The nonfermentable dietary fiber hydroxypropyl ...

Abstract

Diet influences host metabolism and the intestinal microbiota; however, a detailed understanding of this complex relationship remains limited. The purpose of this study was to examine whether the nonfermentable fiber hydroxypropyl methylcellulose (HPMC) could modify the intestinal microbiota and if these alterations would correlate with metabolic improvements. C57B/L6 mice were subjected to a high-fat diet (HFD) and subsequently assigned to three groups: continued HFD (control), HFD supplemented with 10% HPMC, or a low-fat diet (LFD). Notably, both LFD and HPMC interventions led to reduced weight gain relative to the control group, as well as decreased plasma cholesterol and liver triglycerides. Furthermore, through 454-pyrosequencing of microbial 16S rRNA genes, it was demonstrated that both LFD and HPMC impacted intestinal microbiota composition. The supplementation of HPMC significantly increased populations of certain bacteria such as Erysipelotrichaceae while decreasing others, indicating distinct microbial responses influenced by dietary changes. These findings suggest that HPMC serves as an effective prebiotic that could benefit host metabolism by altering gut microbiota.

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Keywords: prebiotics, microbial ecology, obesity, cholesterol, liver adiposity

The gastrointestinal microbiome comprises trillions of microorganisms and is profoundly affected by host genetics and diet. The composition of the intestinal microbiota is also integral to many physiological processes, creating an imperative for effective modulation strategies. Approaches to modify the microbiome commonly encompass the use of antibiotics to target specific populations, probiotics through food or fecal transplants, or prebiotic compounds aimed at fostering the growth of beneficial microorganisms. The advantage of prebiotics lies in their straightforward transport and administration, alongside a favorable safety profile. Historically, research has predominantly concentrated on compounds that are actively metabolized by microbiota, relegating nonfermentable fibers like HPMC to a secondary consideration.

Obesity and metabolic syndrome are escalating health issues both in the United States and globally. These conditions often arise from multiple contributing factors, leading to various treatment pathways focusing on dietary and lifestyle modifications aimed at promoting weight loss and enhancing metabolic health. Reducing caloric and fat intake directly impacts energy balance, which is beneficial for weight management. The addition of indigestible fiber to diets has consistently linked to health gains in both human and animal studies, contributing to weight control, tackling metabolic syndrome, and improving blood cholesterol and glucose levels, despite the underlying mechanisms remaining inadequately understood.

Recent research has increasingly illuminated the role of the intestinal microbiota in regulating host metabolism as a vital contributor to obesity. These microbial communities carry out diverse metabolic functions, including the fermentation of carbohydrates into short-chain fatty acids, influencing energy extraction from food, and bile salt metabolism. The extent of fiber fermentation significantly affects how fiber-induced microbiome alterations impact host metabolism. Notably, fibers span the spectrum from completely fermentable to nonfermentable but have collectively been shown to enhance host metabolic outcomes. While many health benefits associated with fermentable fibers have been attributed to increased short-chain fatty acid production, this is not as clearly observed with nonfermentable fibers.

Hydroxypropyl methylcellulose (HPMC) stands out as a nonfermentable dietary fiber, noted for its beneficial health impacts and serving as a prime substrate for exploring fiber, metabolism, and microbiota interactions, particularly in a system previously thought to exhibit negligible influence on microbial dynamics. As a semi-synthetic cellulose derivative, HPMC includes hydroxypropyl and methyl side chains, making it prevalent in food manufacturing with a long safety track record and classified as 'generally recognized as safe' (GRAS) for daily consumption up to 20g in the United States. HPMC supplementation has been found to reduce cholesterol levels and postprandial insulin spikes in both rodent models and humans, as well as to decrease weight gain and fat mass in rodents consuming a high-fat diet. Importantly, HPMC is not absorbed by the host but can shape the intestinal nutrient environment by modulating bile acid and fat excretion, alongside increasing fecal water content, which, in turn, influences the intestinal microbiota.

In this investigation, we employed high-throughput 16S rRNA taxonomic profiling to evaluate the impact of HPMC on the murine microbiome, aiming to discern whether HPMC and a low-fat diet would lead to similar modifications in the intestinal microbiota, given their comparable metabolic outcomes. Our research was designed to elucidate the overall shifts in microbial community structure following dietary changes and to identify specific taxa linked to distinct diets or metabolic attributes.

MATERIALS AND METHODS

Animals and diets

In total, eighteen-week-old adult C57B6/L6J mice from Jackson Laboratories were acclimated to an HFD for 2 months, followed by stratification into three groups: continuing on HFD, shifting to LFD, or transitioning to HFD supplemented with 10% HPMC. Mice were individually housed, with strict monitoring of food intake over the ensuing 4-week period. This study adhered to protocols sanctioned by the Institutional Animal Care and Use Committee and was executed by In Vivo Services at the Jackson Laboratory West.

Hepatic lipid analysis

Liver samples were processed and analyzed to determine percentages of total hepatic lipids and levels of various cholesterol types and triglycerides using standardized assays and a clinical analyzer.

Microbial diversity and community structure

The assessment of microbial diversity involved calculating richness and evenness metrics from fecal and cecal 16S rRNA sequences, which revealed decreased community richness in LFD and HPMC groups compared to the HFD group. Microbial community structure variations were further evaluated using PCoA analysis, elucidating distinct clustering among diet treatments.

Specific associations of weight change and metabolic variables

In correlation analyses aimed at elucidating the interrelations between dietary intervention and microbiome alterations, we applied partial correlation to control for confounding variables. Significant associations emerged between weight changes in HFD mice and specific microbial populations, suggesting a potential interplay between the microbiome and host metabolism.

DISCUSSION

This study reiterates the understanding that dietary modifications foster improvements in metabolic health in the context of high-caloric diets. The introduction of HPMC disrupts the linear relationship between energy intake and weight change, corroborating findings from earlier studies. This dietary fiber significantly promotes the excretion of bile salts and fats, leading to increased caloric losses. In both LFD and HPMC cohorts, compositional changes to the intestinal microbiota were identified throughout the dietary transition period, suggesting an intricate relationship between fiber supplementation and microbial ecology. These results warrant further research into the underlying mechanisms and potential applications in metabolic health improvement.

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