The retina is short for the optic part of the retina, a visual sensory organ that lies immediately within the inner layer of the choroid. The choroid is a highly vascularized tissue found between the retina and the sclera that gives appropriate oxygen and nutrients to the retina and is engaged in a range of retina-related functions (24).

An investigation has found no substantial changes in retinal thickness during IF (25), which might be due to a stringent self-regulatory system in the retina when perfusion pressures fluctuate dramatically (26, 27). Previously, animal studies found that retinal blood flow self-regulates in a similar manner (28). A similar phenomenon is observed in the human body (29). Unlike the retina, IF can cause choroid thickening (30).

The choroid’s self-regulation may cause a significant negative relationship between choroidal thickness and systolic blood pressure in the sub choroid (31, 32), and IF may thicken the choroid by lowering systolic blood pressure. In addition, there is a connection between neuromodulation and sub choroidal thickness. During IF, blood pressure drops, cardiac blood flow drops (33), and choroidal thickness under fovea increases when sympathetic tone drops and parasympathetic tone rises (16, 25). The choroidal thickness under the fovea increased by nearly 3% during the fasting period compared to the non-fasting period (25). Insulin sensitivity may influence the thickness of the choroidal layer at IF (34). There is a substantial thinning of choroidal thickness in diabetic patients and diabetic retinopathy (DR) patients (35). The nearly 37% reduction in choroidal thickness in the subcentral retinal recess compared to healthy subjects suggests that choroidal thickness is a great early predictor of DR. As a result, increased insulin sensitivity is expected to have a role in choroidal thickness change. Furthermore, nitric oxide levels in the body are greatly elevated during Ramadan (36). This stimulation of endothelial dilatation and intravascular material leakage may contribute to the increased choroidal thickness under the eye fossa (30).

The pressure created by the interplay of the eye’s contents on the eye’s wall and the contents of the eye is known as IOP. The intraocular contents include the lens, vitreous humor, and aqueous humor, of which the aqueous humor is the most critical factor affecting IOP. A balance between aqueous intake and outflow is required to maintain normal IOP. Any factor that interferes with the proper functioning of the aqueous humor circulation pathway may obstruct aqueous humor return and increase IOP. This case is depicted in Figure 3.

Previous studies have reached different conclusions. Some studies comparing the difference between IOP during fasting and non-fasting periods did not significantly change (11, 37). However, IF decreases insulin secretion and increases glucagon levels and sympathetic tone, which increases free fatty acid formation and thus increases local blood flow (38). Norepinephrine and cortisol produced during sympathetic excitation are elevated, and resistance to atrial outflow increases, causing IOP to rise. However, most studies have shown a significant decrease in IOP values during IF (34, 39–44). Kerimoglu et al. (42) found that in the Ramadan fasting population, IOP tended to be higher in the morning (fasting vs. non-fasting: 14.19 ± 3.53 mmHg vs. 12.03 ± 2.99 mmHg) and lower in the afternoon (fasting vs. non-fasting: 11.74 ± 2.39 mmHg vs. 13.13 ± 2.39 mmHg). This phenomenon may be related to dietary habits during Ramadan fasting (42). Fasting people intentionally consume more food and water before sunrise to tolerate hunger and thirst during the day (40), and in the morning, they drink more water, have an abundance of body fluids, and average aqueous humor production; in the afternoon, they become dehydrated because they have not drunk water for a long time, their plasma osmolality rises relatively, and the amount of aqueous humor obtained by ultrafiltration decreases relatively, with a disadvantage. Another study evaluated IOP during fasting in patients with open-angle glaucoma, and these patients showed an IOP decrease of approximately 26–32% at various times compared to the non-fasted state (45).

It has been shown that during IF, low-density lipoprotein (LDL) and apolipoprotein (Apo) B levels decrease, and low-density lipoprotein (HDL) and Apo A-1 levels increase significantly (46). The depletion of lipid stores during this period may reduce prostaglandin secretion, which leads to a decrease in IOP (45). In addition, IOP reduction may also be associated with increased body dehydration, neuro-endocrine system function, and inflammatory mediators in the uveoscleral channels (34).

Studies in recent years have favored IF to reduce IOP, and most of the periods measured were distributed across the period of IF with high reliability. However, further studies with more samples need to be selected to confirm the relationship between IOP and IF.

The anterior segment of the eye includes the anterior chamber, posterior chamber, lens suspensory ligament, atrial angle, conjunctiva, tear film, and other structures in front of the lens. Some parameters commonly used in clinical practice include anterior chamber depth, anterior chamber volume, central corneal thickness (CCT), corneal curvature, etc. These parameters play an essential role in the screening and diagnosis of ophthalmic diseases in clinical practice.

Intermittent fasting alters anterior chamber depth and volume, which is mostly due to dehydration This difference may be noticed in both fasting and non-fasting groups, and at various moments during the fasting period. Compared to the non-fasting group, anterior chamber depth and axial length were dramatically reduced in the fasted group (34, 47). Furthermore, during IF, the depth and volume of the anterior chamber were variable at different times of the day. According to Nowroozzadeh et al. (48), anterior chamber depth increased substantially during Ramadan, with nearly 26% compared to non-fasting periods. The anterior chamber depth values were greater in the morning than in the evening (P = 0.01), but the axial length of the eyes did not show such a significant change (48). Other studies with similar results have also been conducted (40). Furthermore, because there is a link between anterior chamber depth and IOP, with lower IOP being linked to deeper anterior chamber depth (48, 49), it is hypothesized that IF might change the magnitude of anterior chamber depth by affecting IOP.

In addition, Beyoğlu et al. (34) evaluated corneal density and lens density changes in IF During IF, subjects were found to have a decrease in corneal density (fasting vs. non-fasting: right/left eye: 12.81 ± 0.76/12.73 ± 0.73 vs. 13.28 ± 1.01/13.07 ± 0.77) (34), an expression likely due to changes in corneal inflammatory mediators and increased osmolarity as a result of dehydration (50, 51). However, lens density did not differ significantly between the fasting and non-fasting groups (34), probably because of lens microcirculatory water channels (52), which maintain a more stable density even during longer periods of dehydration.

The tear film is a crucial medium for maintaining lubrication between the cornea and the conjunctiva and keeping harmful substances such as bacteria from entering the eye. An aqueous layer, a lipid layer, and a mucin layer make up the typical tear film. Tear secretion levels were substantially lower during IF (42). The assessment of tear break-up time (TBUT) did not change significantly between fasting and non-fasting periods (50). In addition, the activity of several enzymes, such as lysozyme, lactoferrin, and alpha-amylase, was reduced throughout the fasting period in the fasted population (53).

Diabetic retinopathy (DR) is a major cause of low vision and blindness in adults today (54, 55) and is one of the microvascular complications caused by diabetes. The primary pathogenic alterations are retinal ischemia, aberrant neovascularization, retinal inflammation, increased vascular permeability, and neuronal and glial abnormalities (56). The current treatment of DR is mainly retinal laser photocoagulation, vitreous cavity injection, and vitrectomy. However, it is still unable to manage the condition of DR (57), and this therapy is mostly used on patients with advanced DR, with early prevention focusing on food and lifestyle modifications to prevent the disease from progressing further.

The frequency and length of eye use have increased dramatically in modern society, as has the incidence of ocular surface illnesses. Dry eye is a multifactorial ocular surface disease defined by a tear film homeostasis problem, mainly associated with increased tear film instability, increased tear osmolarity and ocular surface inflammation development (78).

Diabetes is a systemic risk factor for dry eye, with more than half of type 2 diabetes patients experiencing dry eye symptoms (79). A sustained hyperglycemic condition damages the corneal epithelium directly, resulting in corneal ulcers and chronic corneal epithelial abnormalities (80). Hyperglycemia causes a decrease in conjunctival goblet cell density, a decrease in mucin density, and a decrease in tear film stability, in addition to direct epithelial damage; at the same time, hyperglycemia causes an increase in tear osmolarity, which causes mucin denaturation, a decrease in tear film stability, and yet another increase in osmolarity, creating a vicious cycle. A hyperglycemic environment can damage corneal neurons and impair neurotrophic function, which leads to the breakdown of corneal barrier integrity, decreased corneal sensitivity, decreased ocular surface gland production and blink frequency, and increased the advancement of dry eye (78, 81).

In diabetic patients, IF can effectively control blood glucose levels (82), resist the stress response, reduce autophagy, downregulate inflammatory expression (63), and reduce the damage caused by diabetes to the lacrimal vascular system and corneal autonomic nerves (80), resulting in corneal protection. On the other hand, a reduction in CD4 T cells has been observed to treat dry eyes in Sjogren’s syndrome, an autoimmune condition (83, 84). CD3, CD4 T cells, and CD19 B cells are all reduced by IF (85). This might potentially how IF helps with dry eye problems. In conclusion, IF may help diabetic individuals with dry eye symptoms and other ocular surface diseases.

However, IF might induce or worsen dry eye problems. Dehydration and decreased tear production can occur while fasting, resulting in dry eye symptoms. There are also substantial changes in tear composition, such as changes in tear film proteins and increased osmolarity (42, 50, 53), which can trigger the production of ocular surface proinflammatory cytokines, chemokines, and matrix metalloproteinases (MMPs) (8, 9, 30), thereby aggravating dry eye. As a result, the effects of IF on dry eye need to be investigated further, and its therapeutic benefits must be considered holistically.

Glaucoma, a progressive optic neuropathy defined by the loss of retinal ganglion cells, is the most prevalent neurodegenerative disease globally and results in permanent blindness (86). IOP that is pathologically raised is a significant risk factor for glaucoma. Glaucoma is caused by a disturbance of the aqueous circulation’s dynamic balance: a few cases are caused by excessive aqueous humor production, while the majority are caused by restricted aqueous outflows, such as constriction or even closure of the anterior chamber angle and trabecular sclerosis. Elevated IOP damages the visual nerve in two ways: mechanical compression and ischemia of the optic nerve. The greater the length of IOP increase, the more serious the visual function degradation (87). Current glaucoma therapy is still centered on reducing IOP. However, effectiveness is insufficient, and the condition might worsen even after the goal IOP is attained, which may be associated with progressive neuropathy.

By modifying the body’s metabolism, IF has been demonstrated to prevent aging and neurodegeneration (88, 89). Additionally, it can successfully reduce IOP and is critical in preventing the development of glaucoma. Although IF has been demonstrated to be advantageous in pathological neuropathy (90), there are minimal clinical data addressing retinal neurodegeneration, notably in glaucoma. Fasting for 48 h dramatically decreased acute IOP elevation-induced retinal ganglion cell loss, according to a recent study (86). The most plausible explanation for this phenomenon is that fasting regimens promote neuroprotection by inhibiting mTOR activity and activating cellular autophagy (91). Autophagy is the process of cytoplasmic breakdown and recycling via the autophagosomal-lysosomal pathway, which allows neurons to adapt to stressful environments and survive and is vital for neuronal homeostasis (91). Autophagic activity is inversely correlated with the activation state of the mammalian target of rapamycin (mTOR) and mTOR complex 1 (mTORC1) formation (92, 93). Activated mTOR inhibits the Unc51-like kinase 1 (ULK1) complex through phosphorylation, which inhibits autophagy (92, 93). In contrast, serine/threonine AMP-activated kinase (AMPK) is activated under low energy conditions and promotes autophagy by inhibiting mTORC1 and activating ULK1 (92, 94, 95). The study found a substantial drop in p-ULK1 in the fasting group of mice, indicating that IF can reduce the neurological damage caused by pathologically increased IOP in glaucoma by activating AMPK and thereby blocking mTOR signaling to promote autophagy.

At the same time, in EAAC1-deficient mice (a normal-tension glaucoma animal model), IF administered every other day for 7 weeks increased neurotrophic factor expression. It lowered oxidative stress levels, preventing retinal ganglion cell degeneration and improving visual impairment (91). Along with promoting neuronal cell survival, IF stimulates retinal glial cells and protects against damage induced by pro-inflammatory factor release. A calorie-restricted feeding regimen reduced ischemia-induced retinal damage and suppressed reactive gliosis in elderly rats (96).

The biochemical mechanisms underpinning the effects of IF on retinal nerve cells and glaucoma remain unknown. There are no conclusive clinical trials establishing a definite link between IF and glaucoma. Further research on the physiological effects of IF on the retina and genetic variables is critical for glaucoma and other ocular illness therapies.

Other visual illnesses, such as autoimmune uveitis, age-related macular degeneration (AMD), and refractive error, may also be affected by IF. However, whether IF may definitively alter the onset and course of certain ocular illnesses is unknown.

Animals with provoked autoimmune uveitis had altered intestinal flora structure (97). As uveitis disease progressed, the experimental group of mice developed an increasingly distinct intestinal flora from controls, as well as an increase in the number of Treg cells in the retina, a decrease in cytokine levels, and the number of effector T cells in peripheral lymphoid tissues, and a decrease in the severity of uveitis following oral antibiotics. Further research (98) confirmed lymphocyte movement between the gut and the eye in uveitis, emphasizing the critical role of the intestinal flora composition in ocular illness. The above phenomenon may be explained by the concept of the intestinal-ocular axis, whereby the eye as a target organ is regulated by inflammatory factors and metabolites produced by flora in the intestine, such as TNF-α, bile acids, and SCFAs. Janowitz et al. (99) discovered that experimental autoimmune uveitis (EAU) mice exhibited lower intestinal α diversity than unimmunized animals before the beginning of ocular inflammation at the most severe stage of uveitis. The intestinal flora of EAU mice comprised Prevotella, Lactobacillus, Anaerobes, Parabacteroides, Firmicutes, and Clostridium, and an increase in the ileum. Intestinal microecology is a new aspect of the metabolic regulatory role of IF, and several studies have shown the potential of IF to alter flora composition. Pinto et al. (100) recently published a systematic review on the role of IF in remodeling the gut microbiota in humans and rats/mice. In this study, the authors found that both alternate-day fasting and time-restricted fasting regimens altered the ratio of intestinal flora, mainly the Firmicutes/Bacteroidetes ratio and Lactobacillus spp abundance. All these findings indicate that intestinal flora plays a role in the development and progression of autoimmune uveitis and that IF may impact disease progression by altering the makeup of the intestinal flora.

Age-related macular degeneration (AMD) is the leading cause of blindness in adults over 50 in developed countries (101) and ranks highly among ocular illnesses. Admas et al. investigated the impact of high and low glycemic index meals on the progression of AMD (102). Aged rats fed a high glycemic index diet developed retinal lesions like those associated with AMD, including hyperpigmentation, atrophy, lipofuscin deposition in the retinal pigment epithelium, and photoreceptor degeneration, whereas mice fed a low glycemic index diet did not. The AMD phenotype was reduced and even reversed in mice fed a high glycemic index diet. A low glycemic diet developed through IF may have the same impact on AMD prevention and therapy.

Refractive errors (RE), which encompasses myopia, hyperopia, astigmatism, refractive error, and presbyopia, is one of the most prevalent ocular illnesses affecting individuals of all ages (103). External parallel light traveling through the eye’s refractive system (the cornea, atrium, lens, and vitreous fluid) at rest does not concentrate on the central depression to generate a clear image. Previous research on IF and refractive error is limited, and the results are inconsistent. Some studies show (38) that Ramadan has no discernible effect on human vision or refractive error. However, several studies (38) discovered a modest difference in the CCT of fasting participants before and after Ramadan. In comparison, Gonen et al. (47) discovered that when fasting, the eye’s axial length was slightly shorter, the corneal thickness was thinner at night, indicating diurnal fluctuation, and the anterior chamber depth decreased throughout the night. Blurred vision during hyperglycemia has been the consequence of temporary refractive alterations produced by lens modifications (104), although it might also be caused by retinal abnormalities. The degree of retinal thickness is connected with visual acuity (105, 106), and can also cause changes in the length of the eye axis, which can result in refractive errors (104). As a result, we may speculate about the role of IF in altering changes in certain ocular biological parameters or reducing refractive errors in diabetic and hyperglycemic conditions through blood glucose control.