prevents intestinal inflammatory disease

Polysaccharide immunomodulators were first discovered over 40 years ago. Although very few have been rigorously studied, recent reports have revealed the mechanism of action and structure-function attributes of some of these molecules. Certain polysaccharide immunomodulators have been identified that have profound effects in the regulation of immune responses during the progression of infectious diseases, and studies have begun to define structural aspects of these molecules that govern their function and interaction with cells of the host immune system. These polymers can influence innate and cell-mediated immunity through interactions with T cells, monocytes, macrophages, and polymorphonuclear lymphocytes. The ability to modulate the immune response in an appropriate way can enhance the host9s immune response to certain infections. In addition, this strategy can be utilized to augment current treatment regimens such as antimicrobial therapy that are becoming less efficacious with the advent of antibiotic resistance. This review focuses on recent studies that illustrate the structural and biologic activities of specific polysaccharide immunomodulators and outlines their potential for clinical use.

Polysaccharide Immunomodulators as Therapeutic Agents: Structural Aspects and Biologic Function

Purpose of reviewThis review examines recent articles on the relationship of cytokines to allergy and asthma with particular emphasis on immune mechanisms involved in disease development in early life.Recent findingsIt was previously proposed that reduced microbial exposure in early life is responsi

Cytokines, allergy, and asthma.

Polysaccharide Processing and Presentation by the MHCII Pathway

The dynamic interactions between a host and its intestinal microflora that lead to commensalism are unclear. Bacteria that colonize the intestinal tract do so despite the development of a specific immune response by the host. The mechanisms used by commensal organisms to circumvent this immune response have yet to be established. Here we demonstrate that the human colonic microorganism, Bacteroides fragilis, is able to modulate its surface antigenicity by producing at least eight distinct capsular polysaccharides-a number greater than any previously reported for a bacterium-and is able to regulate their expression in an on-off manner by the reversible inversion of DNA segments containing the promoters for their expression. This means of generating surface diversity allows the organism to exhibit a wide array of distinct surface polysaccharide combinations, and may have broad implications for how the predominant human colonic microorganisms, the Bacteroides species, maintain an ecological niche in the intestinal tract.

Extensive surface diversity of a commensal microorganism by multiple DNA inversions

The capsular polysaccharide complex from Bacteroides fragilis promotes the formation of intra-abdominal abscesses--a pathologic host response to infecting microorganisms. This complex consists of two distinct polysaccharides, each with repeating units that have positively charged amino groups and negatively charged carboxyl or phosphate groups. Analysis of these polysaccharides as well as other charged carbohydrates before and after chemical modification revealed that these oppositely charged groups are required for the induction of intra-abdominal abscesses in a rat model.

Arthur O. Tzianabos

Papers

Polysaccharide Immunomodulators as Therapeutic Agents: Structural Aspects and Biologic Function

Cytokines, allergy, and asthma.

Polysaccharide Processing and Presentation by the MHCII Pathway

Extensive surface diversity of a commensal microorganism by multiple DNA inversions

Structural features of polysaccharides that induce intra-abdominal abscesses