The presence of RAC is characteristic of a normal stomach without H. pylori. Magnified views of the normal antrum were different from that of the normal corpus.
Prevention of quality of life (QOL) deterioration is associated with the inhibition of geriatric diseases and the regulation of brain function. However, no substance is known that prevents the aging of both body and brain. It is known that polyamine concentrations in somatic tissues (including the brain) decrease with increasing age, and polyamine-rich foods enhance longevity in yeast, worms, flies, and mice, and protect flies from age-induced memory impairment. A main source of exogenous polyamines is the intestinal lumen, where they are produced by intestinal bacteria. We found that arginine intake increased the concentration of putrescine in the colon and increased levels of spermidine and spermine in the blood. Mice orally administered with arginine in combination with the probiotic bifidobacteria LKM512 long-term showed suppressed inflammation, improved longevity, and protection from age-induced memory impairment. This study shows that intake of arginine and LKM512 may prevent aging-dependent declines in QOL via the upregulation of polyamines.
Collecting venules and true capillaries forming a network with gastric pits in the center (type Z-0) were observed in the H. pylori-negative normal mucosa. The magnified views of H. pylori-related gastritis clearly differed from type Z-0.
Intestinal microbiota-derived metabolites have biological importance for the host. Polyamines, such as putrescine and spermidine, are produced by the intestinal microbiota and regulate multiple biological processes. Increased colonic luminal polyamines promote longevity in mice. However, no direct evidence has shown that microbial polyamines are incorporated into host cells to regulate cellular responses. Here, we show that microbial polyamines reinforce colonic epithelial proliferation and regulate macrophage differentiation. Colonisation by wild-type, but not polyamine biosynthesis-deficient, Escherichia coli in germ-free mice raises intracellular polyamine levels in colonocytes, accelerating epithelial renewal. Commensal bacterium-derived putrescine increases the abundance of anti-inflammatory macrophages in the colon. The bacterial polyamines ameliorate symptoms of dextran sulfate sodium-induced colitis in mice. These effects mainly result from enhanced hypusination of eukaryotic initiation translation factor. We conclude that bacterial putrescine functions as a substrate for symbiotic metabolism and is further absorbed and metabolised by the host, thus helping maintain mucosal homoeostasis in the intestine.
Background
Rheumatoid arthritis (RA) is a chronic debilitating autoimmune disorder with a high prevalence, especially in industrialized countries. Dysbiosis of the intestinal microbiota has been observed in RA patients. For instance, new-onset untreated RA (NORA) is associated with the underrepresentation of the
Clostridium
cluster XIVa, including Lachnospiraceae, which are major butyrate producers, although the pathological relevance has remained obscure. Follicular regulatory T (T
FR
) cells play critical regulatory roles in the pathogenesis of autoimmune diseases, including RA. Reduced number of circulating T
FR
cells has been associated with the elevation of autoantibodies and disease severity in RA. However, the contribution of commensal microbe-derived butyrate in controlling T
FR
cell differentiation remains unknown.
Methods
We examined the contribution of microbe-derived butyrate in controlling autoimmune arthritis using collagen-induced arthritis (CIA) and SKG arthritis models. We phenotyped autoimmune responses in the gut-associated lymphoid tissues (GALT) in the colon and joint-draining lymph nodes in the CIA model. We developed an
in vitro
CXCR5
+
Bcl-6
+
Foxp3
+
T
FR
(iT
FR
) cell culture system and examined whether butyrate promotes the differentiation of iT
FR
cells.
Findings
Microbe-derived butyrate suppressed the development of autoimmune arthritis. The immunization of type II collagen (CII) caused hypertrophy of the GALT in the colon by amplifying the GC reaction prior to the onset of the CIA. Butyrate mitigated these pathological events by promoting T
FR
cell differentiation. Butyrate directly induced the differentiation of functional T
FR
cells
in vitro
by enhancing histone acetylation in T
FR
cell marker genes. This effect was attributed to histone deacetylase (HDAC) inhibition by butyrate, leading to histone hyperacetylation in the promoter region of the T
FR
-cell marker genes. The adoptive transfer of the butyrate-treated iT
FR
cells reduced CII-specific autoantibody production and thus ameliorated the symptoms of arthritis.
Interpretation
Accordingly, microbiota-derived butyrate serves as an environmental cue to enhance T
FR
cells, which suppress autoantibody production in the systemic lymphoid tissue, eventually ameliorating RA. Our findings provide mechanistic insights into the link between the gut environment and RA risk.
Funding
This work was supported by
(16gm1010...
found that if collecting venules were visible as numerous minute points, regularly distributed over the entire gastric body, the patients had a normal stomach and no H. pylori infection. 8,9,11 We termed this finding "regular arrangement of collecting venules (RAC)." Further characterization using magnified views showed RAC to consist of collecting venules, a network of true capillaries, and gastric pits with a pinhole-like appearance. [8][9][10][11] Patients in whom RAC was not observed endoscopically (RAC-negative) had H. pylori infection. Compared to culturing and histological diagnosis, the accuracy of RAC in identifying H. pylori infection was 95%. From 1998 onwards, we began using RAC as a diagnostic method, and subsequently we studied the incidence of adenocarcinomas arising in patients with and without H. pylori infection. The RAC method is very practical, given that almost all chronic gastritis is induced by H. pylori and that this bacterium is involved in various disease states.
Regular arrangement of collecting venules (RAC): a characteristic endoscopic feature of the H. pylorinegative normal stomachOn conventional endoscopy, H. pylori-negative normal stomach shows numerous minute points throughout the gastric body (Fig. 1), and it is not unusual to observe these minute points near the pyloric ring, especially in young patients. This endoscopic finding was termed "regular arrangement of collecting venules (RAC)," because the minute points were revealed to be collecting venules. 8-11 On closer observation, the points were shown to be star-fish like arrangements of vessels. Patients in whom RAC is observed endoscopically are termed 9,11 In patients with duodenal ulcer, or young patients with H. pylori infection, minute points are often observed in the middle body or upper gastric body, because the infection does not always ex-
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