Neuro-inflammation has been shown to play a critical role in the development of depression. Beta-hydroxybutyrate (BHB) is a ketone body and has recently been reported to exert anti-inflammatory effects via inhibition of NLRP3 inflammasome. Here, we investigated the potential antidepressant and anti-inflammatory effects of BHB on rats exposed to acute and chronic stress. We examined the influence of repeated BHB administration on depressive and anxiety behaviors in a rodent model of chronic unpredictable stress (CUS). Additionally, the influence of acute immobilization (IMM) stress and single BHB administration on hippocampal interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) were assessed. Repeated administration of BHB attenuated CUS-induced depressive- and anxiety-related behaviors. IMM stress increased levels of IL-1β in the hippocampus, while a single pre-administration of BHB attenuated this increase. Although no effect was observed on hippocampal TNF-α levels after 1 h of IMM stress, a single BHB pre-administration reduced hippocampal TNF-α. Our previous report showed that the release of IL-1β and TNF-α caused by stress is tightly regulated by NLRP3 inflammasome. These findings demonstrate that BHB exerts antidepressant-like effects, possibly by inhibiting NLRP3-induced neuro-inflammation in the hippocampus, and that BHB may be a novel therapeutic candidate for the treatment of stress-related mood disorders.

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Aims Neuroinflammation is deeply related to the pathophysiology of depression. Beta‐hydroxybutyrate (BHB), which is an endogenous ketone body, exerts anti‐inflammatory effects, and peripheral administration of BHB induces antidepressant effects in an animal model of depression; however, it is unclear whether BHB specifically mediates these actions in the brain. Thus, we administered BHB directly into the brain in a rodent model of depression using a chronic unpredictable stress (CUS) paradigm. Methods BHB was continuously microinjected into the prefrontal cortex (PFC) using osmotic pumps for 21 days. Behavioral testing included the forced swim test (FST) and the open field test (OFT); the levels of pro‐inflammatory cytokines, such as interleukin 1β (IL‐1β) and tumor necrosis factor α (TNF‐α), were quantified in the PFC, and the concentration of corticosterone in blood serum was measured. Results BHB administration into the PFC significantly decreased immobility time in the FST, without significantly altering locomotor activity assessed in the OFT. Also, CUS significantly increased the levels of TNF‐α in the PFC and decreased serum corticosterone levels; these changes were attenuated by BHB administration. These findings suggest that a small amount of BHB administered into the PFC directly produces antidepressant effects, possibly through anti‐inflammatory mechanisms, and can improve hypothalamus‐pituitary‐adrenal axis responses. Conclusion BHB may be a novel therapeutic candidate for the treatment of depression based on the neuro‐inflammatory hypothesis, and the PFC is a region implicated in the antidepressant action of BHB.

Accumulating evidence suggests that elevated inflammation contributes to the pathophysiology of post-traumatic stress disorder (PTSD) and that anti-inflammatory drugs might be a new treatment strategy for PTSD. It has been reported that beta-hydroxybutyrate (BHB), one of the main ketone bodies produced, can have an anti-inflammatory and antidepressant effect. Here, we investigated the potential anti-anxiety and anti-inflammatory effects of BHB using a rodent PTSD model, induced by single prolonged stress (SPS). Male, Sprague–Dawley rats were employed in this study. Repeated administration of BHB attenuated SPS-induced anxiety-related behaviors evaluated by the elevated plus maze test. SPS increased the serum levels of TNF-α and IL-1β. In contrast, BHB administration partially attenuated the increase of serum TNF-α. These findings demonstrate that BHB exerts its anxiolytic effects, possibly by inhibiting systemic TNF-α. Hence, BHB may be a novel therapeutic candidate for the treatment of PTSD.

The prevalence of eae-positive Escherichia coli (eaeEC) in Japan was examined using rectal stool samples taken from 35 calves less than 1 month old, 107 calves more than 1 to 3 months old, 88 heifers more than 3 to 6 months old, 214 heifers over 6 months old, and cows from 95 farms. Screening with eae PCR revealed the prevalence to be, with increasing age, 31.4, 8.4, 26.1, and 14.5%, respectively. Of 51 selected eaeEC strains, more than 40% were serotyped as O26, O103, O111, O145, or O157, which are frequently detected as enterohemorrhagic E. coli types. Four strains were identified as recently reported intimin types , , and .Enterohemorrhagic Escherichia coli (EHEC), enteropathogenic E. coli (EPEC), and attaching and effacing E. coli (AEEC) are food-borne pathogens that can cause diarrhea in humans (7,11,15). These pathogenic E. coli types often possess genes coding for Shiga toxins (stx genes) and for intimin (eae), an outer membrane protein. E. coli strains with stx genes are called Shiga toxin-producing E. coli (STEC). Cattle are considered to be the main reservoir of STEC strains, including EHEC strains (2, 3). STEC strains are classified into more than 200 O serotypes (4, 16); however, the majority of outbreaks and/or sporadic cases of hemorrhagic colitis and hemolyticuremic syndrome in humans have been caused by the members of only a few serogroups, such as O26, O111, and O157 (10,17,19). Since the strains of these limited O serogroups almost all possess eae (3, 9), this gene may be a more useful target than the stx genes for screening EHEC strains in cattle fecal samples.We used PCR to investigate the prevalence of eae-positive E. coli in cattle feces and genetically characterized the intimin types found, as well as various virulence genes seen in the isolated strains.E. coli O157:H7 strain ATCC 35150 (American Type Culture Collection, Manassas, Va.) was used as the positive control for stx 1 , stx 2 , eae, and intimin type ␥ (intimin ␥). The E. coli strains JS144, 166, VR299-2, and EPEC108, which were used as positive-control strains for intimins ␣, ␤, and ε and bundleforming pilus (bfp), respectively, were derived from the stock culture collection of the National Institute of Animal Health, Tsukuba, Japan. A total of 444 rectal stool grab samples were collected from healthy dairy cattle (35 calves under 1 month old, 107 calves more than 1 to 3 months old, 88 heifers more than 3 to 6 months old, 214 heifers more than 6 months old, and cows) on 95 farms located in the western and central parts of Japan between May and November 2001. All rectal stool samples were sampled by veterinarians at regional governmental animal hygiene centers. The samples were placed in cool boxes (4 to 8°C) and taken to the laboratory for immediate processing (usually within 24 h). Each sample of 1 g of rectal stool was enriched in 19 ml of Trypticase soy broth (Eiken, Tokyo, Japan) at 37°C for 18 h. Ten microliters of the Trypticase soy broth culture was inoculated onto MacConkey agar (MAC; Eiken). The MAC plates were incubated...