Symptomatic Uncomplicated Diverticular Disease (SUDD) is the most common clinical presentation in patients with colonic diverticulosis, with a prevalence of up to 20% (1). Although the pathogenesis of SUDD is not clearly understood, heredity, inflammation, motility alterations and gut microbiota (GM) imbalance (i.e., dysbiosis) are the main pathogenetic factors hypothesized. In particular, the GM of patients with SUDD has been found to be depleted in taxa with anti-inflammatory properties, such as Clostridium cluster IV, Clostridium cluster IX, Fusobacterium, and Lactobacillaceae (2), while enriched in mucin-degrading bacteria, such as Akkermansia muciniphila (3). More recently, our work using next-generation sequencing has confirmed that specific taxa may be related to SUDD, but the associations vary depending on the severity of abdominal pain (4).

Regarding treatment options, dietary fiber appears to be useful in preventing the onset of colonic diverticulosis, but there is no clear evidence of its benefit in SUDD (5–8). Mesalazine, an intestinal anti-inflammatory drug, may be effective in the symptoms of SUDD and in the prevention of diverticulitis (9), but not in the prevention of recurrence of diverticulitis (10). Probiotics, particularly bifidobacteria, appear to be effective in the prevention of SUDD (3, 11), even in primary care settings (12). Recent studies in general practice have confirmed the high efficacy, safety and excellent tolerability of rifaximin, a non-absorbable enteric antibiotic (12–15). Very often, however, treatment to prevent the symptoms of SUDD is given in a pulsatile manner (7–10 days per month) without scientific evidence (16). Among foods for special purposes, butyric acid may be effective in SUDD by improving gut health in a variety of ways (16, 17). In fact, butyrate is a short-chain fatty acid (SCFA) that serves as an important source of energy for colonocytes, regulates motility, pH and blood flow, improves mucosal barriers, and exerts antioxidant, anti-inflammatory and antimicrobial properties (18). It has been successfully used in the form of sodium butyrate in the treatment of several pathologies affecting the colon, ranging from irritable bowel syndrome (IBS) (19) to inflammatory bowel disease (IBD) (20), but no data are available for SUDD.

Here, we aimed to evaluate the efficacy and safety of a delayed- and colonic-release butyrate formulation in modulating GM and abdominal pain in patients with SUDD treated in primary care. As general practitioners (GPs) often diagnose the disease and request a GM assessment for patients complaining of gastrointestinal symptoms (5, 21), such a study could be helpful for primary care, which is increasingly involved in the management of patients with SUDD.

Here, we investigated the effects of a butyrate formulation (Butyrose®) on GM in patients with SUDD. Moreover, we investigated the effect of this formulation on abdominal pain and its association with GM.

With regard to the primary endpoint, namely the impact of Butyrose® on GM, we found that treatment resulted in an increase in alpha diversity, the reduction of which is a typical hallmark of dysbiosis in a variety of diseases, both local and systemic (35). At the compositional level, the patients’ GM was found to be enriched in several taxa after treatment, including Desulfovibrio (and its family Desulfovibrionaceae and its phylum Desulfobacterota), Alistipes (and its family Rikenellaceae), Barnesiella (and Barnesiellaceae), Eggerthellaceae, Lachnospiraceae_NK4A136_group and Oscillibacter. In particular, Desulfovibrio belongs to sulfate-reducing bacteria, which are considered pathobionts that may contribute to intestinal and extra-intestinal diseases, probably through the production of hydrogen sulfide, lipopolysaccharide and mucolytic enzymes, and the secretion of outer membrane vesicles (36). Although apparently unfavorable, the increase in sulfate-reducing bacteria may be related to their ability to use various organic compounds, including butyric acid, as electron donors for sulfate reduction (37–39). It should be noted that some Desulfovibrio species/strains appear to have more pathogenic potential than others, particularly in unhealthy individuals (36), highlighting the need for high-resolution taxonomic profiling and in-depth assessment of context-dependent features, including interaction networks within the microbial community and with the host. Another potentially harmful genus enriched after treatment was Alistipes, a bile-tolerant microorganism that has been shown to contribute to some diseases but also to protect against others (40), again emphasizing the need for further studies, including animal models, to better understand its role in health and disease. On the other hand, the increases in the SCFA producers Oscillibacter and Lachnospiraceae_NK4A136_group can certainly be considered positive, in addition to being consistent with the available literature on the effects of Butyrose® on the GM of patients with IBD (41). In particular, Lachnospiraceae_NK4A136_group has been shown to have protective and anti-inflammatory effects, including improvement of gut barrier function (42–44). Oscillibacter, together with Alistipes species, has recently been found to be enriched in subjects with lower plasma triglycerides and glucose and higher plasma HDL in ethnically distinct cohorts (45), suggesting a role in cardiovascular health, the impairment of which may be related to SUDD (46).

Based on our previous work showing that the GM of SUDD patients stratified by severity of abdominal pain (as assessed by VAS) (4), we next investigated the effects of Butyrose® in patients with mild vs. moderate vs. severe SUDD. While the increase in alpha diversity was common to all severity groups, the compositional variations were closely related to baseline severity (of abdominal pain and dysbiosis), with the severe group showing an overall greater rearrangement compared to the other groups. In particular, the severe group showed an enrichment in Rikenellaceae (and Alistipes), Lachnospiraceae, Bacteroidaceae (and Bacteroides), Erysipelotrichaceae_UCG-003 and Phascolarctobacterium, and a depletion in Veillonellaceae (and Dialister) after treatment. Again, some changes could be beneficial, such as those in the SCFA producers Lachnospiraceae and Phascolarctobacterium (47), while others could not, notably that in Erysipelotrichaceae_UCG-003, which has previously been linked to intestinal dysfunction, inflammation and metabolic disorders (48). Conversely, the other severity groups showed fewer changes, in line with the lower extent of their dysbiosis, namely an enrichment in Lachnospiraceae_NK4A136_group and [Eubacterium] coprostanoligenes_group and a depletion in Blautia in the moderate group, and an enrichment in Barnesiellaceae (and Barnesiella), Coriobacteriaceae (and Collinsella) and Oscillospirales_UCG-010 in the mild group. Among these, it is worth noting that Blautia has previously been positively associated with gastrointestinal symptoms (particularly diarrhea) and IBS (49), making its reduction potentially desirable also in the context of SUDD. On the other hand, the increase in Collinsella is again questionable, as this genus has been negatively associated with IBS severity (50), but is also known as a pathobiont capable of increasing gut permeability and triggering pro-inflammatory cytokines (51, 52).

With regard to secondary endpoints, we found that Butyrose® was effective in controlling abdominal pain, the main symptom characterizing SUDD patients. This was expected as butyrate is a SCFA that, among other effects, improves gut permeability, increases the rate of cell regeneration, reduces oxidative stress and mucosal inflammation (18), and has previously been shown to be reduced in stool samples from patients with SUDD (4, 5). In contrast, no changes in stool appearance were recorded under treatment with Butyrose®. This may mean that other factors, such as colonic motility, are involved in determining stool form in these patients and/or that the type of fecal output did not influence the clinical response to butyrate. Importantly, however, this means that Butyrose® does not cause constipation, an adverse event that has often been hypothesized but never confirmed with older formulations of butyrate (53). As for adverse events, their incidence was quite low in our population (~5%). However, it is not easy to explain this occurrence, in particular for patients experiencing diarrhea. In fact, sodium butyrate is recommended for the treatment of diarrheal disorders such as traveler’s diarrhea (54). However, we are not sure that these adverse events could really be related to butyrate, as they all occurred during a concurrent epidemic of viral gastroenteritis.

The main limitations of the study include: (i) the use of 16S rRNA amplicon sequencing, which is still the gold standard for microbiota profiling, but does not allow high-resolution taxonomic profiling down to species level and functional insights; (ii) the lack of mechanistic information; and (iii) the retrospective design. In particular, the retrospective design may have led to the loss of information that could have influenced the final results (e.g., recall of symptom severity may not have been reliable, and GM-associated confounding factors, such as proton pump inhibitor use, may not have been captured).

In conclusion, Butyrose® supplementation for 90 days significantly modulated the GM of patients with SUDD. Specifically, it led to increased diversity and some compositional changes that were closely related to baseline abdominal pain severity. Some changes may be beneficial, such as the increase in SCFA producers, while others may not be, such as the increase in taxa with dubious pathogenic potential. Regardless of the significance of the increase in these taxa, these changes in GM were associated with a significant improvement in abdominal pain. Further studies in larger cohorts with longer observation periods and using other omics, such as metagenomics and metabolomics, are needed to validate our findings and to gain deeper insights into the impact of Butyrose® on SUDD, including the composition (down to species level, including interaction networks) and function of the GM. Such studies could pave the way for personalized intervention strategies based on disease severity for faster and more effective resolution of symptoms.