Impact of diet on hydrogen sulfide production: implications for gut health

Abstract

Purpose of review

Excessive hydrogen sulfide (H₂S) production by the gut microbiota may contribute to the pathogenesis of multiple intestinal diseases, including colon cancer and ulcerative colitis. Therefore, understanding of dietary drivers of H₂S production has potential implications for nutritional strategies to optimize gut health and treat intestinal diseases.

Recent findings

Recent studies support a positive relationship between dietary protein intake and H₂S production. However, protein rarely exists in isolation in the diet, and dietary fiber intake could reduce H₂S production in humans and animals, even with ~30% of calories derived from protein.

Summary

These findings suggest that increased fiber intake may reduce H₂S production irrespective of protein intake, enabling the ability to meet the metabolic demands of the illness while supporting gut health. Here we discuss two recent ulcerative colitis diet studies that illustrate this point.

INTRODUCTION

Hydrogen sulfide (H₂S) is an important, albeit incompletely understood, signaling molecule in humans. Within the body, H₂S is produced endogenously by the host and exogenously via the intestinal microbiota. Endogenously produced H₂S supports physiological mechanisms such as glycemic control [1], blood pressure regulation [2], immunity [3], and protection against respiratory disease [4]. However, excessive H₂S production may be involved in the pathogenesis of cancer [5] and neurodegenerative diseases [6]. In the colon, microbiota-generated H₂S is capable of stimulating colonic muscle contractions [7] and can have anti-inflammatory effects [8]. However, excess quantities of H₂S can negatively impact the integrity of the intestinal barrier [9] and contribute to the development of ulcerative colitis [10^▪▪] and early onset colorectal cancer [11]. The amount of H₂S produced in the intestine is dependent on nutrient flow to the gut microbiota, as well as its metabolic potential. Herein we review recent literature that has advanced the understanding of dietary protein intake and gut health through the lens of H₂S production.

DIETARY FACTORS AFFECTING HYDROGEN SULFIDE PRODUCTION BY THE GUT MICROBIOTA

The two principal routes of microbial sulfidogenesis in the human gut are reduction of inorganic sulfur (sulfate and sulfite) and fermentation of sulfur-containing amino acids (cysteine, cystine, methionine, and taurine) [12^▪▪]. Inorganic sulfur may be supplied by diet or by degradation of sulfated bile acids and mucins. In western countries, dietary protein likely constitutes the more important substrate for H₂S production. Increasing the amount of dietary protein increases the amount of nitrogen leaving the terminal ileum [13], and fecal sulfide concentrations increase proportionately with the amount of meat intake [14]. A recent cross-over diet study compared short-term animal-based and plant-based diet interventions and identified protein (as percentage calories and total protein in grams) as a positive contributor to H₂S production [15^▪]. No effect of short-term diet interventions was observed on the taxonomic composition of the gut microbiota or functional gene analysis targeting dissimilatory sulfite reductase subunit A (dsrA), which is an enzyme associated with sulfate reduction [15^▪]. Interestingly, a diet enriched for casein, the dominant protein in milk, was shown to increase the abundance of mucin-degrading bacteria, which can also increase H₂S production from inorganic sulfur [16].

In contrast, increased dietary fiber intake is associated with decreased H₂S production in animals and humans [15^▪,17]. In a protein-controlled feeding trial (16.3% crude protein) conducted in swine, compared with a low-fiber diet, a high-fiber diet led to lower protein-associated gas emissions in feces, including a 30% lower ammonia and 17% lower H₂S [17]. In humans, the total fiber in grams, the insoluble fiber in grams, and carbohydrate content reduced H₂S production [15^▪]. Soluble fiber and H₂S production tended (P = 0.06) to be associated. Given the crude nature of the definition of fiber, including subcategories such as soluble and insoluble, it is difficult to treat dietary fiber-intake data in the available studies as anything other than a broad category at this time. However, given the diversity in physical and chemical characteristics of fiber, it is likely that certain characteristics impact H₂S production differently [18]. The effects of dietary fiber intake on H₂S production may be partly because of their anticipated effect on increased short-chain fatty acid (SCFA) production. Higher content of SCFAs in an in-vitro fecal slurry fermentation model resulted in lower pH and reduced H₂S and the relative abundances of bacteria that promote H₂S production [19]. In addition, dietary fiber deprivation was found in a mouse study to result in increased degradation of mucin, which increases release of sulfur substrate for H₂S production [20]. Therefore, the H₂S-mediated gut health implications of dietary protein intake need to be considered in the context of the entire diet rather than protein intake in isolation (Fig. 1).

FIGURE 1.

General relationship between dietary protein and fiber and hydrogen sulfide production by the colonic microbiota. Dietary protein positively impacts hydrogen sulfide (H₂S) production in the colon, while dietary fiber reduces H₂S production. Adding fiber can mitigate the increased H₂S production driven by dietary protein.

A recent amino acid-controlled feeding trial in mice underscores the difficulty in diet trials intended to measure an isolated change, such as protein. Although amino acid-restricted diet reduced symptoms and inflammation in dextran sodium sulfate (DSS)-induced colitis, the fiber content of the intervention diets increased to more than 8% from 5% in the control [21]. The contrasting effects of protein and fiber on H₂S production and gut health also have important implications for the growing interest in animal-based and plant-based protein sources, given the absence of fiber in animal-based protein sources and the presence of fiber in plant-based protein sources [22]. Plant-based protein within a minimally processed diet (i.e. where fiber matrices are maintained) led to lower H₂S production, while animal protein contained in a highly processed, western-style diet (i.e. low-fiber) resulted in higher H₂S production [15^▪].

THE ROLE OF DIET AND HYDROGEN SULFIDE IN ULCERATIVE COLITIS

Excessive H₂S production and/or limited capacity for its detoxification has long been hypothesized to play a role in the pathogenesis of ulcerative colits [15^▪]. Although the biogeography of ulcerative colits is consistent with a toxin (e.g. H₂S) being concentrated along the transit throughout the colon, it is also compatible with beneficial metabolites (e.g. SCFAs) being diluted [23]. The relationship between diet and colonic H₂S production suggests the potential for dietary interventions in the treatment of ulcerative colits [15^▪].

Two recent studies provide useful insights into the effects of diet on H₂S production and the inflammatory activity of ulcerative colits in adults (median age of participants in both studies was 42 years) [10^▪▪,24]. The 4-SURE study was an 8-week open-label trial aimed primarily at determining diet tolerability with secondary outcomes assessing clinical response and microbial metabolites, including SCFAs, in patients with mild-to-moderately active ulcerative colits [10^▪▪]. No H₂S-specific variables were captured, but the 4-SURE diet targeted a lower H₂S production through an increased fiber intake (10–15 g/day of resistant starch and 5 g/day slowly fermentable nonstarch polysaccharide), moderate protein intake (≤1.2 g/kg/day total protein and ≤1.5–2.0 g/day sulfur-containing amino acids), and avoidance of specific food additives (sulfite/sulfate, nitrite/nitrate, and carrageenan). The diet intervention resulted in reduced total protein (1.21 vs. 0.98 g/kg/day) and fat (95 vs. 72 g/day) intakes and an increase in fiber (22 vs. 34 g/day) intake. No difference was observed in the intake of sulfur-containing protein. Total fecal SCFA content increased by 69% on the 4-SURE diet, which was specifically driven by increased acetate, and clinical and endoscopic improvement was observed in 46 and 36% of participants, respectively. In a randomized clinical trial, utilizing a low-fat, high-fiber diet (LFD) intervention, improvements in quality of life and inflammation (assessed by C-reactive protein) in patients with ulcerative colitis in remission were observed [24]. This diet study was a 10-week, cross-over diet study with 4-week intervention periods and a 2-week washout interval. The intervention diets were the LFD diet and an ‘improved standard American diet’. In contrast to the reduced protein intake observed with the 4-SURE diet intervention [10^▪▪] (91 and 72 g/day protein at baseline and during the intervention, respectively), the LFD diet [24] resulted in an increased protein intake (81 and 105 g/day protein at baseline and during the intervention, respectively). Notably, the increased protein intake occurred in the context of increased fiber and decreased fat intake, which represents a similar change in diet composition to the 4-SURE diet, although the LFD diet had a greater reduction in fat intake (71 vs. 24%). On the LFD diet, similar to the 4-SURE diet, acetate was the only SCFA with a measurable increase.

Although it is impossible to know if either of the diets impacted H₂S production specifically, given the general relationships between protein and fiber intake on H₂S production in both humans and animals [17], both diets underscore the importance of fiber to support gut health, regardless of protein intake. Considering dietary fiber content has enormous clinical nutrition implications, particularly for inflammatory conditions in the gut, such as ulcerative colitis, where protein intake is traditionally prioritized to meet the metabolic demands of inflammation. The capacity of fiber to reduce H₂S production capacity [15^▪,17], and findings of disease improvement with increased fiber intake, both in the context of reduced [10^▪▪] and increased protein intake [24], would suggest that dietary protein can negatively impact gut health [16,25], especially in the context of a low-fiber intake.

CONCLUSION

Further research is required to fully elucidate the relationship between dietary protein intake and H₂S production by the gut microbiota. An important next step will be to further characterize the individual H₂S production responses to dietary interventions in the context of person-specific configurations of gut microbiota [26]. Exploratory work has identified taxonomic differences between H₂S-responsive and nonresponsive individuals that can help inform this work [15^▪]. Importantly, tests capable of differentiating H₂S production potential need to be rapid to be clinically relevant. This should be feasible with qPCR-based technologies. However, the current understanding of the microbial sulfur metabolism in the human gut remains incomplete. Historically, investigators targeted the dissimilatory sulfite reductase (dsr) genes as molecular markers of H₂S production. However, recent work by Wolf et al. [12^▪▪] greatly expanded the spectrum of relevant pathways and, consequently, the number of potentially relevant targets for testing. Finally, clinical relevance requires longer term (> 1 week) diet intervention studies and the impact of fiber or protein supplementation on H₂S production. Given the increasing interest in, and access to, dietary protein sources, it will also be important to determine the potential implications of protein source on H₂S production as part of this work. Ultimately, further elucidation of the mechanistic relationships between dietary protein intake and gut health will have important clinical nutrition implications for health and disease.

KEY POINTS.

• Excess hydrogen sulfide (H₂S) production by the gut microbiota has been implicated in diseases of the colon.

• Protein has a positive association with H₂S production, and fiber has a negative association.

• Balancing protein intake with fiber intake offers a potential therapeutic avenue to meet the metabolic demands of illness while minimizing excess H₂S production.