Gut Failure: A Review of the Pathophysiology and Therapeutic Potentials in the Gut-Heart Axis

Abstract

Despite considerable advances in the field, heart failure (HF) still poses a significant disease burden among affected individuals since it continues to cause high morbidity and mortality rates. Inflammation is considered to play a key role in disease progression, but the exact underlying pathophysiological mechanisms involved have not yet been fully elucidated. The gut, as a potential source of inflammation, could feasibly explain the state of low-grade inflammation seen in patients with chronic HF. Several derangements in the composition of the microbiota population, coupled with an imbalance between favorable and harmful metabolites and followed by gut barrier disruption and eventually bacterial translocation, could contribute to cardiac dysfunction and aggravate HF. On the other hand, HF-associated congestion and hypoperfusion alters intestinal function, thereby creating a vicious cycle. Based on this evidence, novel pharmaceutical agents have been developed and their potential therapeutic use has been tested in both animal and human subjects. The ultimate goal in these efforts is to reverse the aforementioned intestinal derangements and block the inflammation cascade. This review summarizes the gut-related causative pathways implicated in HF pathophysiology, as well as the associated therapeutic interventions described in the literature.

Keywords: SCFA; TMAO; gut; heart failure; inflammation; intestinal barrier integrity; microbiota; therapeutic potential.

Figure 1

The gut–heart axis and its potential therapeutic targets.

Figure 2

Simplified illustration of the gut-related causative pathways implicated in the pathophysiology of Heart Failure (HF). The underlying pathophysiological mechanisms can be roughly divided into 3 compartments. Within the colonic lumen, altered microbial diversity is characterized by an increase in Trimethylamine (TMA)-producing species and a concurrent reduction in Short-chain fatty acid (SCFA)-producing species, which collectively favor the preponderance of harmful metabolites. Regarding the second compartment, the proper functioning of intestinal enterocytes (IEC) is crucial for maintaining intestinal barrier integrity. IECs receive both luminal and capillary nutritional supply and are physiologically covered by a mucous layer, which restricts their contact with the colonic bacteria. Thus, under normal conditions, they can regulate proper transcellular absorption while at the same time they seal the paracellular pathway via the apical junctional complex (AJC). However, in HF, erosions of the mucous layer and overgrowth of adhesive pathogenic bacteria create the ideal environment for bacteria to impinge on IECs. Moreover, SCFA depletion, in combination with hemodynamic changes (hypoperfusion and congestion) and mechanical bowel wall derangements (collagen deposition), results in decreased trophic status of IECs. These changes disrupt the barrier and lead to an increase in paracellular permeability due to malfunctional AJCs, as well as a concomitant reduction in the transcellular nutrient absorption. In the third stage, bacterial translocation leads to high endotoxin levels in the systemic circulation and recruitment of immune cells with subsequent cytokine release. Successively, cytokines further compromise the already dysfunctional barrier, thus promoting an ongoing bacterial translocation. Cumulatively, systemic inflammation, combined with high Trimethylamine-N-oxide (TMAO) levels and decreased SCFA levels, aggravate myocardial dysfunction. This in turn causes hemodynamic and mechanical changes within the bowel wall, thereby generating a relentless vicious cycle between the dysfunctional compartments of the gut–heart axis. AJC = Apical junctional complex; B.M. = Basement membrane; HF = Heart failure; IEC = Intestinal enterocyte; LPS = Lipopolysaccharide; SCFA = Short-chain fatty acids; TMA = Trimethylamine; TMAO = Trimethylamine-N-oxide.