Promote or Prevent? Gut Microbial Function and Immune Status May Determine the Effect of Fiber in Inflammatory Bowel Disease

See “Unfermented β-fructan fibers fuel inflammation in select inflammatory bowel disease patients,” by Armstrong HK, Bording-Jorgensen M, Santer DM, et al, on page 228. See “Unfermented β-fructan fibers fuel inflammation in select inflammatory bowel disease patients,” by Armstrong HK, Bording-Jorgensen M, Santer DM, et al, on page 228. The benefit of dietary fiber in promoting human health has been long recognized and is largely based on the lower prevalence of Western diseases such as diabetes, heart disease, and colorectal cancer among populations that consume higher amounts of dietary fiber.1Makki K. Deehan E.C. Walter J. et al.The impact of dietary fiber on gut microbiota in host health and disease.Cell Host Microbe. 2018; 23: 705-715Abstract Full Text Full Text PDF PubMed Scopus (1029) Google Scholar, 2Sonnenburg J.L. Sonnenburg E.D. Vulnerability of the industrialized microbiota.Science. 2019; 366Crossref Scopus (103) Google Scholar, 3Sonnenburg E.D. Sonnenburg J.L. The ancestral and industrialized gut microbiota and implications for human health.Nat Rev Microbiol. 2019; 17: 383-390Crossref PubMed Scopus (156) Google Scholar, 4Burkitt D.P. Walker A.R. Painter N.S. Effect of dietary fibre on stools and the transit-times, and its role in the causation of disease.Lancet. 1972; 2: 1408-1412Abstract PubMed Scopus (805) Google Scholar Although not well-understood, the protective effects of fiber had been previously attributed to faster transit time and stool size, which may facilitate the removal of toxic metabolic products.5Trowell H. Burkitt D. Physiological role of dietary fiber: a ten-year review.Bol Asoc Med P R. 1986; 78: 541-544PubMed Google Scholar However, recent studies show that microbial fermentation likely underlies the benefits of dietary fiber.6Desai M.S. Seekatz A.M. Koropatkin N.M. et al.A dietary fiber-deprived gut microbiota degrades the colonic mucus barrier and enhances pathogen susceptibility.Cell. 2016; 167: 1339-1353.e21Abstract Full Text Full Text PDF PubMed Scopus (1345) Google Scholar,7Llewellyn S.R. Britton G.J. Contijoch E.J. et al.Interactions Between Diet and the Intestinal Microbiota Alter Intestinal Permeability and Colitis Severity in Mice.Gastroenterology. 2018; 154: 1037-1046.e2Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar Gut microbiota harbor a diverse set of enzymes such as glycoside hydrolases and polysaccharide lyases that help to break down specific linkages in complex carbohydrates derived from host glycans or dietary fiber into simple sugars. The enzymes profile of these communities will likely determine the specific carbohydrates that can be fermented by an individual’s gut microbiota. The resulting fermentation end-products, such as short chain fatty acids,8Lee M. Chang E.B. Inflammatory bowel diseases (IBD) and the microbiome-searching the crime scene for clues.Gastroenterology. 2021; 160: 524-537Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar regulate important aspects of host physiology including metabolism, cell turnover, and the immune system. Hence, one would expect to see beneficial effects with fiber supplementation. However, human interventional studies show significant interindividual variability in responses to fiber as well as differences based on fiber type.9Peters V. Dijkstra G. Campmans-Kuijpers M.J.E. Are all dietary fibers equal for patients with inflammatory bowel disease? A systematic review of randomized controlled trials.Nutr Rev. 2022; 80: 1179-1193Crossref PubMed Scopus (3) Google Scholar In this issue of Gastroenterology, Armstrong et al10Armstrong H.K. Bording-Jorgensen M. Santer D.M. et al.Unfermented β-fructan fibers fuel inflammation in select inflammatory bowel disease patients.Gastroenterology. 2023; 164: 228-240Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar systematically address the complexity that underlies differences in response to fiber by investigating the effects of different β-fructan fibers on barrier function and inflammation using a combination of human specimens, ex vivo culture of colonic biopsies, and cell culture models. One of the challenges in the field is that carbohydrates that differ in chemical composition and size, resulting in varying potentials to undergo microbial fermentation along with nonfermentable components, such as lignin are all categorized as fiber. Armstrong et al10Armstrong H.K. Bording-Jorgensen M. Santer D.M. et al.Unfermented β-fructan fibers fuel inflammation in select inflammatory bowel disease patients.Gastroenterology. 2023; 164: 228-240Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar found that certain β-fructans such as fructo-oligosaccharide (FOS) and inulin, but not barley, maltodextrin, or starch, triggered a proinflammatory response in THP-1–derived macrophage cell lines and primary peripheral blood mononuclear cells from healthy donors as evidenced by increased release of IL-1β. This finding suggests that different carbohydrates classified as fiber can evoke different biologic responses. However, Armstrong et al10Armstrong H.K. Bording-Jorgensen M. Santer D.M. et al.Unfermented β-fructan fibers fuel inflammation in select inflammatory bowel disease patients.Gastroenterology. 2023; 164: 228-240Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar found the proinflammatory effect was not only dependent on the fiber type, but also on immune status of an individual and the fermentative capacity of their gut microbiota (Figure 1A). The authors cultured colonic biopsies from pediatric patients with Crohn’s disease and ulcerative colitis with both active and quiescent disease and from controls without inflammatory bowel disease (IBD). They found higher levels of CD45+ cells in biopsies from patients with IBD. FOS significantly increased IL-1β secretion in colonic biopsies from patients with active IBD and, to a lesser extent, from those with quiescent disease, but decreased IL-1β secretion in biopsies from controls without IBD. The proinflammatory effect of FOS was mediated via the NLRP3 and TLR2 pathways. Thus, FOS can differentially affect immune responses based on the underlying immune cell population in the gut. Interestingly, the authors also found that the avoidance of FOS among pediatric patients with IBD correlated with a proinflammatory response to FOS, suggesting that FOS consumption during health may decrease the severity of inflammation subsequently. This observation raises additional questions about the mechanisms underlying the effect of distinct fibers on the gut–immune system in different states of health and disease. Armstrong et al10Armstrong H.K. Bording-Jorgensen M. Santer D.M. et al.Unfermented β-fructan fibers fuel inflammation in select inflammatory bowel disease patients.Gastroenterology. 2023; 164: 228-240Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar assessed the effect of microbial fermentative capacity on the inflammatory response by exposing THP-1 cells to supernatants from colonic washes cultured in the presence or absence of FOS. They found the fermentative capacity of the gut microbiota as evidenced by levels of FOS and short chain fatty acids negatively correlated with the inflammatory response evoked by FOS. The dampened immune response was dependent on both a decrease in FOS as well as an increase in short chain fatty acids, suggesting potential complementary mechanisms underlying this effect. To complement their observations with findings in human subjects, these authors used samples from a clinical trial of adult patients with ulcerative colitis treated with β-fructans and found that symptom flares during β-fructan supplementation correlated with increased inflammatory cytokines in intestinal biopsy lysates. The findings of Armstrong et al raise as many questions as they answer. In this study, the authors deconstructed the complexity of food by investigating individual carbohydrates with varying complexity. Authors found that select carbohydrates can affect immune function, but because these molecules were purified from chicory roots, the potential role of microbial contaminants that may copurify with β-fructans cannot be ruled out. Moving forward, it will be important to build back this complexity by combining different carbohydrates to better understand the impact of complex foods, as well as the modifications that occur with food preparation and cooking. Interventional studies11David L.A. Maurice C.F. Carmody R.N. et al.Diet rapidly and reproducibly alters the human gut microbiome.Nature. 2014; 505: 559-563Crossref PubMed Scopus (5667) Google Scholar have shown that rapid shifts in the gut microbiota and associated changes in microbial metabolism occur with short-term dietary changes and that food-derived microbes can be detected in the distal gut. Single fiber effects do not occur in isolation. Indeed, other investigators have reported the benefits of combining fiber consumption with reduced protein intake for reducing colitis severity in animal models.7Llewellyn S.R. Britton G.J. Contijoch E.J. et al.Interactions Between Diet and the Intestinal Microbiota Alter Intestinal Permeability and Colitis Severity in Mice.Gastroenterology. 2018; 154: 1037-1046.e2Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar Although the study focuses on mucosa-associated microbiota, it is potentially important to also assess the luminal microbiota to determine overall fermentative capacity in different segments of the gut (Figure 1A). Further, the study uses metagenomics to assess the functional capacity of the microbiome, but it is difficult to predict the phenotypic ability of bacteria to use specific carbohydrates based on metagenomic sequences alone, given that bacteria do not express all their genes in a given environment. In addition to promoting the growth of the specific microbes that use them, dietary carbohydrates can also promote other microbes that depend on the end-products of primary fermenters (cross-feeding). Hence, it is not surprising that, although functional differences were observed in the microbiota between FOS responders and nonresponders, these differences do not directly explain the differential capacity for FOS fermentation. Thus, it will be important to complement sequencing data with biochemical characterization to determine specific enzymatic activity in a microbial community which in turn provides a therapeutic target (Figure 1A). The acquisition of enzymes capable of digesting algae by the microbiome in Japanese individuals12Hehemann J.H. Correc G. Barbeyron T. et al.Transfer of carbohydrate-active enzymes from marine bacteria to Japanese gut microbiota.Nature. 2010; 464: 908-912Crossref PubMed Scopus (730) Google Scholar highlights one potential pathway for introducing missing enzymatic capabilities into a microbial community. The findings of Armstrong et al are compelling and have implications beyond IBD. Another recent study found specific foods (gluten, wheat, soy, milk) may evoke pain through local immune responses with mast cell activation in patients with irritable bowel syndrome.13Aguilera-Lizarraga J. Florens M.V. Viola M.F. et al.Local immune response to food antigens drives meal-induced abdominal pain.Nature. 2021; 590: 151-156Crossref PubMed Scopus (94) Google Scholar,14Schroeder B.O. Birchenough G.M.H. Stahlman M. et al.Bifidobacteria or fiber protects against diet-induced microbiota-mediated colonic mucus deterioration.Cell Host Microbe. 2018; 23: 27-40.e7Abstract Full Text Full Text PDF PubMed Scopus (354) Google Scholar It is plausible because the differential fermentative capacity of small intestinal microbiomes plays a role in determining food-evoked pain. The current study highlights the complexity of factors involved in an individual’s response to fiber, such as the carbohydrate chemical structure, the enzyme repertoire of the gut microbiota, and host immune status. Although there are likely additional determinants, these observations help to explain the interindividual differences in response to fiber supplementation and underscore the need for precision nutrition approaches rather than the one-size-fits-all fiber supplementation strategy in disease states (Figure 1B). A broader approach of fiber supplementation may still be relevant in health, especially among populations with overall low fiber consumption. Unfermented β-fructan Fibers Fuel Inflammation in Select Inflammatory Bowel Disease PatientsGastroenterologyVol. 164Issue 2PreviewInflammatory bowel diseases (IBD) are affected by dietary factors, including nondigestible carbohydrates (fibers), which are fermented by colonic microbes. Fibers are overall beneficial, but not all fibers are alike, and some patients with IBD report intolerance to fiber consumption. Given reproducible evidence of reduced fiber-fermenting microbes in patients with IBD, we hypothesized that fibers remain intact in select patients with reduced fiber-fermenting microbes and can then bind host cell receptors, subsequently promoting gut inflammation. Full-Text PDF Open Access