Chondroitin Sulfate Elicits Systemic Pathogenesis In Mice By Interfering With Gut Microbiota Homeostasis

Abstract

Whether chondroitin sulfate (CS), a common ingredient naturally occurring in livestock and poultry products, improves osteoarthritis remains debating.Here, we show for the first time that CS induces steatogenesis, atherogenesis, and dementia-like pathogenesis in mice. Gut microbiome analysis revealed the sulfatase-secreting bacteria Rikenella and the sulfate-reducing bacteria Desulfovibrio are enriched. Surprisingly, berberine use boosts CS-induced multi-loci inflammatory manifestations by further increasing the abundance of Rikenella and Desulfovibrio, whereas cephalosporin reinforces the colon mucus barrier via flourishing Akkermansia muciniphila and upregulating mucin expression. Mechanistically, berberine aggravates mucus lining injury by prompting mucin degradation, endotoxin leakage, neutralizing antibody induction, pro-inflammatory cytokine burst, lactic acid accumulation and energy currency depletion in multiple organs and tissues. Taken together, CS evokes the early-phase pathogenesis toward steatohepatitis, atherosclerosis, and dementia upon augmenting gut opportunistic infection, and a sustained antibiotic monotherapy does not deprive the risk of CS-driven systemic inflammatory disorders.SSB overgrowth, and then SSB degrade the O-glycon-containing mucin, hence opening the mucin-crossing mucus barrier, and leaking the bacterial endotoxin lipopolysaccharide (LPS) into the blood. The circulated LPS would elicit production of neutralizing antibody and secretion of pro-inflammatory cytokines to scavenge LPS, during which organs without LPS might show an anti-inflammatory feature, whereas organs with LPS might exhibit a pro-proinflammatory character. Of course, CS either ameliorates or aggravates OA might be also dependent on the individual gut microbiota status.We fed mice with 25 mg of CS daily to induce gut opportunistic infection, and also used 100 mg/ml berberine (BER) or 100 mg/ml cephalosporin (CEF) to control gut opportunistic infection. BER is considered antibiotic (Li & Zuo, 2010) albeit with a low bioavailability (Liu et al., 2016), so it should directly and non-selectively kill gut bacteria. Upon fed CS combined with or without BER or CEF, we disclosed for the first time that CS not only flourishes SSB and interferes with gut microbiota homeostasis, but also induces the multiple inflammatory pathogenesis, such as steatogenesis, atherogenesis, and dementia-like amyloidosis and cognitive deficits. Surprisingly, BER use for one month was noticed to aggravate the multiple pathogenic alterations by increasing the richness of SSB. It could be anticipated that the astonishing achievements regarding CS-and BER/CEF-exerted dual effects of anti-and pro-inflammation should pave a path toward a thorough elucidation of the rationale underlying gut opportunistic infection-originated inflammatory disorders and metabolic syndromes.

Chondroitin Sulfate Flourishes Gut Sulfatase-Secreting Bacteria To Damage Mucus Layers, Leak Bacterial Debris, And Trigger Inflammatory Lesions In Mice

“…However, it remains inclusive why CS.NM with the overgrown SSB (A.muciniphila) does not show synovitis. In our recent finding, A.muciniphila was observed to induce mucin expression and reinforce mucus integrity, thereby compromising LPS-mediated pro-inflammatory stimuli [33]. Accumulating evidence supports that A. muciniphila has therapeutic values in metabolic diseases, including an inverse correlation of A. muciniphila with obesity and diabetes in mice and humans [34,35].…”

“…Accordingly, we found in the present study that LPS upregulates the NALFD-related genes in a large scale. However, our recent work indicated that most of the NALFD-related genes are downregulated in CS mice as compared with AL mice [33]. The latter result addressed that CS might not raise the hepatic LPS level to upregulate the NALFD-related genes, otherwise it should have reduced the hepatic LPS level to downregulate the NALFD-related genes.…”

Akkermansia muciniphila May Determine Chondroitin Sulfate Ameliorating or Aggravating Osteoarthritis

“…Consequently, cephalosporin significantly mitigated colonic mucus lesions and delayed the early pathogenesis of dementia, steatohepatitis, and atherosclerosis. Berberine significantly aggravated colonic mucus lesions and enhanced multi-systemic pathogenesis (Liao et al, 2017a ). It has also been observed that germ-free rats had thinner colonic mucus layers, suggesting that microbial colonization is required for mucin production (Desai et al, 2016 ).…”

New Progress Regarding the Use of Lactic Acid Bacteria as Live Delivery Vectors, Treatment of Diseases and Induction of Immune Responses in Different Host Species Focusing on Lactobacillus Species

“…Administration of Lactobacillus johnsonii N6.2 considerably decreases the happening of indigestion, abdominal pain, and cephalic syndromes were observed. Additionally, some studies demonstrated that monocytes and natural killer cell numbers were increased significantly and an increase of circulating effector Th1 cells (CD45RO +CD183+CD196−) and cytotoxic CD8+T cells subset was observed in the Lactobacillus johnsonii N6.2 group [109,112].…”

“…Current review study revealed that construction of a recombinant strain of Lactobacillus gasseri, Lactobacillus paracasei elicits various health benefits through its antimicrobial activity, bacteriocin production, and immunomodulation of the innate and adaptive systems therefore had significantly reduced blood glucose levels and increased insulin levels [109][110][111]. Also Lactobacillus species such as: Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus paracasei, Lactobacillus bulgaricus have been known to improve obesity-associated metabolic problems.…”