Modulation of Gut Microbiome Composition and Function in Experimental Colitis Treated with Sulfasalazine

Abstract

Inflammatory bowel disease (IBD) results from alterations in intestinal flora and the immune system. Sulfasalazine (SASP) is a sulfa antimicrobial used to treat IBD in clinic for years. However, how SASP affects gut microbes and its potential functions remains unclear. To investigate the relationships of SASP, IBD, and gut microbiome, we used 2,4,6-trinitrobenzenesulfonic acid (TNBS) to induce experimental colitis in rats, and analyzed the microbiota in the fecal samples, which come from the control group (treated with ethanol + saline), the model group (treated with TNBS-ethanol + saline) and the SASP group (treated with TNBS-ethanol + SASP), with 16S gene sequencing and followed up a subset sample using shotgun sequencing. The study found that SASP treatment could not only restore the TNBS-induced gut dysbiosis, which was proved by the increasing amount of SCFAs-producing bacteria and lactic acid-producing bacteria as well as the decreasing amount of Proteobacteria, but also modulate the dysregulated function of the TNBS-induced colitis to resemble that of the control group, including an increased capacity for basic metabolism (carbohydrate metabolism, citrate cycle) and a decrease in the oxidative stress (riboflavin, sulfur, cysteine) as well as bacterial pathogenesis (cell motility and secretion, bacterial motility proteins, flagellar assembly). Moreover, a higher proportion of Mycoplasma was observed in the SASP group, which may associate with infertility. In all, the study provides insight into specific microbial clades and pathways linked with SASP treatment to elaborate the mechanism for treatment of IBD.

Intestinal Immune Dysregulation Driven by Dysbiosis Promotes Barrier Disruption and Bacterial Translocation in Rats With Cirrhosis

“…This contention is based on (1) the increasing severity of intestinal overexpression of the proinflammatory cytokines TNFα and IFNγ from the preascitic to ascitic stage of cirrhosis, which was concomitant with an abnormal distribution of zonula occludens‐1 and E‐cadherin and with fecal albumin loss, and (2) direct correlation between IFNγ‐expressing Tc LPLs and fecal albumin. The underlying pathogenetic mechanisms of barrier damage could be related to the effect of proinflammatory cytokines on the intestinal epithelium, where they induce a variety of changes that include endocytosis of tight junction proteins and increased myosin light chain kinase protein expression, resulting in augmented tight junction permeability . It is likely that Th17 depletion will also contribute to barrier damage as IL17 plays a role in intestinal epithelium homeostasis by inducing tight junction function and antimicrobial peptide production …”

“…The underlying pathogenetic mechanisms of barrier damage could be related to the effect of proinflammatory cytokines on the intestinal epithelium, where they induce a variety of changes that include endocytosis of tight junction proteins and increased myosin light chain kinase protein expression, resulting in augmented tight junction permeability. (3,8,23) It is likely that Th17 depletion will also contribute to barrier damage as IL17 plays a role in intestinal epithelium homeostasis by inducing tight junction function and antimicrobial peptide production. (24,25) The host gut microbiome and immune system have a dynamic symbiotic relationship that maintains intestinal barrier homeostasis.…”

“…The gut microbiome sets the stage for the liver–gut axis as it is the source of bacterial products and metabolites that reach the liver . Pathological changes in the microbiome (i.e., dysbiosis) can be induced by environmental (e.g., alcohol), dietary (e.g., high‐fat diet), or genetic (e.g., inflammatory bowel disease) factors . In these situations, dysbiosis modifies the burden of bacterial components and/or metabolites that challenge the hepatic and systemic immune system.…”

“…(4) Pathological changes in the microbiome (i.e., dysbiosis) can be induced by environmental (e.g., alcohol), dietary (e.g., high-fat diet), or genetic (e.g., inflammatory bowel disease) factors. (5)(6)(7)(8) In these situations, dysbiosis modifies the burden of bacterial components and/or metabolites that challenge the hepatic and systemic immune system. Whereas the distribution and function of circulating immune cell populations in cirrhosis have been the subject of intense research, little is known about the patterns of infiltration of immune cells in the intestinal mucosa.…”

Introductory Chapter: Inflammatory Bowel Disease

“…Sulfasalazine is a sulfa antimicrobial that is used not only to treat IBD that affects gut microbes in the fecal samples by the increasing amount of SCFA-producing bacteria and lactic acid-producing bacteria as well as the decreasing amount of Proteobacteria but also to modulate the dysregulated function of the TNBS-induced colitis, increased capacity for carbohydrate metabolism and citrate cycle, and a decrease in the oxidative stress of riboflavin, sulfur, cysteine as well as bacterial pathogenesis like cell motility and secretion, bacterial motility proteins, and flagellar assembly. Furthermore, a higher proportion of Mycoplasma concentration [42].…”