Study Shorts 3 * IBS – Bifido * Osteoarthritis – Bifido * Iron – Huntington’s * High-Fat – Compulsive Eating * Chronic Stress – Serotonin *

Protease signaling through protease activated receptor 1 mediate nerve activation by mucosal supernatants from irritable bowel syndrome but not from ulcerative colitis patients

Searching for biomarkers for irritable bowel syndrome, researchers found (supernatant) fluid from IBS patients expressed different enzymes that break down protein (protease). Elevated elastase in IBS potentates serotonin and histamine. A protease inhibitor from the bacteria Bifidobacterium longum NCC2705 prevented nerve activation from IBS fluid (supernatants). Decreased bifidobacteriumm are associated with a lot of chronic disease.

“Altered nerve function has emerged as an important pathogenic factor as IBS mucosal biopsy supernatants consistently activate enteric and sensory neurons. We investigated the neurally active molecular components of such supernatants from patients with IBS and quiescent ulcerative colitis (UC)…
Proteome analysis of the supernatants identified 204 proteins, among them 17 proteases as differentially expressed between IBS, UC and HC. Of those the four proteases elastase 3a, chymotrypsin C, proteasome subunit type beta-2 and an unspecified isoform of complement C3 were significantly more abundant in IBS compared to HC and UC supernatants. Of eight proteases, which were upregulated in IBS, the combination of elastase 3a, cathepsin L and proteasome alpha subunit-4 showed the highest prediction accuracy of 98% to discriminate between IBS and HC groups. Elastase synergistically potentiated the effects of histamine and serotonin–the two other main neuroactive substances in the IBS supernatants. A serine protease inhibitor isolated from the probiotic Bifidobacterium longum NCC2705 (SERPINBL), known to inhibit elastase-like proteases, prevented nerve activation by IBS supernatants.”

Targeting the gut microbiome to treat the osteoarthritis of obesity

High fat diet alters gut microbiota, causing obesity and (OA) osteoarthritis (in mice). Restoration of healthier microbiota is possible with supplemental oligofructose. Increases in bifidobacterium are associated with significant improvement in osteoarthritis.

“The impact of obesity on OA is driven by systemic inflammation, and increased systemic inflammation is now understood to be caused by gut microbiome dysbiosis. Oligofructose, a nondigestible prebiotic fiber, can restore a lean gut microbial community profile in the context of obesity, suggesting a potentially novel approach to treat the OA of obesity. Here, we report that — compared with the lean murine gut — obesity is associated with loss of beneficial Bifidobacteria, while key proinflammatory species gain in abundance. A downstream systemic inflammatory signature culminates with macrophage migration to the synovium and accelerated knee OA. Oligofructose supplementation restores the lean gut microbiome in obese mice, in part, by supporting key commensal microflora, particularly Bifidobacterium pseudolongum. This is associated with reduced inflammation in the colon, circulation, and knee and protection from OA. This observation of a gut microbiome–OA connection sets the stage for discovery of potentially new OA therapeutics involving strategic manipulation of specific microbial species inhabiting the intestinal space.”

Brain mitochondrial iron accumulates in Huntington’s disease, mediates mitochondrial dysfunction, and can be removed pharmacologically

Huntington’s Disease includes an accumulation of iron in brain mitochondria of mice and humans. In mice this  excessive iron leads to lipid peroxidation and oxidative stress. Oxygen uptake is decreased. Removal of iron reversed pathologies in mice. Iron supplementation led to Huntington’s type pathology in mice.

“Mitochondrial bioenergetic dysfunction is involved in neurodegeneration in Huntington’s disease (HD). Iron is critical for normal mitochondrial bioenergetics but can also contribute to pathogenic oxidation. The accumulation of iron in the brain occurs in mouse models and in human HD. Yet the role of mitochondria-related iron dysregulation as a contributor to bioenergetic pathophysiology in HD is unclear. We demonstrate here that human HD and mouse model HD (12-week R6/2 and 12-month YAC128) brains accumulated mitochondrial iron and showed increased expression of iron uptake protein mitoferrin 2 and decreased iron-sulfur cluster synthesis protein frataxin. Mitochondria-enriched fractions from mouse HD brains had deficits in membrane potential and oxygen uptake and increased lipid peroxidation. In addition, the membrane-permeable iron-selective chelator deferiprone (1 μM) rescued these effects ex-vivo, whereas hydrophilic iron and copper chelators did not. A 10-day oral deferiprone treatment in 9-week R6/2 HD mice indicated that deferiprone removed mitochondrial iron, restored mitochondrial potentials, decreased lipid peroxidation, and improved motor endurance. Neonatal iron supplementation potentiates neurodegeneration in mouse models of HD by unknown mechanisms. We found that neonatal iron supplementation increased brain mitochondrial iron accumulation and potentiated markers of mitochondrial dysfunction in HD mice. Therefore, bi-directional manipulation of mitochondrial iron can potentiate and protect against markers of mouse HD. Our findings thus demonstrate the significance of iron as a mediator of mitochondrial dysfunction and injury in mouse models of human HD and suggest that targeting the iron-mitochondrial pathway may be protective.”

Time‐course and dynamics of obesity‐related behavioral changes induced by energy‐dense foods in mice

Access to high-fat food (alongside normal chow) initiates compulsive feeding patterns in mice. They eat more, faster and increase their eating hours. Access to chocolate based snacks had a similar effect, though not as pronounced.

“…we here examine mice meal pattern upon long‐term exposure to a free‐choice chocolate‐mixture diet and a high‐fat diet with face validity for a rapid development of obesity induced by unhealthy food regularly consumed in our societies. We identified rapid diet‐specific behavioral changes after exposure to those high‐caloric diets. Mice fed with high‐fat chow, showed long‐lasting meal pattern disturbances, which initiate with a stable loss of circadian feeding rhythmicity. Mice receiving a chocolate‐mixture showed qualitatively similar changes, though less marked, consisting in a transient disruption of the feeding behavior and the circadian feeding rhythmicity. Strikingly, compulsive‐like eating behavior is triggered immediately after exposure to both high‐fat food and chocolate‐mixture diet, well before any changes in body weight could be observed. We propose these changes as behavioral biomarkers of prodromal states of obesity that could allow early intervention.”

Chronic stress increases serotonin and noradrenaline in rat brain and sensitizes their responses to a further acute stress.

The title is a pretty good summary. 5-HIAA is a serotonin metabolite. Blocking or otherwise lowering serotonin may be useful after chronic stress.

“The effects of 1 h/day restraint in plastic tubes for 24 days on the levels of serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), tryptophan (TP), and noradrenaline (NA) in six regions of rat brain 20 h after the last restraint period were investigated. The levels of 5-HT, 5-HIAA, and NA but not TP increased in several regions. The effects of 1 h of immobilization on both control and chronically restrained rats were also studied. Immobilization per se did not alter brain 5-HT, 5-HIAA, and TP levels, but decreased NA in the pons plus medulla oblongata and hypothalamus. However, immobilization after chronic restraint decreased 5-HT, increased 5-HIAA, and decreased NA in most brain regions in comparison with values for the chronically restrained rats. We suggest that chronic restraint leads to compensatory increases of brain 5-HT and NA synthesis and sensitizes both monoaminergic systems to an additional acute stress. These changes may affect coping with stress demands.”