PMID- 35315698 OWN - NLM STAT- MEDLINE DCOM- 20220429 LR - 20240214 IS - 2165-0497 (Electronic) IS - 2165-0497 (Linking) VI - 10 IP - 2 DP - 2022 Apr 27 TI - Modulation of Gut Microbiota Metabolism in Obesity-Related Type 2 Diabetes Reduces Osteomyelitis Severity. PG - e0017022 LID - 10.1128/spectrum.00170-22 [doi] LID - e00170-22 AB - Staphylococcus aureus is an opportunistic pathogen causing osteomyelitis through hematogenous seeding or contamination of implants and open wounds following orthopedic surgeries. The severity of S. aureus-mediated osteomyelitis is enhanced in obesity-related type 2 diabetes (obesity/T2D) due to chronic inflammation impairing both adaptive and innate immunity. Obesity-induced inflammation is linked to gut dysbiosis, with modification of the gut microbiota by high-fiber diets leading to a reduction in the symptoms and complications of obesity/T2D. However, our understanding of the mechanisms by which modifications of the gut microbiota alter host infection responses is limited. To address this gap, we monitored tibial S. aureus infections in obese/T2D mice treated with the inulin-like fructan fiber oligofructose. Treatment with oligofructose significantly decreased S. aureus colonization and lowered proinflammatory signaling postinfection in obese/T2D mice, as observed by decreased circulating inflammatory cytokines (tumor necrosis factor-alpha [TNF-alpha]) and chemokines (interferon-gamma-induced protein 10 kDa [IP-10], keratinocyte-derived chemokine [KC], monokine induced by interferon-gamma [MIG], monocyte chemoattractant protein-1 [MCP-1], and regulated upon activation, normal T cell expressed and presumably secreted [RANTES]), indicating partial reduction in inflammation. Oligofructose markedly shifted diversity in the gut microbiota of obese/T2D mice, with notable increases in the anti-inflammatory bacterium Bifidobacterium pseudolongum. Analysis of the cecum and plasma metabolome suggested that polyamine production was increased, specifically spermine and spermidine. Oral administration of these polyamines to obese/T2D mice resulted in reduced infection severity similar to oligofructose supplementation, suggesting that polyamines can mediate the beneficial effects of fiber on osteomyelitis severity. These results demonstrate the contribution of gut microbiota metabolites to the control of bacterial infections distal to the gut and polyamines as an adjunct therapeutic for osteomyelitis in obesity/T2D. IMPORTANCE Individuals with obesity-related type 2 diabetes (obesity/T2D) are at a five times increased risk for invasive Staphylococcus aureus osteomyelitis (bone infection) following orthopedic surgeries. With increasing antibiotic resistance and limited discoveries of novel antibiotics, it is imperative that we explore other avenues for therapeutics. In this study, we demonstrated that the dietary fiber oligofructose markedly reduced osteomyelitis severity and hyperinflammation following acute prosthetic joint infections in obese/T2D mice. Reduced infection severity was associated with changes in gut microbiota composition and metabolism, as indicated by increased production of natural polyamines in the gut and circulating plasma. This work identifies a novel role for the gut microbiome in mediating control of bacterial infections and polyamines as beneficial metabolites involved in improving the obesity/T2D host response to osteomyelitis. Understanding the impact of polyamines on host immunity and mechanisms behind decreasing susceptibility to severe implant-associated osteomyelitis is crucial to improving treatment strategies for this patient population. FAU - Bui, Tina I AU - Bui TI AUID- ORCID: 0000-0002-4110-3263 AD - Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA. FAU - Gill, Ann Lindley AU - Gill AL AD - Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA. FAU - Mooney, Robert A AU - Mooney RA AD - Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA. AD - Center for Musculoskeletal Research, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA. FAU - Gill, Steven R AU - Gill SR AUID- ORCID: 0000-0002-2408-1373 AD - Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA. AD - Center for Musculoskeletal Research, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA. LA - eng GR - T90 DE021985/DE/NIDCR NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20220322 PL - United States TA - Microbiol Spectr JT - Microbiology spectrum JID - 101634614 RN - 0 (Polyamines) RN - 82115-62-6 (Interferon-gamma) SB - IM MH - Animals MH - *Diabetes Mellitus, Type 2/complications MH - *Gastrointestinal Microbiome MH - Humans MH - Inflammation MH - Interferon-gamma MH - Mice MH - Obesity/complications MH - *Osteomyelitis/complications/drug therapy/microbiology MH - Polyamines MH - *Staphylococcal Infections/complications/drug therapy/microbiology MH - Staphylococcus aureus PMC - PMC9045376 OTO - NOTNLM OT - Staphylococcus aureus OT - gut microbiota OT - obesity OT - oligofructose OT - osteomyelitis OT - polyamines OT - type 2 diabetes COIS- The authors declare no conflict of interest. EDAT- 2022/03/23 06:00 MHDA- 2022/04/30 06:00 PMCR- 2022/03/22 CRDT- 2022/03/22 12:09 PHST- 2022/03/23 06:00 [pubmed] PHST- 2022/04/30 06:00 [medline] PHST- 2022/03/22 12:09 [entrez] PHST- 2022/03/22 00:00 [pmc-release] AID - 00170-22 [pii] AID - spectrum.00170-22 [pii] AID - 10.1128/spectrum.00170-22 [doi] PST - ppublish SO - Microbiol Spectr. 2022 Apr 27;10(2):e0017022. doi: 10.1128/spectrum.00170-22. Epub 2022 Mar 22.