PPARα-targeted mitochondrial bioenergetics mediate repair of intestinal barriers at the host–microbe intersection during SIV infection

Abstract

Chronic gut inflammatory diseases are associated with disruption of intestinal epithelial barriers and impaired mucosal immunity. HIV-1 (HIV) causes depletion of mucosal CD4+ T cells early in infection and disruption of gut epithelium, resulting in chronic inflammation and immunodeficiency. Although antiretroviral therapy (ART) is effective in suppressing viral replication, it is incapable of restoring the “leaky gut,” which poses an impediment for HIV cure efforts. Strategies are needed for rapid repair of the epithelium to protect intestinal microenvironments and immunity in inflamed gut. Using an in vivo nonhuman primate intestinal loop model of HIV/AIDS, we identified the pathogenic mechanism underlying sustained disruption of gut epithelium and explored rapid repair of gut epithelium at the intersection of microbial metabolism. Molecular, immunological, and metabolomic analyses revealed marked loss of peroxisomal proliferator-activated receptor-α (PPARα) signaling, predominant impairment of mitochondrial function, and epithelial disruption both in vivo and in vitro. To elucidate pathways regulating intestinal epithelial integrity, we introduced probiotic Lactobacillus plantarum into Simian immunodeficiency virus (SIV)-inflamed intestinal lumen. Rapid recovery of the epithelium occurred within 5 h of L. plantarum administration, independent of mucosal CD4+ T cell recovery, and in the absence of ART. This intestinal barrier repair was driven by L. plantarum-induced PPARα activation and restoration of mitochondrial structure and fatty acid β-oxidation. Our data highlight the critical role of PPARα at the intersection between microbial metabolism and epithelial repair in virally inflamed gut and as a potential mitochondrial target for restoring gut barriers in other infectious or gut inflammatory diseases.

Fenofibrate promotes PPARα-targeted recovery of the intestinal epithelial barrier at the host-microbe interface in dogs with diabetes mellitus

“…Understanding these networks might help identify post-biotic therapeutic targets such as PPARα. Beneficial intestinal microbes such as Lactobacillus plantarum activate PPARα, leading to improved intestinal barrier function 6 . Similar beneficial gut microbes have been shown to improve metabolic status in obesity and DM 40 , which may also involve PPARα signaling.…”

“…Studies show that hyperglycemia contributes to intestinal barrier disruption, leading to an influx of microbial pathogens and products that exacerbate inflammation 34 . We previously reported that PPARα activation by beneficial microbes may restore intestinal barrier function during chronic inflammation in rhesus macaques by rescuing mitochondrial function 6 . Combined with the in vivo findings in canine DM and in vitro findings on human epithelial cell cultures, our results point to PPARα agonists as a potential therapeutic target in the prevention and amelioration of intestinal barrier dysfunction and mucosal inflammation.…”

“…For gene knockdown studies, Caco-2 cells were seeded in a 12-well plate and transfected with PPARα siRNA (AM51331, Thermo Fisher) or nontargeting control siRNA (AM4611). Cells were treated overnight and lysed for quantitative reverse transcriptase PCR (qRT-PCR) of PPARα gene expression, as previously described 6 .…”

“…There is a great need for targeted therapies, but a critical gap exists between understanding the mechanistic link between metabolic disorders and gastrointestinal dysfunction 5 . We previously reported that peroxisome proliferator-activated receptor-alpha (PPARα) signaling, which regulates mitochondrial fatty acid beta-oxidation, may be key to restoring integrity of the intestinal barrier during chronic intestinal inflammation 6 . In this proof-of-concept study, we investigate the effects of fenofibrate, a PPARα agonist, on lipid profiles, systemic and intestinal inflammation, and intestinal barrier function in a canine DM model.…”

The Impact of Oxidative Stress in Human Pathology: Focus on Gastrointestinal Disorders

“…Other sources of intestinal ROS are mitochondria, particularly electron transport chain and NO synthases (NOS) [ 126 ]. It has been demonstrated that mitochondria have a prominent role in the modulation of gut functions as intestinal barrier protection, mucosal immune response [ 130 , 131 ], and maintenance of an eubiotic intestinal microbiota. A crosstalk between the gut microbiota and mitochondria during exercise is known in the literature.…”