PMID- 36515524
OWN - NLM
STAT- MEDLINE
DCOM- 20230126
LR  - 20230617
IS  - 1098-5522 (Electronic)
IS  - 0019-9567 (Print)
IS  - 0019-9567 (Linking)
VI  - 91
IP  - 1
DP  - 2023 Jan 24
TI  - Butyrate Ameliorates Intraocular Bacterial Infection by Promoting Autophagy and 
      Attenuating the Inflammatory Response.
PG  - e0025222
LID - 10.1128/iai.00252-22 [doi]
LID - e00252-22
AB  - Despite an important link between the gut and ocular health, the role of the 
      gut-eye axis remains elusive in ocular infections. In this study, we investigated 
      the role of butyrate, a gut microbial metabolite, in the pathobiology of 
      intraocular bacterial (Staphylococcus aureus) infection, endophthalmitis. We 
      found that intravitreal administration of butyrate derivatives, sodium butyrate 
      (NaB), or phenylbutyrate (PBA) reduced intraocular bacterial growth and retinal 
      inflammatory response. The ocular tissue architecture and retinal function were 
      preserved in butyrate-treated eyes. In cultured mouse bone marrow-derived 
      macrophages (BMDMs) and human retinal Muller glia, NaB or PBA treatment reduced 
      S. aureus-induced inflammatory response by inhibiting NOD-like receptor family 
      pyrin domain containing 3 (NLRP3) inflammasome. However, in vivo data showed 
      NLRP3-independent effects of butyrate. The butyrate-treated mouse retina and 
      cells exhibited induced expression of antimicrobial molecules CRAMP (LL37) and 
      S100A7/A8, resulting in increased bacterial phagocytosis and killing. Moreover, 
      butyrate treatment enhanced AMP-activated protein kinase (AMPK)-dependent 
      autophagy and promoted the co-localization of CRAMP in autophagosomes, indicating 
      autophagy-mediated bacterial killing. Furthermore, pharmacological inhibition of 
      autophagy in mice revealed its role in butyrate-mediated protection. Finally, 
      butyrate exhibited synergy with antibiotic in promoting endophthalmitis 
      resolution. Collectively, our study demonstrated the protective mechanisms of 
      butyrate in ameliorating bacterial endophthalmitis. Therefore, butyrate 
      derivatives could be explored as immunomodulatory and anti-bacterial therapeutics 
      to improve visual outcomes in ocular bacterial infections.
FAU - Singh, Sukhvinder
AU  - Singh S
AD  - Department of Ophthalmology, Visual and Anatomical Sciences, Kresge Eye 
      Institute, Wayne State University School of Medicine, Detroit, Michigan, USA.
FAU - Singh, Pawan Kumar
AU  - Singh PK
AD  - Department of Ophthalmology/Mason Eye Institute, University of Missouri School of 
      Medicine, Columbia, Missouri, USA.
FAU - Kumar, Ashok
AU  - Kumar A
AUID- ORCID: 0000-0001-6332-6591
AD  - Department of Ophthalmology, Visual and Anatomical Sciences, Kresge Eye 
      Institute, Wayne State University School of Medicine, Detroit, Michigan, USA.
AD  - Department of Biochemistry, Microbiology, and Immunology, Wayne State University 
      School of Medicine, Detroit, Michigan, USA.
LA  - eng
GR  - R01 EY026964/EY/NEI NIH HHS/United States
GR  - R01 EY027381/EY/NEI NIH HHS/United States
GR  - P30 EY004068/EY/NEI NIH HHS/United States
GR  - R21 AI149385/AI/NIAID NIH HHS/United States
GR  - R01 EY032495/EY/NEI NIH HHS/United States
GR  - R21 AI140033/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20221214
PL  - United States
TA  - Infect Immun
JT  - Infection and immunity
JID - 0246127
RN  - 0 (Butyrates)
RN  - 0 (NLR Family, Pyrin Domain-Containing 3 Protein)
RN  - 0 (Inflammasomes)
RN  - 7WY7YBI87E (4-phenylbutyric acid)
SB  - IM
MH  - Humans
MH  - Animals
MH  - Mice
MH  - Butyrates/pharmacology
MH  - Staphylococcus aureus/metabolism
MH  - NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
MH  - Autophagy
MH  - Inflammasomes
MH  - *Staphylococcal Infections/drug therapy/microbiology
MH  - *Endophthalmitis/drug therapy/microbiology
MH  - *Eye Infections, Bacterial
MH  - Mice, Inbred C57BL
PMC - PMC9872663
OTO - NOTNLM
OT  - AMPK
OT  - Staphylococcus aureus
OT  - autophagy
OT  - butyrate
OT  - endophthalmitis
OT  - eye
OT  - inflammation
OT  - innate immunity
OT  - retina
COIS- The authors declare no conflict of interest.
EDAT- 2022/12/15 06:00
MHDA- 2023/01/27 06:00
PMCR- 2023/06/14
CRDT- 2022/12/14 09:04
PHST- 2022/12/15 06:00 [pubmed]
PHST- 2023/01/27 06:00 [medline]
PHST- 2022/12/14 09:04 [entrez]
PHST- 2023/06/14 00:00 [pmc-release]
AID - 00252-22 [pii]
AID - iai.00252-22 [pii]
AID - 10.1128/iai.00252-22 [doi]
PST - ppublish
SO  - Infect Immun. 2023 Jan 24;91(1):e0025222. doi: 10.1128/iai.00252-22. Epub 2022 
      Dec 14.