http://www.umassmed.edu/globalassets/immunology-and-microbiology/documents/papers-for-bbs821-2015/nov-24-reviewfor-general-info.pdf

Role of the Microbiota in Immunity and Inflammation

Microbial Influences in Inflammatory Bowel Diseases

Insulin resistance is a forerunner state of ischaemic cardiovascular disease and type 2 diabetes. Here we show how the human gut microbiome impacts the serum metabolome and associates with insulin resistance in 277 non-diabetic Danish individuals. The serum metabolome of insulin-resistant individuals is characterized by increased levels of branched-chain amino acids (BCAAs), which correlate with a gut microbiome that has an enriched biosynthetic potential for BCAAs and is deprived of genes encoding bacterial inward transporters for these amino acids. Prevotella copri and Bacteroides vulgatus are identified as the main species driving the association between biosynthesis of BCAAs and insulin resistance, and in mice we demonstrate that P. copri can induce insulin resistance, aggravate glucose intolerance and augment circulating levels of BCAAs. Our findings suggest that microbial targets may have the potential to diminish insulin resistance and reduce the incidence of common metabolic and cardiovascular disorders.

Human gut microbes impact host serum metabolome and insulin sensitivity

Changes in the microbial community structure are observed in individuals with intestinal inflammatory disorders. These changes are often characterized by a depletion of obligate anaerobic bacteria, whereas the relative abundance of facultative anaerobic Enterobacteriaceae increases. The mechanisms by which the host response shapes the microbial community structure, however, remain unknown. We show that nitrate generated as a by-product of the inflammatory response conferred a growth advantage to the commensal bacterium Escherichia coli in the large intestine of mice. Mice deficient in inducible nitric oxide synthase did not support the growth of E. coli by nitrate respiration, suggesting that the nitrate generated during inflammation was host-derived. Thus, the inflammatory host response selectively enhances the growth of commensal Enterobacteriaceae by generating electron acceptors for anaerobic respiration.

https://science.sciencemag.org/content/sci/339/6120/708.full.pdf

Host-Derived Nitrate Boosts Growth of E. coli in the Inflamed Gut

Allogeneic haematopoietic stem cell transplantation is used to treat a variety of disorders, but its efficacy is limited by the occurrence of graft-versus-host disease (GVHD). The past decade has brought impressive advances in our understanding of the role of stimulatory and suppressive elements of the adaptive and innate immune systems from both the donor and the host in GVHD pathogenesis. New insights from basic immunology, preclinical models and clinical studies have led to novel approaches for prevention and treatment. This Review highlights the recent advances in understanding the pathophysiology of GVHD and its treatment, with a focus on manipulations of the immune system that are amenable to clinical application.

Advances in graft-versus-host disease biology and therapy

Oral infection of susceptible mice with Toxoplasma gondii results in Th1-type immunopathology in the ileum. We investigated gut flora changes during ileitis and determined contributions of gut bacteria to intestinal inflammation. Analysis of the intestinal microflora revealed that ileitis was accompanied by increasing bacterial load, decreasing species diversity, and bacterial translocation. Gram-negative bacteria identified as Escherichia coli and Bacteroides/Prevotella spp. accumulated in inflamed ileum at high concentrations. Prophylactic or therapeutic administration of ciprofloxacin and/or metronidazole ameliorated ileal immunopathology and reduced intestinal NO and IFN-gamma levels. Most strikingly, gnotobiotic mice in which cultivable gut bacteria were removed by quintuple antibiotic treatment did not develop ileitis after Toxoplasma gondii infection. A reduction in total numbers of lymphocytes was observed in the lamina propria of specific pathogen-free (SPF), but not gnotobiotic, mice upon development of ileitis. Relative numbers of CD4(+) T cells did not differ in naive vs infected gnotobiotic or SPF mice, but infected SPF mice showed a significant increase in the frequencies of activated CD4(+) T cells compared with gnotobiotic mice. Furthermore, recolonization with total gut flora, E. coli, or Bacteroides/Prevotella spp., but not Lactobacillus johnsonii, induced immunopathology in gnotobiotic mice. Animals recolonized with E. coli and/or total gut flora, but not L. johnsonii, showed elevated ileal NO and/or IFN-gamma levels. In conclusion, Gram-negative bacteria, i.e., E. coli, aggravate pathogen-induced intestinal Th1-type immunopathology. Thus, pathogen-induced acute ileitis may prove useful to study bacteria-host interactions in small intestinal inflammation and to test novel therapies based on modulation of gut flora.

/pdf/gram-negative-bacteria-aggravate-murine-small-intestinal-th1-2i73hhx381.pdf

Gram-Negative Bacteria Aggravate Murine Small Intestinal Th1-Type Immunopathology following Oral Infection with Toxoplasma gondii

Background: In the course of inflammatory bowel diseases (IBD) and acute murine ileitis following peroral Toxoplasma gondii infection, commensal Escherichia coli accumulate at inflamed mucosal sites and aggravate small intestinal immunopathology. Aim: To unravel the molecular mechanisms by which commensal E coli exacerbate ileitis. Methods: Ileitis was investigated in mice that lack Toll-like receptors (TLR) 2 or 4, specific for bacterial lipoproteins (LP) or lipopolysaccharide (LPS), respectively. Gnotobiotic mice, in which any cultivable gut bacteria were eradicated by antibiotic treatment, were used to study the role of LPS in ileitis. Results: Microbiological analyses revealed that E coli increase in the inflamed ileum. TLR4 −/− , but not TLR2 −/− , mice displayed reduced mortality and small intestinal immunopathology. Decreased interferon (IFN)-γ and nitric oxide (NO) levels in the inflamed terminal ileum of TLR4 −/− mice indicated that TLR4 signalling aggravates ileitis via local mediator release from immune cells. E coli strains isolated from the inflamed ileum activated cultured mouse macrophages and induced TLR4-dependent nuclear factor κB activation and NO production in human embryonic kidney 293 cells and in peritoneal macrophages, respectively. Most strikingly, in contrast with wild-type mice, gnotobiotic TLR4 −/− mice were protected from induction of ileitis by treatment with purified E coli lipid A or colonisation with live E coli . Finally, prophylactic treatment with the LPS scavenger polymyxin B ameliorated T gondii -induced ileitis. Conclusion: These findings highlight the innate immune system as a key player in T gondii -induced ileal immunopathology. Treatment with LPS or TLR4 antagonists may represent a novel strategy for prophylaxis and/or therapy of small intestinal inflammation in IBD.

/pdf/exacerbation-of-murine-ileitis-by-toll-like-receptor-4-4e5jrepzbg.pdf

Exacerbation of murine ileitis by Toll-like receptor 4 mediated sensing of lipopolysaccharide from commensal Escherichia coli

Background: Gut bacteria trigger colitis in animal models and are suspected to aggravate inflammatory bowel diseases. We have recently reported that Escherichia coli accumulates in murine ileitis and exacerbates small intestinal inflammation via Toll-like receptor (TLR) signaling.

Methodology and principal findings: Because knowledge on shifts in the intestinal microflora during colitis is limited, we performed a global survey of the colon flora of C57BL/10 wild-type (wt), TLR2(-/-), TLR4(-/-), and TLR2/4(-/-) mice treated for seven days with 3.5% dextrane-sulfate-sodium (DSS). As compared to wt animals, TLR2(-/-), TLR4(-/-), and TLR2/4(-/-) mice displayed reduced macroscopic signs of acute colitis and the amelioration of inflammation was associated with reduced IFN-gamma levels in mesenteric lymph nodes, lower amounts of neutrophils, and less FOXP3-positive T-cells in the colon in situ. During acute colitis E. coli increased in wt and TLR-deficient mice (P<0.05), but the final numbers reached were significantly lower in TLR2(-/-), TLR4(-/-) and TLR2/4(-/-) animals, as compared to wt controls (P<0.01). Concentrations of Bacteroides/ Prevotella spp., and enterococci did not increase during colitis, but their numbers were significantly reduced in the colon of DSS-treated TLR2/4(-/-) animals (P<0.01). Numbers of lactobacilli and clostridia remained unaffected by colitis, irrespective of the TLR-genotype of mice. Culture-independent molecular analyses confirmed the microflora shifts towards enterobacteria during colitis and showed that the gut flora composition was similar in both, healthy wt and TLR-deficient animals.

Conclusions and significance: 
DSS-induced colitis is characterized by a shift in the intestinal microflora towards pro-inflammatory Gram-negative bacteria. Bacterial products exacerbate acute inflammation via TLR2- and TLR4-signaling and direct the recruitment of neutrophils and regulatory T-cells to intestinal sites. E. coli may serve as a biomarker for colitis severity and DSS-induced barrier damage seems to be a valuable model to further identify bacterial factors involved in maintaining intestinal homeostasis and to test therapeutic interventions based upon anti-TLR strategies.

/pdf/shift-towards-pro-inflammatory-intestinal-bacteria-2v3wc1yupz.pdf

Shift towards pro-inflammatory intestinal bacteria aggravates acute murine colitis via Toll-like receptors 2 and 4.

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Gram-Negative Bacteria Aggravate Murine Small Intestinal Th1-Type Immunopathology following Oral Infection with Toxoplasma gondii

Exacerbation of murine ileitis by Toll-like receptor 4 mediated sensing of lipopolysaccharide from commensal Escherichia coli

Shift towards pro-inflammatory intestinal bacteria aggravates acute murine colitis via Toll-like receptors 2 and 4.