Diet effects on colonic health influence the efficacy of Bin1 mAb immunotherapy for ulcerative colitis

Abstract

Ulcerative colitis (UC) is an idiopathic disease of the large intestine linked to high fat-high protein diets, a dysbiotic microbiome, and a metabolome linked to diet and/or aberrant circadian rhythms associated with poor sleeping patterns. Understanding diet-affected factors that negatively influence colonic health may offer new insights into how to prevent UC and enhance the efficacy of UC immunotherapy. In this preclinical study, we found that standard or high fiber diets in mice positively influenced their colonic health, whereas a high fat-high protein diet negatively influenced colonic health, consistent with clinical findings. Animals fed a high fat/high protein diet experienced obesity and a reduced colon length, illustrating a phenotype we suggest calling peinosis [hunger-like-condition; Greek, peina: hunger; osis: condition], as marked by a lack of nutrient energy remaining in fecal pellets. Notably, a high fat/high protein diet also led to signs of muscle weakness that could not be explained fully by weight gain. In contrast, mice on a high fiber diet ranked highest compared to other diets in terms of colon length and lack of muscle weakness. That said, mice on a high fiber diet were more prone to UC and toxic responses to immunotherapy, consistent with clinical observations. Recent studies have suggested that a standard diet may be needed to support the efficacy of immunotherapeutic drugs used to prevent and treat UC. Here we observed that protection against UC by Bin1 mAb, a passive UC immunotherapy that acts by coordinately enforcing intestinal barrier function, protecting enteric neurons, and normalizing the microbiome, was associated with increased colonic levels of healthful short-chain fatty acids (SCFA), particularly butyric acid and propionic acid, which help enforce intestinal barrier function. This work offers a preclinical platform to investigate how diet affects UC immunotherapy and the potential of dietary SCFA supplements to enhance it. Further, it suggests that the beneficial effects of passive immunotherapy by Bin1 mAb in UC treatment may be mediated to some extent by promoting increased levels of healthful SCFA.

Crosstalk between hypoxia-inducible factor-1α and short-chain fatty acids in inflammatory bowel disease: key clues toward unraveling the mystery

“…Occludin and claudins, especially claudins, are critical transmembrane proteins for tight junction ( 160 ). Studies have indicated SCFAs significantly upregulate tight junction proteins like zonula occludens-1 (ZO-1), occludin, and claudins, thus protecting IEB and attenuating inflammation ( 161 , 162 ). The gut mucus layer, a physical barrier protecting IEC from harmful substances and the first line of defense for gut health, is mainly composed of mucins produced by goblet cells in IEC and nourishes the gut’s symbiotic flora ( 163 – 165 ).…”

Fatty acids and lipid mediators in inflammatory bowel disease: from mechanism to treatment

“…However, Sunil Thomas et al. suggest caution in supplementing with dietary fiber, as high-fiber diets might amplify immunotherapy-associated toxicity in UC ( 243 ). Moreover, the efficacy of sodium butyrate in pediatric IBD appears limited ( 244 ).…”

“…Butyrate salts derived from dietary fiber fermentation have shown promise in raising butyrate levels and improving symptoms like abdominal pain and reflux (242). However, Sunil Thomas et al suggest caution in supplementing with dietary fiber, as high-fiber diets might amplify immunotherapy-associated toxicity in UC (243). Moreover, the efficacy of sodium butyrate in pediatric IBD appears limited (244).…”